Climate Change and Human Metabolonomic Evolution

Climate Change and Human Metabolonomic Evolution

Ravikumar Kurup Parameswara Achutha Kurup

ISBN: 978-1-941926-48-2

© 2016 Ravikumar Kurup. Licensee Open Science Publishers. © 2016 Parameswara Achutha Kurup. Licensee Open Science Publishers.

This work is distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Published in 2016 by Open Science Publishers 228 Park Ave., S#45956, New York, NY 10003, U.S.A. http://www.openscienceonline.com

Contents Preface .............................................................................................................. VII Chapter 1 Climate Change and Generation of Porphyrions ............................... 1 Chapter 2 Global Warming Induced Archaeaon - A New Cell Organelle - The Master Organelle of the Cell ................................... 5 Chapter 3 Global Warming Induced Porphyrions - Role of Porphyrins in Environmental Communication/Modulation of Digital Information Storage/Processing System - Low Level of Electromagnetic Fields and Human Disease - Porphyrions, the Internet and Mind ................................. 21 Chapter 4 Global Warming Induced Extinction of Homo Sapiens and Symbiotic Neanderthalisation - Relation to Archaeal Mediated RNA Viroids and Amyloidosis .................... 59 Chapter 5 Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Bile Acids from Cholesterol Regulates Cellular Function ............................................................ 69 Chapter 6 Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of PAH from Cholesterol Regulates Cell Function................................................................... 77 Chapter 7 Global Warming Induced Endosymbiontic Actinidic Archaeal Synthesis of Digoxin from Cholesterol Regulates Cellular Function and Contributes to Disease Pathology ................ 87 Chapter 8 Global Warming Induced Endosymbiotic Actinidic Archaeal Generation of Ammonia and Thiocyanate Regulates Cell/Neuro-Immuno-Endocrine System and Provides a Substrate for Archaeal Energetics................................................. 99

IV

Contents

Chapter 9 Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Pyruvate from Cholesterol and the GABA Shunt Pathway Regulates Cell Function ................................................................................. 111 Chapter 10 Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Short Chain Fatty Acid Butyrate and Propionate from Cholesterol Regulates Cellular Function ..................................... 125 Chapter 11 Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Neurotransmitters by Cholesterol Catabolism Regulates Brain Function ......................................... 135 Chapter 12 Global Warming Induced Membrane Sodium Potassium ATPase Inhibition Mediated ATP Synthesis Induced by Digoxin, Photoinduction and Electromagnetic Fields ................. 145 Chapter 13 Global Warming Induced Endosymbiotic Actinidic Archaeal Digoxin Inhibited Sodium Potassium ATPase Mediated ATP Synthesis and Archaeal Ectoatpases Produce Neuro-Immuno-Metabolic-Endrocrine/Cell Cycle Regulation ......................................................................... 157 Chapter 14 Global Warming Induced Endosymbiotic Actinidic Archaeal Mediated Warburg Phenotype Mediates Human Disease State ................................................................... 167 Chapter 15 Global Warming Induced Endosymbiotic Actinidic Archaeal Cholesterol Catabolic Syndrome - Hypocholesterolemia and Human Diseases.................................................................... 177 Chapter 16 Global Warming Induced Endosymbiotic Actinidic Archaea and Viroids - Role in Metabolic/Endocrine Regulation ................................................. 189

Contents

V

Chapter 17 Global Warming Induced Stem Cell Conversion Produces an Epidemic Benjamin Buttons Reverse Aging Syndrome ............................................................ 205 Chapter 18 Global Warming Induced Endosymbiotic Actinidic Archaea and Viroids - Role in Genomic Regulation ................... 221 Chapter 19 Global Warming Induced Neo-neanderthalisation and Metabolic Syndrome - Type 2 Diabetes Mellitus with Coronary Artery Disease and Stroke ................................... 233

Preface Climate change and related stress leads to increased porphyrin synthesis leading onto porphyrinuria and porphyria. The stimulus for porphyrin synthesis comes from heme deficiency. Heme suppresses ALA synthase. Stress induces heme oxygenase which converts heme to carbon monoxide and bilirubin. Thus heme is depleted from the system. Heme oxygenase is induced by environmental stress. Climatic changes of global warming and ice age can induce heme oxygenase. Heme oxygenase is also induced by EMF pollution of the environment. Thus there is increased porphyrin synthesis from succinyl CoA and glycine. Defect in heme synthesis and heme depletion leads to deficiency of heme enzymes. Deficiency cytochrome C oxidase and aconitase leads to mitochondrial oxidative phosphorylation defects and TCA cycle defects. This leads to pyruvate dehydrogenase deficiency and defect in synthesis of acetyl CoA. There is increase in glycolysis consequent to porphyrin photo-oxidation induced free radical generation and HIF alpha induction. This produces the Warburg phenotype. The increased level of pyruvate that is generated is converted to glutamate and ammonia. Thus there is hyperammonemia as a consequence of the metabolic defect. Since glycine is utilized for porphyrin synthesis serine is not synthesized leading onto deficiency of the substrate for synthesis of cystathionine. This leads to accumulation of homocysteine and homocystinuria. Deficiency of acetyl CoA leads to defects in the isoprenoid pathway and defective synthesis of cholesterol and ubiquinone. There is also deficiency of the heme containing cholesterol synthesizing enzyme lanosterol synthase. This leads to a cholesterol depleted state. The increase in porphyrins leads to cortical dysfunction and prefrontal cortex atrophy. The porphyrins can destroy the human endogenous retroviruses and the jumping genes leading to lack of dynamicity of the genome. This leads onto maldevelopment of the prefrontal cortex. This leads onto cerebellar dominance and a cerebellar cognitive affective disorder. This produces porphyrin related

VIII

Preface

quantal perception. Porphyrins are dipolar molecules and in the setting of porphyrin mediated membrane sodium potassium ATPase inhibition induced pumped phonon system can produce a quantal perceptive state. Porphyrins are macromolecules which can have both a wave and particle existence and can bridge the particulate world and the quantal world. Membrane sodium potassium ATPase inhibition induced dipolar porphyrin mediated pumped phonon system can lead onto a cellular plasma state and EMF signal transduction. Macromolecules like RNA, DNA, protein and the cell itself can have an EMF signature. This porphyrin generated macromolecular cellular EMF signature is important in regulation of cell function. The porphyrins can have quantal perception of low level EMF fields leading to prefrontal cortex atrophy. This leads onto cortical dysfunction and lack of functioning of the conscious brain. The cerebellum dominates and the unconscious takes over. This leads onto Neanderthalisation of the brain and schizophrenia and autism. The heme deficiency leads to lack of synthesis of the heme enzyme cytochrome P420 dependent sex hormones and a widespread asexual state. The mitochondrial dysfunction leads onto insulin resistance and metabolic syndrome x. The Warburg phenotype and increased glycolysis leads to oncogenesis. The mitochondrial dysfunction can produce neurodegeneration. The increase in lymphocyte glycolysis can produce immune activation and autoimmune disease. Thus the stress induced porphyria due to climatic change and environmental pollution can lead to civilisational disease.

Chapter 1

Climate Change and Generation of Porphyrions

2


Climate change and related stress leads to increased porphyrin synthesis leading onto porphyrinuria and porphyria. The stimulus for porphyrin synthesis comes from heme deficiency. Heme suppresses ALA synthase. Stress induces heme oxygenase which converts heme to carbon monoxide and bilirubin. Thus heme is depleted from the system. Heme oxygenase is induced by environmental stress. Climatic changes of global warming and ice age can induce heme oxygenase. Heme oxygenase is also induced by EMF pollution of the environment. Thus there is increased porphyrin synthesis from succinyl CoA and glycine. Defect in heme synthesis and heme depletion leads to deficiency of heme enzymes. Deficiency cytochrome C oxidase and aconitase leads to mitochondrial oxidative phosphorylation defects and TCA cycle defects. This leads to pyruvate dehydrogenase deficiency and defect in synthesis of acetyl CoA. There is increase in glycolysis consequent to porphyrin photo-oxidation induced free radical generation and HIF alpha induction. This produces the Warburg phenotype. The increased level of pyruvate that is generated is converted to glutamate and ammonia. Thus there is hyperammonemia as a consequence of the metabolic defect. Since glycine is utilized for porphyrin synthesis serine is not synthesized leading onto deficiency of the substrate for synthesis of cystathionine. This leads to accumulation of homocysteine and homocystinuria. Deficiency of acetyl CoA leads to defects in the isoprenoid pathway and defective synthesis of cholesterol and ubiquinone. There is also deficiency of the heme containing cholesterol synthesizing enzyme lanosterol synthase. This leads to a cholesterol depleted state. The increase in porphyrins leads to cortical dysfunction and prefrontal cortex atrophy. The porphyrins can destroy the human endogenous retroviruses and the jumping genes leading to lack of dynamicity of the genome. This leads onto maldevelopment of the prefrontal cortex. This leads onto cerebellar dominance and a cerebellar cognitive affective disorder. This produces porphyrin related


3

quantal perception. Porphyrins are dipolar molecules and in the setting of porphyrin mediated membrane sodium potassium ATPase inhibition induced pumped phonon system can produce a quantal perceptive state. Porphyrins are macromolecules which can have both a wave and particle existence and can bridge the particulate world and the quantal world. Membrane sodium potassium ATPase inhibition induced dipolar porphyrin mediated pumped phonon system can lead onto a cellular plasma state and EMF signal transduction. Macromolecules like RNA, DNA, protein and the cell itself can have an EMF signature. This porphyrin generated macromolecular cellular EMF signature is important in regulation of cell function. The porphyrins can have quantal perception of low level EMF fields leading to prefrontal cortex atrophy. This leads onto cortical dysfunction and lack of functioning of the conscious brain. The cerebellum dominates and the unconscious takes over. This leads onto Neanderthalisation of the brain and schizophrenia and autism. The heme deficiency leads to lack of synthesis of the heme enzyme cytochrome P420 dependent sex hormones and a widespread asexual state. The mitochondrial dysfunction leads onto insulin resistance and metabolic syndrome x. The Warburg phenotype and increased glycolysis leads to oncogenesis. The mitochondrial dysfunction can produce neurodegeneration. The increase in lymphocyte glycolysis can produce immune activation and autoimmune disease. Thus the stress induced porphyria due to climatic change and environmental pollution can lead to civilisational disease. The porphyrins can self organize to form macromolecular structures which can self replicate to form a porphyrin organism.1 The photon induced transfer of electrons along the macromolecule can lead to light induced ATP synthesis. The porphyrins can form a template on which RNA and DNA can form generating viroids. The porphyrins can also form a template on which prions can form. They all can join together - RNA viroids, DNA viroids, prions - to form

4


primitive archaea. Thus the archaea are capable of self replication on porphyrin templates. The self replicating archaea can sense gravity which gives rise to consciousness. They can also sense the anti-gravity fields which gives rise to the unconscious brain. Thus there can be both self replicating archaea and anti-archaea regulating the conscious and unconscious brain. Thus the climate change stress mediated increased porphyrin synthesis leads to prefrontal cortex atrophy, cerebellar dominance, cerebellar cognitive affective disorder, quantal perception and Neanderthalisation of the population. The porphyrions are self replicating supramolecular organisms which forms the precursor template on which the viroids, prions and nanoarchaea originate. Stress induced template directed abiogenesis of porphyrions, prions, viroids and archaea is a continuous process and can contribute to changes in brain structure and behavior as well as disease process.

References [1] Anderson, S., Anderson, H. L., Bashall, A., McPartlin, M., Sanders, J. K. M. (1995). "Assembly and Crystal Structure of a Photoactive Array of Five Porphyrins". Angewandte Chemie International Edition in English, 34(10): 1096.

Chapter 2

Global Warming Induced Archaeaon - A New Cell Organelle - The Master Organelle of the Cell

6


Introduction Climate change and related stress leads to increased porphyrin synthesis leading onto porphyrinuria and porphyria. The stimulus for porphyrin synthesis comes from heme deficiency. Heme suppresses ALA synthase. Stress induces heme oxygenase which converts heme to carbon monoxide and bilirubin. Thus heme is depleted from the system. Heme oxygenase is induced by environmental stress. Climatic changes of global warming and ice age can induce heme oxygenase. Heme oxygenase is also induced by EMF pollution of the environment. Thus there is increased porphyrin synthesis from succinyl CoA and glycine. The porphyrins can self organize to form macromolecular structures which can self replicate to form a porphyrin organism. 1 The photon induced transfer of electrons along the macromolecule can lead to light induced ATP synthesis. The porphyrins can form a template on which RNA and DNA can form generating viroids. The porphyrins can also form a template on which prions can form. They all can join together - RNA viroids, DNA viroids, prions - to form primitive archaea. Thus the archaea are capable of self replication on porphyrin templates. The self replicating archaea can sense gravity which gives rise to consciousness. They can also sense the anti-gravity fields which gives rise to the unconscious brain. Thus there can be both self replicating archaea and anti-archaea regulating the conscious and unconscious brain. Thus the climate change stress mediated increased porphyrin synthesis leads to prefrontal cortex atrophy, cerebellar dominance, cerebellar cognitive affective disorder, quantal perception and Neanderthalisation of the population. The porphyrions are self replicating supramolecular organisms which forms the precursor template on which the viroids, prions and nanoarchaea originate. Stress induced template directed abiogenesis of porphyrions, prions, viroids and archaea is a


7

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis (EMF) along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile, endogenous digoxin as well as organisms like phytoplasmas and viroids have been implicated in the etiology of these diseases.1-4 Endogenous digoxin has been related to the pathogenesis of Schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.4 The possibility of endogenous digoxin synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered.5-8 An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described.7, 9 Metal actinides in beach sands have been postulated to play a role in abiogenesis.7 A hypothesis of cholesterol as the primal prebiotic molecule synthesised on actinide surfaces with all other biomolecules arising from it and a self replicating cholesterol lipid organism as the initial life form is presented. The archaea exists as an endosymbiont in the human cell and can be considered as a cellular organelle. All cell organelle are basically endosymbionts according to the endosymbiotic theory of cell origin put forward by Lynn Margulis. The endosymbiotic archaea concerned cell regulation as well as neuro-immuno-endocrine-genetic-metabolic regulation is an organelle. The endosymbiotic archaeal organelle can be termed the archaeaon.

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob disease and acquired

8


immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10 Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: - Cytochrome F420, free RNA, free DNA, polycyclic aromatic hydrocarbon, hydrogen peroxide, dopamine, serotonin, pyruvate, ammonia, glutamate, cytochrome C, hexokinase, ATP synthase, HMG CoA reductase, digoxin and bile acids.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Polycyclic aromatic hydrocarbon was estimated by measuring hydrogen peroxide liberated by using glucose reagent. Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while


9

addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in tables 1-7 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time. Table 1 Effect of rutile and antibiotics on cytochrome F420 and PAH.

Group

CYT F420 %

CYT F420 %

PAH % change

PAH % change

(Increase with Rutile)

(Decrease with Doxy+Cipro)


(Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

4.45

0.14

18.25

0.72

Schizo

23.24

2.01

58.72

7.08

23.01

1.69

59.49

4.3

Seizure

23.46

1.87

59.27

8.86

22.67

2.29

57.69

5.29

AD

23.12

2

56.9

6.94

23.26

1.53

60.91

7.59

MS

22.12

1.81

61.33

9.82

22.83

1.78

59.84

7.62

NHL

22.79

2.13

55.9

7.29

22.84

1.42

66.07

3.78

DM

22.59

1.86

57.05

8.45

23.4

1.55

65.77

5.27

AIDS

22.29

1.66

59.02

7.5

23.23

1.97

65.89

5.05

CJD

22.06

1.61

57.81

6.04

23.46

1.91

61.56

4.61

Autism

21.68

1.9

57.93

9.64

22.61

1.42

64.48

6.9

EMF

22.7

1.87

60.46

8.06

23.73

1.38

65.2

6.2

F value

306.749

130.054

391.318

257.996

P value

< 0.001

< 0.001

< 0.001

< 0.001

10


Table 2 Effect of rutile and antibiotics on free RNA and DNA.

Group

DNA % change (Increase with Rutile) Mean ±SD

DNA % change (Decrease with Doxy+Cipro) Mean ±SD

RNA % change (Increase with Rutile) Mean ±SD

RNA % change (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.37

0.15

18.39

0.38

4.37

0.13

18.38

0.48

Schizo

23.28

1.70

61.41

3.36

23.59

1.83

65.69

3.94

Seizure

23.40

1.51

63.68

4.66

23.08

1.87

65.09

3.48

AD

23.52

1.65

64.15

4.60

23.29

1.92

65.39

3.95

MS

22.62

1.38

63.82

5.53

23.29

1.98

67.46

3.96

NHL

22.42

1.99

61.14

3.47

23.78

1.20

66.90

4.10

DM

23.01

1.67

65.35

3.56

23.33

1.86

66.46

3.65

AIDS

22.56

2.46

62.70

4.53

23.32

1.74

65.67

4.16

CJD

23.30

1.42

65.07

4.95

23.11

1.52

66.68

3.97

Autism

22.12

2.44

63.69

5.14

23.33

1.35

66.83

3.27

EMF

22.29

2.05

58.70

7.34

22.29

2.05

67.03

5.97

F value

337.577

356.621

427.828

654.453

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 3 Effect of rutile and antibiotics on HMG CoA reductase and ATP synthase.

Group

HMG CoA R % change (Increase with Rutile) Mean ±SD

HMG CoA R % change(Decrease with Doxy+Cipro) Mean ±SD

ATP synthase % (Increase with Rutile) Mean ±SD

ATP synthase % (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.30

0.20

18.35

0.35

4.40

0.11

18.78

0.11

Schizo

22.91

1.92

61.63

6.79

23.67

1.42

67.39

3.13

Seizure

23.09

1.69

61.62

8.69

23.09

1.90

66.15

4.09

AD

23.43

1.68

61.68

8.32

23.58

2.08

66.21

3.69

MS

23.14

1.85

59.76

4.82

23.52

1.76

67.05

3.00

NHL

22.28

1.76

61.88

6.21

24.01

1.17

66.66

3.84

DM

23.06

1.65

62.25

6.24

23.72

1.73

66.25

3.69

AIDS

22.86

2.58

66.53

5.59

23.15

1.62

66.48

4.17

CJD

22.38

2.38

60.65

5.27

23.00

1.64

66.67

4.21

Autism

22.72

1.89

64.51

5.73

22.60

1.64

66.86

4.21

EMF

22.92

1.48

61.91

7.56

23.37

1.31

63.97

3.62

F value

319.332

199.553

449.503

673.081

P value

< 0.001

< 0.001

< 0.001

< 0.001


11

Table 4 Effect of rutile and antibiotics on digoxin and bile acids.

Group Normal Schizo Seizure AD MS NHL DM AIDS CJD Autism EMF F value P value

Digoxin (ng/ml) (Increase with Rutile) Mean ±SD 0.11 0.00 0.55 0.06 0.51 0.05 0.55 0.03 0.52 0.03 0.54 0.04 0.47 0.04 0.56 0.05 0.53 0.06 0.53 0.08 0.51 0.05 135.116 < 0.001

Digoxin (ng/ml) (Decrease with Doxy+Cipro) Mean ±SD 0.054 0.003 0.219 0.043 0.199 0.027 0.192 0.040 0.214 0.032 0.210 0.042 0.202 0.025 0.220 0.052 0.212 0.045 0.205 0.041 0.213 0.033 71.706 < 0.001

Bile Acids % change (Increase with Rutile) Mean ±SD 4.29 0.18 23.20 1.87 22.61 2.22 22.12 2.19 21.95 2.11 22.98 2.19 22.87 2.58 22.29 1.47 23.30 1.88 22.21 2.04 23.41 1.41 290.441 < 0.001

Bile Acids % change (Decrease with Doxy+Cipro) Mean ±SD 18.15 0.58 57.04 4.27 66.62 4.99 62.86 6.28 65.46 5.79 64.96 5.64 64.51 5.93 64.35 5.58 62.49 7.26 63.84 6.16 58.70 7.34 203.651 < 0.001

Table 5 Effect of rutile and antibiotics on pyruvate and hexokinase.

Group

Pyruvate % change (Increase with Rutile) Mean ±SD

Pyruvate % change (Decrease with Doxy+Cipro) Mean ±SD

Hexokinase % change (Increase with Rutile) Mean ±SD

Hexokinase % change (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.34

0.21

18.43

0.82

4.21

0.16

18.56

0.76

Schizo

20.99

1.46

61.23

9.73

23.01

2.61

65.87

5.27

Seizure

20.94

1.54

62.76

8.52

23.33

1.79

62.50

5.56

AD

22.63

0.88

56.40

8.59

22.96

2.12

65.11

5.91

MS

21.59

1.23

60.28

9.22

22.81

1.91

63.47

5.81

NHL

21.19

1.61

58.57

7.47

22.53

2.41

64.29

5.44

DM

20.67

1.38

58.75

8.12

23.23

1.88

65.11

5.14

AIDS

21.21

2.36

58.73

8.10

21.11

2.25

64.20

5.38

CJD

21.07

1.79

63.90

7.13

22.47

2.17

65.97

4.62

Autism

21.91

1.71

58.45

6.66

22.88

1.87

65.45

5.08

EMF

22.29

2.05

62.37

5.05

21.66

1.94

67.03

5.97

F value

321.255

115.242

292.065

317.966

P value

< 0.001

< 0.001

< 0.001

< 0.001

12


Table 6 Effect of rutile and antibiotics on hydrogen peroxide and delta amino levulinic acid.

Group

H2O2 % (Increase with Rutile) Mean ±SD

H2O2 % (Decrease with Doxy+Cipro) Mean ±SD

ALA % (Increase with Rutile) Mean ±SD

ALA % (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

Schizo

22.50

1.66

60.21

7.42

22.52

1.90

66.39

4.20

Seizure

23.81

1.19

61.08

7.38

22.83

1.90

67.23

3.45

AD

22.65

2.48

60.19

6.98

23.67

1.68

66.50

3.58

MS

21.14

1.20

60.53

4.70

22.38

1.79

67.10

3.82

NHL

23.35

1.76

59.17

3.33

23.34

1.75

66.80

3.43

DM

23.27

1.53

58.91

6.09

22.87

1.84

66.31

3.68

AIDS

23.32

1.71

63.15

7.62

23.45

1.79

66.32

3.63

CJD

22.86

1.91

63.66

6.88

23.17

1.88

68.53

2.65

Autism

23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

EMF

23.29

1.67

60.52

5.38

22.29

2.05

61.91

7.56

F value

380.721

171.228

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 7 Effect of rutile and antibiotics on dopamine and serotonin.

Group

DOPAMINE % (Increase with Rutile) Mean ±SD

DOPAMINE % (Decrease with Doxy+Cipro) Mean ±SD

5 HT % change (Increase with Rutile) Mean ±SD

5 HT % change (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.41

0.15

18.63

0.12

4.34

0.15

18.24

0.37

Schizo

21.88

1.19

66.28

3.60

23.02

1.65

67.61

2.77

Seizure

22.29

1.33

65.38

3.62

22.13

2.14

66.26

3.93

AD

23.66

1.67

65.97

3.36

23.09

1.81

65.86

4.27

MS

22.92

2.14

67.54

3.65

21.93

2.29

63.70

5.63

NHL

23.81

1.90

66.95

3.67

23.12

1.71

65.12

5.58

DM

24.10

1.61

65.78

4.43

22.73

2.46

65.87

4.35

AIDS

23.43

1.57

66.30

3.57

22.98

1.50

65.13

4.87

CJD

23.70

1.75

68.06

3.52

23.81

1.49

64.89

6.01

Autism

22.76

2.20

67.63

3.52

22.79

2.20

64.26

6.02

EMF

22.28

1.52

64.05

2.79

22.82

1.56

64.61

4.95

F value

403.394

680.284

348.867

364.999

P value

< 0.001

< 0.001

< 0.001

< 0.001


13

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea exists as endosymbionts in the human cell and can be considered as a cell organelle. The other cell organelle also has a microbial origin. The mitochondria are of rickettsial origin. The nucleus is derived phylogenetically from the pox virus. The peroxisome is of acinetobacter origin. The symbiotic theory of cell origin was put forward by Lynn Margulis. The archaea can synthesize and use cholesterol as a carbon and energy source.6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15 There was also an increase in archaeal HMG CoA reductase activity indicating increased cholesterol synthesis by the archaeal

mevalonate

pathway.

The

archaeal

beta

hydroxyl

steroid

dehydrogenase activity indicating digoxin synthesis and archaeal cholesterol hydroxylase activity indicating bile acid synthesis were increased.8 The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide.14 The pyruvate gets converted to glutamate and ammonia by the GABA shunt pathway. The archaeal aromatization of cholesterol generating PAH, serotonin and dopamine was also detected.16 The archaeal glycolytic hexokinase activity and archaeal extracellular ATP synthase activity were increased. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.17 There was an increase in free RNA indicating self replicating RNA viroids and free DNA indicating generation of viroid complementary DNA strands by archaeal reverse transcriptase activity. The actinides modulate RNA folding and catalyse its ribozymal action. Digoxin can cut and paste the viroidal strands by modulating

14


RNA splicing generating RNA viroidal diversity. The viroids are evolutionarily escaped archaeal group I introns which have retrotransposition and self splicing qualities.18 Archaeal pyruvate can produce histone deacetylase inhibition resulting in endogenous retroviral (HERV) reverse transcriptase and integrase expression. This can integrate the RNA viroidal complementary DNA into the noncoding region of eukaryotic non coding DNA using HERV integrase as has been described for borna and ebola viruses.19 The noncoding DNA is lengthened by integrating RNA viroidal complementary DNA with the integration going on as a continuing event. The archaea genome can also get integrated into human genome using integrase as has been described for trypanosomes.20 The integrated viroids and archaea can undergo vertical transmission and can exist as genomic parasites.19, 20 This increases the length and alters the grammar of the noncoding region producing memes or memory of acquired characters as well as eukaryotic speciation and individuality.21 The viroidal complementary DNA can function as jumping genes producing a dynamic genome important in storage of synaptic information, HLA gene expression and developmental gene expression. The RNA viroids can regulate mRNA function by RNA interference.18 The phenomena of RNA interference can modulate T cell and B cell function, insulin signalling lipid metabolism, cell growth

and

differentiation,

apoptosis,

neuronal

transmission

and

euchromatin/heterochromatin expression. The archaea and viroids can regulate the nervous system including the NMDA/GABA perception.

4, 22

thalamo-cortico-thalamic

pathway

mediating

conscious

NMDA/GABA receptors can be modulated by digoxin induced

calcium oscillations resulting NMDA/GAD activity induction, PAH increasing NMDA activity and inducing GAD as well as viroid induced RNA interference.4 The cholesterol ring oxidase generated pyruvate can be converted by the GABA shunt pathway to glutamate and GABA. The dipolar PAH and


15

archaeal magnetite in the setting of digoxin induced sodium potassium ATPase inhibition can produce a pumped phonon system mediated Frohlich model superconducting state

22

inducing quantal perception with nanoarchaeal sensed

gravity producing the orchestrated reduction of the quantal possibilities to the macroscopic world.4, 22 The archaea can regulate limbic lobe transmission with archaeal

cholesterol

aromatase/ring

dopamine, serotonin and acetyl choline.

oxidase 16

generated

norepinephrine,

The higher degree of integration of

the archaea into the genome produces increased digoxin synthesis producing right hemispheric dominance and lesser degree producing left hemispheric dominance.4 The increased integration of archaea into the neuronal genome can produce increased cholesterol oxidase and aromatase mediated monoamine and NMDA transmission producing Schizophrenia and Autism. Archaea and RNA viroid can bind the TLR receptor induce NFKB producing immune activation and cytokine TNF alpha secretion. The archaeal DXP and mevalonate pathway metabolites can bind  TCR and digoxin induced calcium signalling can activate NFKB producing chronic immune activation.4,

23

The archaea and

viroid induced chronic immune activation and generation of superantigens can lead on to autoimmune disease. Archaea, viroids and digoxin can induce the host AKT PI3K, AMPK, HIF alpha and NFKB producing the Warburg metabolic phenotype.24 The increased glycolytic hexokinase activity, decrease in blood ATP, leakage of cytochrome C, increase in serum pyruvate and decrease in acetyl CoA indicates the generation of the Warburg phenotype. There is induction of glycolysis, inhibition of PDH activity and mitochondrial dysfunction resulting in inefficient energetics and metabolic syndrome. The archaea and viroid generated cytokines can lead to TNF alpha induced insulin resistance and metabolic syndrome x. The accumulated pyruvate enters the GABA shunt pathway and is converted to citrate which is acted upon by citrate lyase and converted to acetyl CoA, used for cholesterol synthesis.24 The

16


pyruvate can be converted to glutamate and ammonia which is oxidised by archaea for energy needs. The increased cholesterol substrate leads to increased archaeal growth and digoxin synthesis leading to metabolic channelling to the mevalonate pathway. The archaeal bile acids are steroidal hormones which can bind GPCR and modulate D2 regulating the conversion of T4 to T3 which activates uncoupling proteins, can activate NRF ½ inducing NQO1, GST, HOI reducing redox stress, can bind FXR regulating insulin receptor sensitivity and bind PXR inducing the bile acid shunt pathway of cholesterol detoxification. 25 The archaea and viroid induced monocyte activation and Warburg phenotype induced increased cholesterol synthesis leads to atherogenesis. The Warburg phenotype induced increased mitochondrial PT pore hexokinase, archaeal PAH and viroid induced RNA interference can lead on to malignant transformation. The digoxin and PAH induced increased intracellular calcium can lead to PT pore dysfunction, cell death and neuronal degeneration.4 The archaeal cholesterol catabolism can deplete the cell membranes of cholesterol resulting in organelle dysfunction and degeneration. The RNA viroids can recombine with HERV sequences and get encapsulated in microvesicles contributing to the retroviral state. The prion protein conformation is modulated by RNA viroid binding producing Prion Disease. The archaeal digoxin and rutile induced magnesium depletion can lead MPS deposition and produce EMF, CCP, MNG and mucoid angiopathy.4 The metal actinides provide radiolytic energy, catalysis for oligomer formation and provide a coordinating ion for metalloenzymes all important in abiogenesis.7 The metal actinide surfaces would by surface metabolism generate acetate which could get converted to acetyl CoA and then to cholesterol which functions as the primal prebiotic molecule self organizing into self replicating supramolecular systems, the lipid organism.9, 26, 27 Cholesterol by radiolysis by actinides would have formed PAH generating PAH aromatic organism.9 Cholesterol radiolysis


17

would generate pyruvate which would get converted to amino acids, sugars, nucleotides, porphyrins, fatty acids and TCA acids. Anastase and rutile surfaces can produce polymerization of amino acids, isoprenyl residues, PAH and nucleotides to generate the initial lipid organism, PAH organism, prions and RNA viroids which would have symbiosed to generate the archaeal protocell. The archaea evolved into gram negative and gram positive bacteria with a mevalonate pathway which had a evolutionary advantage and the symbiosis of archaea with gram negative organism generated the eukaryotic cell.28 The data supports the persistence of an actinide and cholesterol based shadow biosphere which throws light on the actinide based origin of life and cholesterol as the premier prebiotic molecule. The archaea exists as an endosymbiont in the human cell and can be considered as a cellular organelle. All cell organelle are basically endosymbionts according to the endosymbiotic theory of cell origin put forward by Lynn Margulis. The endosymbiotic archaea concerned cell regulation as well as neuro-immuno-endocrine-genetic-metabolic regulation is an organelle. The endosymbiotic archaeal organelle can be termed the archaeaon.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers.

18


[5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N.O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870.


19

[17] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [18] Tsagris E. M., de Alba, A.E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [19] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87. [20] Hecht M., Nitz, N., Araujo, P., Sousa, A., Rosa, A., Gomes, D. (2010). Genes from Chagas parasite can transfer to humans and be passed on to children. Inheritance of DNA Transferred from American Trypanosomes to Human Hosts, PLoS ONE, 5, 2-10. [21] Flam F. (1994). Hints of a language in junk DNA, Science, 266, 1320. [22] Lockwood, M. (1989). Mind, Brain and the Quantum. Oxford: B. Blackwell. [23] Eberl M., Hintz, M., Reichenberg, A., Kollas, A., Wiesner, J., Jomaa, H. (2010). Microbial isoprenoid biosynthesis and human γδ T cell activation, FEBS Letters, 544(1), 4-10. [24] Wallace D.C. (2005). Mitochondria and Cancer: Warburg Addressed, Cold Spring Harbor Symposia on Quantitative Biology, 70, 363-374. [25] Lefebvre P., Cariou, B., Lien, F., Kuipers, F., Staels, B. (2009). Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation, Physiol Rev, 89(1), 147-91. [26] Wächtershäuser, G. (1988). Before enzymes and templates: theory of surface metabolism. Microbiol Rev, 52(4), 452-84. [27] Russell, M. J., Martin W. (2004). The rocky roots of the acetyl-CoA Pathway. Trends in Biochemical Sciences, 29(7). [28] Margulis, L. (1996). Archaeal-eubacterial mergers in the origin of Eukarya: phylogenetic classification of life. Proc Natl Acad Sci USA, 93, 1071-1076.

Chapter 3 Global Warming Induced Porphyrions - Role of Porphyrins in Environmental Communication/Modulation of Digital Information Storage/Processing System - Low Level of Electromagnetic Fields and Human Disease - Porphyrions, the Internet and Mind

22




23

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Actinidic archaea has also been described as endosymbionts in humans. Actinidic archaea have a mevalonate pathway and are cholesterol catabolizing. They can use cholesterol as a carbon and energy source. Archaeal cholesterol catabolism can generate porphyrins via the cholesterol ring oxidase generated pyruvate and GABA shunt pathway. Archaea can produce a secondary porphyria by inducing the enzyme heme oxygenase resulting in heme depletion and activation of the enzyme ALA synthase. This can lead to porphyrinogenesis. Low level of electromagnetic fields and geomagnetic fields can induce porphyrin synthesis by inhibiting the enzyme ferrochelatase which has got a ferromagnetic core. Inhibition of ferrochelatase produces deficiency of heme resulting in induction of ALA synthase. Low level of EMF can also induce heme oxygenase depleting heme and inducing ALA synthase. Porphyrins can undergo autooxidation generating biophotons and a quantal state. Porphyrin auto-oxidation is modulated by low level of electromagnetic fields and geomagnetic fields. Porphyrin microarrays can function as quantal computers storing information and can serve the purpose of extrasensory perception. Porphyrins can serve as a two way communicating bridge between digital information storage systems generating low level electromagnetic fields and human systems. The low level of EMF produced by digital system enhances porphyrin synthesis and serves the purpose of two way extrasensory perception and communication. The porphyrin quantal computers can in turn by biophoton emission modulate digital information storage system. Actinidic archaea have been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration. An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described. Porphyrins have been related to schizophrenia,

24


metabolic syndrome x, malignancy, systemic lupus erythematosis, multiple sclerosis and Alzheimer’s diseases. Porphyrins can mediate the pathogenesis of low level electromagnetic fields inducing the above mentioned disease states. A hypothesis regarding the role of porphyrins and quantal perception as well as the role of porphyrins in environmental communication/modulation of digital information storage/processing system is presented. They can function as self replicating supramolecular organisms which can be called as porphyrions. The porphyrions are self replicating supramolecular organisms which forms the precursor template on which the viroids, prions and nanoarchaea originate. Stress induced template directed abiogenesis of porphyrions, prions, viroids and archaea is a continuous process and can contribute to changes in brain structure and behavior as well as disease process. The relationship between low level of electromagnetic fields and human disease is highlighted.1-5 There is increased porphyrin synthesis leading onto porphyrinuria and porphyria. The stimulus for porphyrin synthesis comes from heme deficiency. Heme suppresses ALA synthase. Stress induces heme oxygenase which converts heme to carbon monoxide and bilirubin. Thus heme is depleted from the system. Heme oxygenase is induced by environmental stress. Climatic changes of global warming and ice age can induce heme oxygenase. Heme oxygenase is also induced by EMF pollution of the environment. Thus there is increased porphyrin synthesis from succinyl CoA and glycine. Defect in heme synthesis and heme depletion leads to deficiency of heme enzymes. Deficiency cytochrome C oxidase and aconitase leads to mitochondrial oxidative phosphorylation defects and TCA cycle defects. This leads to pyruvate dehydrogenase deficiency and defect in synthesis of acetyl CoA. There is increase in glycolysis consequent to porphyrin photo-oxidation induced free radical generation and HIF alpha induction. This produces the Warburg phenotype. The increased level of pyruvate that is generated is converted to


25

glutamate and ammonia. Thus there is hyperammonemia as a consequence of the metabolic defect. Since glycine is utilized for porphyrin synthesis serine is not synthesized leading onto deficiency of the substrate for synthesis of cystathionine. This leads to accumulation of homocysteine and homocystinuria. Deficiency of acetyl CoA leads to defects in the isoprenoid pathway and defective synthesis of cholesterol and ubiquinone. There is also deficiency of the heme containing cholesterol synthesizing enzyme lanosterol synthase. This leads to a cholesterol depleted state. The increase in porphyrins leads to cortical dysfunction and prefrontal cortex atrophy. The porphyrins can destroy the human endogenous retroviruses and the jumping genes leading to lack of dynamicity of the genome. This leads onto maldevelopment of the prefrontal cortex. This leads onto cerebellar dominance and a cerebellar cognitive affective disorder. This produces porphyrin related quantal perception. Porphyrins are dipolar molecules and in the setting of porphyrin mediated membrane sodium potassium ATPase inhibition induced pumped phonon system can produce a quantal perceptive state. Porphyrins are macromolecules which can have both a wave and particle existence and can bridge the particulate world and the quantal world. Membrane sodium potassium ATPase inhibition induced dipolar porphyrin mediated pumped phonon system can lead onto a cellular plasma state and EM F signal transduction. Macromolecules like RNA, DNA, protein and the cell itself can have an EMF signature. This porphyrin generated macromolecular cellular EMF signature is important in regulation of cell function. The porphyrins can have quantal perception of low level EMF fields leading to prefrontal cortex atrophy. This leads onto cortical dysfunction and lack of functioning of the conscious brain. The cerebellum dominates and the unconscious takes over. This leads onto Neanderthalisation of the brain and schizophrenia and autism. The heme deficiency leads to lack of synthesis of the heme enzyme cytochrome P420

26


dependent sex hormones and a widespread asexual state. The mitochondrial dysfunction leads onto insulin resistance and metabolic syndrome X. The Warburg phenotype and increased glycolysis leads to oncogenesis. The mitochondrial dysfunction can produce neurodegeneration. The increase in lymphocyte glycolysis can produce immune activation and autoimmune disease. Thus the stress induced porphyria due to climatic change and environmental pollution can lead to civilisational disease. The porphyrins can self organize to form macromolecular structures which can self replicate to form a porphyrin organism. The photon induced transfer of electrons along the macromolecule can lead to light induced ATP synthesis. The porphyrins can form a template on which RNA and DNA can form generating viroids. The porphyrins can also form a template on which prions can form. They all can join together - RNA viroids, DNA viroids, prions - to form primitive archaea. Thus the archaea are capable of self replication on porphyrin templates. The self replicating archaea can sense gravity which gives rise to consciousness. They can also sense the anti-gravity fields which gives rise to the unconscious brain. Thus there can be both self replicating archaea and anti-archaea regulating the conscious and unconscious brain. Thus the climate change stress mediated increased porphyrin synthesis leads to prefrontal cortex atrophy, cerebellar dominance, cerebellar cognitive affective disorder, quantal perception and Neanderthalisation of the population. The porphyrions are self replicating supramolecular organisms which forms the precursor template on which the viroids, prions and nanoarchaea originate. Stress induced template directed abiogenesis of porphyrions, prions, viroids and archaea is a continuous process and can contribute to changes in brain structure and behavior as well as disease process.


27

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. There were also 10 normal people with right hemispheric dominance, left hemispheric dominance and bi-hemispheric dominance included in the study selected from the normal population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond. Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: - Cytochrome F420, free RNA, free DNA, polycyclic aromatic hydrocarbon, hydrogen peroxide, pyruvate, ammonia, glutamate, delta aminolevulinic acid, succinate, glycine and digoxin. Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Polycyclic aromatic hydrocarbon was estimated by measuring hydrogen peroxide liberated by using glucose reagent. The study also involved estimating the following parameters in the patient population - digoxin, bile acid, hexokinase, porphyrins, pyruvate, glutamate, ammonia, acetyl CoA, acetyl choline, HMG CoA reductase, cytochrome C, blood ATP, ATP synthase, ERV RNA (endogenous retroviral

28


RNA), H2O2 (hydrogen peroxide), NOX (NADPH oxidase), TNF alpha and heme oxygenase.6-9 Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients and those with exposure to low level of EMF showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma and those with exposure to low level of EMF caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in tables section 1: 1-6 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time. There was upregulated archaeal porphyrin synthesis in the patient population and those with exposure to low level of EMF which was archaeal in origin as indicated by actinide catalysis of the reactions. The cholesterol oxidase pathway generated pyruvate which entered the GABA shunt pathway. This resulted in synthesis of succinate and glycine which are substrates for ALA synthase. The study showed the patient’s blood, those with exposure to low level of EMF and right hemispheric dominance had increased heme oxygenase activity and porphyrins. The hexokinase activity was high. The pyruvate, glutamate and ammonia levels were elevated indicating blockade of PDH activity, and


29

operation of the GABA shunt pathway. The acetyl CoA levels were low and acetyl choline was decreased. The cyto C levels were increased in the serum indicating mitochondrial dysfunction suggested by low blood ATP levels. This was indicative of the Warburg’s phenotype. There was increased NOX and TNF alpha level indicating immune activation. The HMG CoA reductase activity was high indicating cholesterol synthesis. The bile acid levels were low indicating depletion of cytochrome P450. The normal population with right hemispheric dominance had values resembling the patient population with increased porphyrin synthesis. The normal population with left hemispheric dominance had low values with decreased porphyrin synthesis.

Section 1: Experimental Study Table 1 Effect of rutile and antibiotics on cytochrome F420 and PAH.

Group

CYT F420 % (Increase with Rutile)

CYT F420 % (Decrease with Doxy+Cipro)

PAH % change (Increase with Rutile)

PAH % change (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

4.45

0.14

18.25

0.72

Schizo

23.24

2.01

58.72

7.08

23.01

1.69

59.49

4.30

Seizure

23.46

1.87

59.27

8.86

22.67

2.29

57.69

5.29

AD

23.12

2.00

56.90

6.94

23.26

1.53

60.91

7.59

MS

22.12

1.81

61.33

9.82

22.83

1.78

59.84

7.62

NHL

22.79

2.13

55.90

7.29

22.84

1.42

66.07

3.78

DM

22.59

1.86

57.05

8.45

23.40

1.55

65.77

5.27

AIDS

22.29

1.66

59.02

7.50

23.23

1.97

65.89

5.05

CJD

22.06

1.61

57.81

6.04

23.46

1.91

61.56

4.61

Autism

21.68

1.90

57.93

9.64

22.61

1.42

64.48

6.90

Low level EMF

22.70

1.87

60.46

8.06

23.73

1.38

65.20

6.20

F value

306.749

130.054

391.318

257.996

P value

< 0.001

< 0.001

< 0.001

< 0.001

30


Table 2 Effect of rutile and antibiotics on free RNA and DNA.

Group

DNA % change (Increase with Rutile) Mean ±SD

DNA % change (Decrease with Doxy+Cipro) Mean ±SD

RNA % change (Increase with Rutile) Mean ±SD

RNA % change (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.37

0.15

18.39

0.38

4.37

0.13

18.38

0.48

Schizo

23.28

1.70

61.41

3.36

23.59

1.83

65.69

3.94

Seizure

23.40

1.51

63.68

4.66

23.08

1.87

65.09

3.48

AD

23.52

1.65

64.15

4.60

23.29

1.92

65.39

3.95

MS

22.62

1.38

63.82

5.53

23.29

1.98

67.46

3.96

NHL

22.42

1.99

61.14

3.47

23.78

1.20

66.90

4.10

DM

23.01

1.67

65.35

3.56

23.33

1.86

66.46

3.65

AIDS

22.56

2.46

62.70

4.53

23.32

1.74

65.67

4.16

CJD

23.30

1.42

65.07

4.95

23.11

1.52

66.68

3.97

Autism Low level EMF F value

22.12

2.44

63.69

5.14

23.33

1.35

66.83

3.27

22.29

2.05

58.70

7.34

22.29

2.05

67.03

5.97

337.577

356.621

427.828

654.453

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 3 Effect of rutile and antibiotics on digoxin and delta aminolevulinic acid.

Group

Digoxin (ng/ml) (Increase with Rutile) Mean ±SD

Digoxin (ng/ml) (Decrease with Doxy+Cipro) Mean ±SD

ALA % (Increase with Rutile) Mean ±SD

ALA % (Decrease with Doxy+Cipro) Mean ±SD

Normal

0.11

0.00

0.054

0.003

4.40

0.10

18.48

0.39

Schizo

0.55

0.06

0.219

0.043

22.52

1.90

66.39

4.20

Seizure

0.51

0.05

0.199

0.027

22.83

1.90

67.23

3.45

AD

0.55

0.03

0.192

0.040

23.67

1.68

66.50

3.58

MS

0.52

0.03

0.214

0.032

22.38

1.79

67.10

3.82

NHL

0.54

0.04

0.210

0.042

23.34

1.75

66.80

3.43

DM

0.47

0.04

0.202

0.025

22.87

1.84

66.31

3.68

AIDS

0.56

0.05

0.220

0.052

23.45

1.79

66.32

3.63

CJD

0.53

0.06

0.212

0.045

23.17

1.88

68.53

2.65

Autism

0.53

0.08

0.205

0.041

23.20

1.57

66.65

4.26

Low level EMF

0.51

0.05

0.213

0.033

22.29

2.05

61.91

7.56

F value

135.116

71.706

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001


31

Table 4 Effect of rutile and antibiotics on succinate and glycine.

Group

Succinate % (Increase with Rutile) Mean ±SD

Succinate % (Decrease with Doxy+Cipro) Mean ±SD

Glycine % change (Increase with Rutile) Mean ±SD

Glycine % change (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.41

0.15

18.63

0.12

4.34

0.15

18.24

0.37

Schizo

22.76

2.20

67.63

3.52

22.79

2.20

64.26

6.02

Seizure

22.28

1.52

64.05

2.79

22.82

1.56

64.61

4.95

AD

23.81

1.90

66.95

3.67

23.12

1.71

65.12

5.58

MS

24.10

1.61

65.78

4.43

22.73

2.46

65.87

4.35

NHL

23.43

1.57

66.30

3.57

22.98

1.50

65.13

4.87

DM

23.70

1.75

68.06

3.52

23.81

1.49

64.89

6.01

AIDS

23.66

1.67

65.97

3.36

23.09

1.81

65.86

4.27

CJD

22.92

2.14

67.54

3.65

21.93

2.29

63.70

5.63

Autism

21.88

1.19

66.28

3.60

23.02

1.65

67.61

2.77

EMF

22.29

1.33

65.38

3.62

22.13

2.14

66.26

3.93

F value

403.394

680.284

348.867

364.999

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 5 Effect of rutile and antibiotics on pyruvate and glutamate.

Group



Glutamate (Increase with Rutile) Mean ±SD

Glutamate (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.34

0.21

18.43

0.82

4.21

0.16

18.56

0.76

Schizo

20.99

1.46

61.23

9.73

23.01

2.61

65.87

5.27

Seizure

20.94

1.54

62.76

8.52

23.33

1.79

62.50

5.56

AD

22.63

0.88

56.40

8.59

22.96

2.12

65.11

5.91

MS

21.59

1.23

60.28

9.22

22.81

1.91

63.47

5.81

NHL

21.19

1.61

58.57

7.47

22.53

2.41

64.29

5.44

DM

20.67

1.38

58.75

8.12

23.23

1.88

65.11

5.14

AIDS

21.21

2.36

58.73

8.10

21.11

2.25

64.20

5.38

CJD

21.07

1.79

63.90

7.13

22.47

2.17

65.97

4.62

Autism

21.91

1.71

58.45

6.66

22.88

1.87

65.45

5.08

Low level EMF

22.29

2.05

62.37

5.05

21.66

1.94

67.03

5.97

F value

321.255

115.242

292.065

317.966

P value

< 0.001

< 0.001

< 0.001

< 0.001

32


Table 6 Effect of rutile and antibiotics on hydrogen peroxide and ammonia.

Group

H2O2 % (Increase with Rutile)

H2O2 % (Decrease with Doxy+Cipro)

Ammonia % (Increase with Rutile)

Ammonia % (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

Schizo

22.50

1.66

60.21

7.42

22.52

1.90

66.39

4.20

Seizure

23.81

1.19

61.08

7.38

22.83

1.90

67.23

3.45

AD

22.65

2.48

60.19

6.98

23.67

1.68

66.50

3.58

MS

21.14

1.20

60.53

4.70

22.38

1.79

67.10

3.82

NHL

23.35

1.76

59.17

3.33

23.34

1.75

66.80

3.43

DM

23.27

1.53

58.91

6.09

22.87

1.84

66.31

3.68

AIDS

23.32

1.71

63.15

7.62

23.45

1.79

66.32

3.63

CJD

22.86

1.91

63.66

6.88

23.17

1.88

68.53

2.65

Autism

23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

Low level EMF

23.29

1.67

60.52

5.38

22.29

2.05

61.91

7.56

F value

380.721

171.228

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001

Abbreviations Schizo: Schizophrenia AD: Alzheimer’s disease MS: Multiple sclerosis NHL: Non-Hodgkin’s lymphoma DM: Diabetes mellitus AIDS: Acquired immunodeficiency syndrome CJD: Creutzfeldt Jakob’s disease


Section 2: Patient Study Table 1 Group

RBC Digoxin Cytochrome (ng/ml RBC Susp) F 420

HERV RNA (ug/ml)

H2O2 (umol/ml RBC)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

NO/BHCD

0.58

0.07

1.00

0.00

17.75

0.72

177.43

6.71

RHCD

1.41

0.23

4.00

0.00

55.17

5.85

278.29

7.74

LHCD

0.18

0.05

0.00

0.00

8.70

0.90

111.63

5.40

Schizo

1.38

0.26

4.00

0.00

51.17

3.65

274.88

8.73

Seizure

1.23

0.26

4.00

0.00

50.04

3.91

278.90

11.20

HD

1.34

0.31

4.00

0.00

51.16

7.78

295.37

3.78

AD

1.10

0.08

4.00

0.00

51.56

3.69

277.47

10.90

MS

1.21

0.21

4.00

0.00

47.90

6.99

280.89

11.25

SLE

1.50

0.33

4.00

0.00

48.20

5.53

278.59

11.51

NHL

1.26

0.23

4.00

0.00

51.08

5.24

283.39

10.67

Glio

1.27

0.24

4.00

0.00

51.57

2.66

278.19

12.80

DM

1.35

0.26

4.00

0.00

51.98

5.05

280.89

10.58

CAD

1.22

0.16

4.00

0.00

50.00

5.91

280.89

13.79

CVA

1.33

0.27

4.00

0.00

51.06

4.83

287.33

9.47

AIDS

1.31

0.24

4.00

0.00

50.15

6.96

278.58

12.72

CJD

1.48

0.27

4.00

0.00

49.85

6.40

286.16

10.90

Autism

1.19

0.24

4.00

0.00

52.87

7.04

274.52

9.29

DS

1.34

0.25

4.00

0.00

47.28

3.55

283.04

9.17

Cerebral Palsy

1.44

0.19

4.00

0.00

53.49

4.15

273.70

12.37

CRF

1.26

0.26

4.00

0.00

49.39

5.51

285.51

8.79

Cirr/Hep Fail

1.50

0.20

4.00

0.00

46.82

4.73

275.97

10.66

Muc Angio

1.40

0.32

4.00

0.00

46.37

4.87

290.37

9.10

EMF

1.51

0.29

4.00

0.00

47.47

4.34

287.49

9.81

CCP

1.35

0.22

4.00

0.00

48.54

5.97

277.50

7.51

Exposure to EMF 1.41

0.30

4.00

0.00

51.01

4.77

276.49

10.92

F value

60.288

0.001

194.418

713.569

P value

< 0.001

< 0.001

< 0.001

< 0.001

33

34


Table 2 Group

NOX (OD diff/hr/mgpro)

TNF ALP (pg/ml)

ALA (umol24)

PBG (umol24)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

NO/BHCD

0.012

0.001

17.94

0.59

15.44

0.50

20.82

1.19

RHCD

0.036

0.008

78.63

5.08

63.50

6.95

42.20

8.50

LHCD

0.007

0.001

9.29

0.81

3.86

0.26

12.11

1.34

Schizo

0.036

0.009

78.23

7.13

66.16

6.51

42.50

3.23

Seizure

0.038

0.007

79.28

4.55

68.28

6.02

46.54

4.55

HD

0.035

0.011

82.13

3.97

67.30

5.98

47.25

4.19

AD

0.036

0.007

79.65

5.57

67.32

5.40

49.83

3.45

MS

0.034

0.009

80.18

5.67

64.00

7.33

46.85

3.49

SLE

0.038

0.008

81.03

6.22

65.01

5.42

48.55

3.81

NHL

0.041

0.006

77.98

5.68

63.21

6.55

47.17

4.86

Glio

0.038

0.007

79.18

5.88

67.67

5.69

46.84

4.43

DM

0.041

0.005

78.36

6.68

64.72

6.81

48.15

3.36

CAD

0.038

0.009

78.15

3.72

66.66

7.77

47.00

3.81

CVA

0.037

0.007

77.59

5.24

69.02

4.86

46.33

4.01

AIDS

0.039

0.010

79.17

5.88

67.78

4.41

48.03

3.64

CJD

0.039

0.006

80.41

5.70

66.99

3.71

47.94

5.33

Autism

0.036

0.006

76.71

5.25

68.16

4.92

42.04

2.38

DS

0.035

0.009

80.30

6.65

64.99

6.72

45.69

4.18

Cerebral Palsy

0.038

0.008

80.02

6.82

65.56

6.28

44.58

4.52

CRF

0.039

0.008

81.36

5.37

67.61

5.55

46.81

4.62

Cirr/Hep Fail

0.037

0.010

77.61

4.42

66.28

6.55

48.23

2.36

Muc Angio

0.039

0.010

79.38

5.14

67.86

5.65

44.08

2.81

EMF

0.035

0.008

80.04

4.69

64.76

5.23

44.82

3.46

CCP

0.040

0.006

80.34

4.73

66.68

4.14

48.70

3.35

Exposure to EMF

0.038

0.007

76.41

5.96

68.41

5.53

47.27

3.42

F value

44.896

427.654

295.467

183.296

P value

< 0.001

< 0.001

< 0.001

< 0.001


Table 3 Group

Uroporphyrin (nmol24)

Coproporphyrin Protoporphyrin (nmol/24) (Ab unit)

Heme (uM)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

NO/BHCD

50.18

3.54

137.94

4.75

10.35

0.38

30.27

0.81

RHCD

250.28

23.43

389.01

54.11

42.46

6.36

12.47

2.82

LHCD

9.51

1.19

64.33

13.09

2.64

0.42

50.55

1.07

Schizo

267.81

64.05

401.49

50.73

44.30

2.66

12.82

2.40

Seizure

290.44

57.65

436.71

52.95

49.59

1.70

13.03

0.70

HD

286.84

24.18

432.22

50.11

49.36

4.18

11.81

0.80

AD

259.61

33.18

433.17

45.61

49.68

3.30

12.09

1.12

MS

277.36

15.48

440.35

25.34

50.81

3.21

11.87

1.84

SLE

294.51

58.62

447.39

39.84

52.94

3.67

12.95

1.53

NHL

310.25

40.44

495.98

39.11

54.80

4.04

11.76

1.37

Glio

304.19

14.16

479.35

58.86

53.73

5.34

13.68

1.67

DM

285.46

29.46

422.27

33.86

49.80

4.01

12.83

2.07

CAD

314.01

17.82

426.14

24.28

49.51

2.27

11.39

1.10

CVA

320.85

24.73

402.16

33.80

46.74

4.28

11.26

0.95

AIDS

306.61

22.47

429.72

24.97

49.32

5.13

11.60

1.23

CJD

317.92

29.63

429.24

18.29

50.02

4.58

11.76

1.32

Autism

318.84

82.90

423.29

47.57

47.50

2.87

12.37

2.09

DS

258.33

37.85

421.52

36.57

50.97

7.07

11.81

1.14

Cerebral Palsy

280.16

26.14

431.39

28.88

49.23

3.91

11.61

1.36

CRF

301.78

48.22

427.57

33.55

49.66

4.41

12.03

1.40

Cirr/Hep Fail

276.51

16.66

436.44

25.65

50.56

1.63

11.92

1.33

Muc Angio

303.86

13.91

441.58

25.51

47.86

3.34

12.13

1.10

EMF

300.90

31.96

443.22

38.14

51.37

4.86

12.61

2.00

CCP

287.09

15.63

442.85

49.61

50.36

3.49

12.01

1.53

Exposure to EMF 288.21

26.17

444.94

38.89

50.59

1.71

12.36

1.26

F value

160.533

279.759

424.198

1472.05

P value

< 0.001

< 0.001

< 0.001

< 0.001

35

36


Table 4 Group

Bilirubin (mg/dl)

Biliverdin (Ab unit)

ATP Synthase (umol/gHb)

SE ATP (umol/dl)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

NO/BHCD

0.55

0.02

0.030

0.001

0.36

0.13

0.42

0.11

RHCD

1.70

0.20

0.067

0.011

2.73

0.94

2.24

0.44

LHCD

0.21

0.00

0.017

0.001

0.09

0.01

0.02

0.01

Schizo

1.74

0.08

0.073

0.013

2.66

0.58

1.26

0.19

Seizure

1.84

0.07

0.070

0.015

3.09

0.65

1.66

0.56

HD

1.83

0.09

0.071

0.014

3.34

0.84

1.27

0.26

AD

1.77

0.13

0.073

0.016

3.34

0.75

2.06

0.19

MS

1.81

0.10

0.079

0.007

3.05

0.52

1.63

0.26

SLE

1.82

0.08

0.061

0.006

2.85

0.34

1.59

0.22

NHL

1.84

0.08

0.077

0.011

3.01

0.55

1.73

0.26

Glio

1.76

0.11

0.073

0.012

2.70

0.62

1.48

0.32

DM

1.77

0.19

0.067

0.014

3.19

0.89

1.97

0.11

CAD

1.75

0.12

0.080

0.007

2.99

0.65

1.57

0.37

CVA

1.82

0.10

0.079

0.009

2.98

0.78

1.49

0.27

AIDS

1.79

0.08

0.072

0.013

3.29

0.63

1.59

0.38

CJD

1.82

0.09

0.066

0.009

3.21

0.95

1.69

0.43

Autism

1.83

0.16

0.072

0.014

2.67

0.80

2.03

0.12

DS

1.85

0.07

0.071

0.015

3.15

0.73

1.17

0.11

Cerebral Palsy

1.85

0.09

0.069

0.012

3.14

0.46

1.56

0.39

CRF

1.76

0.22

0.070

0.012

3.14

0.57

1.53

0.33

Cirr/Hep Fail

1.81

0.10

0.076

0.009

3.01

0.47

1.32

0.26

Muc Angio

1.78

0.24

0.067

0.014

2.92

0.55

1.35

0.29

EMF

1.79

0.07

0.074

0.009

3.12

0.60

1.56

0.48

CCP

1.84

0.07

0.073

0.011

3.15

0.46

1.51

0.38

Exposure to EMF

1.75

0.22

0.073

0.013

3.39

1.03

1.37

0.27

F value

370.517

59.963

54.754

67.588

P value

< 0.001

< 0.001

< 0.001

< 0.001


Table 5 Cyto C (ng/ml)

Lactate (mg/dl)

Pyruvate (umol/l)

RBC Hexokinase (ug glu phos / hr/mgpro)

Mean ±SD

Mean ±SD

Mean

±SD

Mean

±SD

NO/BHCD

2.79

7.38

40.51

1.42

1.66

0.45

RHCD

12.39 1.23

25.99 8.10

100.51 12.32

5.46

2.83

LHCD

1.21

2.75

0.41

23.79

2.51

0.68

0.23

Schizo

11.58 0.90

22.07 1.06

96.54

9.96

7.69

3.40

Seizure

12.06 1.09

21.78 0.58

90.46

8.30

6.29

1.73

HD

12.65 1.06

24.28 1.69

95.44

12.04

9.30

3.98

AD

11.94 0.86

22.04 0.64

97.26

8.26

8.46

3.63

MS

11.81 0.67

23.32 1.10

102.48 13.20

8.56

4.75

SLE

11.73 0.56

23.06 1.49

100.51 9.79

8.02

3.01

NHL

11.91 0.49

22.83 1.24

95.81

12.18

7.41

4.22

Glio

13.00 0.42

22.20 0.85

96.58

8.75

7.82

3.51

DM

12.95 0.56

25.56 7.93

96.30

10.33

7.05

1.86

CAD

11.51 0.47

22.83 0.82

97.29

12.45

8.88

3.09

CVA

12.74 0.80

23.03 1.26

103.25 9.49

7.87

2.72

AIDS

12.29 0.89

24.87 4.14

95.55

7.20

9.84

2.43

CJD

12.19 1.22

23.02 1.61

96.50

5.93

8.81

4.26

Autism

12.48 0.79

21.95 0.65

92.71

8.43

6.95

2.02

DS

12.79 1.15

23.69 2.19

91.81

4.12

8.68

2.60

Cerebral Palsy

12.14 1.30

23.12 1.81

95.33

11.78

7.92

3.32

CRF

12.66 1.01

23.42 1.20

97.38

10.76

7.75

3.08

Cirr/Hep Fail

12.81 0.90

26.20 5.29

97.77

13.24

8.99

3.27

Muc Angio

12.84 0.74

23.64 1.43

96.19

12.15

10.12

1.75

EMF

12.72 0.92

25.35 5.52

103.32 13.04

9.44

3.40

CCP

12.23 0.94

23.66 1.64

94.36

8.53

2.64

Exposure to EMF

12.26 1.00

23.31 1.46

103.28 11.47

7.58

3.09

F value

445.772

162.945

154.701

18.187

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group

0.28 0.38

0.31

8.06

37

38


Table 6 ACOA (mg/dl)

ACH (ug/ml)

Glutamate (mg/dl)

Mean

±SD

Mean

±SD

Mean

±SD

NO/BHCD

8.75

0.38

75.11

2.96

0.65

0.03

RHCD

2.51

0.36

38.57

7.03

3.19

0.32

LHCD

16.49

0.89

91.98

2.89

0.16

0.02

Schizo

2.51

0.57

48.52

6.28

3.41

0.41

Seizure

2.15

0.22

33.27

5.99

3.67

0.38

HD

1.95

0.06

35.02

5.85

3.14

0.32

AD

2.19

0.15

42.84

8.26

3.53

0.39

MS

2.03

0.09

39.99

12.61

3.58

0.36

SLE

2.54

0.38

49.30

7.26

3.37

0.38

NHL

2.30

0.26

50.58

3.82

3.48

0.46

Glio

2.34

0.43

42.51

11.58

3.28

0.39

DM

2.17

0.40

41.31

10.69

3.53

0.44

CAD

2.37

0.44

49.19

6.86

3.61

0.28

CVA

2.25

0.44

37.45

7.93

3.31

0.43

AIDS

2.11

0.19

38.40

7.74

3.45

0.49

CJD

2.10

0.27

34.97

4.24

3.94

0.22

Autism

2.42

0.41

50.61

6.32

3.30

0.32

DS

2.01

0.08

39.34

8.15

3.30

0.48

Cerebral Palsy

2.06

0.35

40.79

9.34

3.24

0.34

CRF

2.24

0.32

37.52

4.37

3.26

0.43

Cirr/Hep Fail

2.13

0.17

46.20

4.95

3.25

0.40

Muc Angio

2.51

0.42

45.51

7.56

3.11

0.36

EMF

2.19

0.19

42.48

8.62

3.27

0.39

CCP

2.04

0.10

37.95

8.82

3.33

0.25

Exposure to EMF

2.14

0.19

37.75

7.31

3.47

0.37

F value

1871.04

116.901

200.702

P value

< 0.001

< 0.001

< 0.001

Group


Table 7 Group

Se. Ammonia (ug/dl)

HMG Co A (HMG CoA/MEV)

Bile Acid (mg/ml)

Mean

±SD

Mean

±SD

Mean

±SD

NO/BHCD

50.60

1.42

1.70

0.07

79.99

3.36

RHCD

93.43

4.85

1.16

0.10

25.68

7.04

LHCD

23.92

3.38

2.21

0.39

140.40

10.32

Schizo

94.72

3.28

1.11

0.08

22.45

5.57

Seizure

95.61

7.88

1.14

0.07

22.98

5.19

HD

94.60

8.52

1.08

0.13

28.93

4.93

AD

95.37

4.66

1.10

0.07

26.26

7.34

MS

93.42

3.69

1.13

0.08

24.12

6.43

SLE

101.18

17.06

1.14

0.07

19.62

1.97

NHL

91.62

3.24

1.12

0.10

23.45

5.01

Glio

93.20

4.46

1.10

0.09

23.43

6.03

DM

93.38

7.76

1.09

0.12

22.77

4.94

CAD

93.93

4.86

1.07

0.12

24.55

6.26

CVA

103.18

27.27

1.05

0.09

22.39

3.35

AIDS

92.47

3.97

1.08

0.11

23.28

5.81

CJD

93.13

5.79

1.09

0.12

21.26

4.81

Autism

94.01

5.00

1.12

0.06

23.16

5.78

DS

98.81

15.65

1.09

0.11

21.31

4.49

Cerebral Palsy

92.09

3.21

1.07

0.09

22.80

5.02

CRF

98.76

11.12

1.03

0.10

26.47

5.30

Cirr/Hep Fail

94.77

2.86

1.04

0.10

24.91

5.06

Muc Angio

92.40

4.34

1.12

0.08

24.37

4.38

EMF

95.37

5.76

1.08

0.08

25.17

3.80

CCP

93.42

5.34

1.01

0.09

23.87

4.00

Exposure to EMF

102.62

26.54

1.00

0.07

22.58

5.07

F value

61.645

159.963

635.306

P value

< 0.001

< 0.001

< 0.001

39

40


Abbreviations NO/BHCD: Normal/Bi-hemispheric chemical dominance RHCD: Right hemispheric chemical dominance LHCD: Left hemispheric chemical dominance HD: Huntington’s disease AD: Alzheimer’s disease MS: Multiple sclerosis SLE: Systemic lupus erythematosis NHL: Non-Hodgkin’s lymphoma Glio: Glioma DM: Diabetes mellitus CAD: Coronary artery disease CVA: Cerebrovascular accident AIDS: Acquired immunodeficiency syndrome CJD: Creutzfeldt Jakob’s disease DS: Down syndrome CRF: Chronic renal failure Cirr/Hep Fail - Cirrhosis/Hepatic failure EMF: Endomyocardial fibrosis CCP: Chronic calcific pancreatitis


41

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 2, 10 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.11 The archaeal beta hydroxyl steroid dehydrogenase activity indicating digoxin synthesis.12 The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide.10 The pyruvate gets converted to glutamate and ammonia by the GABA shunt pathway. The pyruvate is converted to glutamate by serum glutamate pyruvate transaminase. The glutamate gets acted upon by glutamate dehydrogenase to generate alpha ketoglutarate and ammonia. Alanine is most commonly produced by the reductive amination of pyruvate via alanine transaminase. This reversible reaction involves the interconversion of alanine and

pyruvate,

coupled

to the

interconversion

of

alpha-ketoglutarate

(2-oxoglutarate) and glutamate. Alanine can contribute to glycine. Glutamate is acted upon by Glutamic acid decarboxylase to generate GABA. GABA is converted to succinic semialdehyde by GABA transaminase. Succinic semialdehyde is converted to succinic acid by succinic semialdehyde dehydrogenase. Glycine combines with succinyl CoA to generate delta aminolevulinic acid catalysed by the enzyme ALA synthase. There was upregulated archaeal porphyrin synthesis in the patient population which was archaeal in origin as indicated by actinide catalysis of the reactions. The cholesterol oxidase pathway generated pyruvate which entered the GABA shunt pathway. This resulted in synthesis of succinate and glycine which are

42


substrates for ALA synthase. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.13 Low level electromagnetic fields and its porphyrin messengers can regulate the brain mediating conscious and quantal perception. Porphyrin microarrays serve the purpose of quantal and conscious perception. The archaea and viroids via porphyrin synthesis can regulate the nervous system including the NMDA/GABA


pathway

mediating

conscious

perception. Porphyrin photo-oxidation can generate free radicals which can modulate NMDA transmission. Free radicals can increase NMDA transmission. Free radicals can induce GAD and increase GABA synthesis. ALA blocks GABA transmission and upregulates NMDA. Protoporphyrins bind to GABA receptor and promote GABA transmission. Thus porphyrins can modulate the thalamo-cortico-thalamic pathway of conscious perception. The dipolar porphyrins in the setting of digoxin induced sodium potassium ATPase inhibition can produce a pumped phonon system mediated Frohlich model superconducting state inducing quantal perception with nanoarchaeal sensed gravity producing the orchestrated reduction of the quantal possibilities to the macroscopic world. ALA can produce sodium potassium ATPase inhibition resulting in a pumped phonon system mediated quantal state involving dipolar porphyrins. Porphyrin molecules have a wave particle existence and can bridge the dividing line between quantal state and particulate state. Thus the porphyrins can mediate conscious and quantal perception. Porphyrins binding to proteins, nucleic acids and cell membranes can produce biophoton emission. Porphyrins by autooxidation can generate biophotons and are involved in quantal perception. Biophotons can mediate quantal perception. Cellular porphyrins photo-oxidation are involved in sensing of earth magnetic fields and low level biomagnetic fields. Thus porphyrin microarrays can function as a quantal computer mediating extrasensory perception. Porphyrin microarrays in human


43

systems and brain owing to the wave particle nature of porphyrins can bridge the quantal world and particulate world. The porphyrins can modulate hemispheric dominance. There is increased porphyrin synthesis and RHCD and decreased porphyrin synthesis in LHCD. The increase in archaeal porphyrins can contribute to the pathogenesis of schizophrenia and autism. Porphyria can lead to psychiatric disorders and seizures. Altered porphyrin metabolism has been described in autism. Porphyrins by modulating conscious and quantal perception is involved in the pathogenesis of schizophrenia and autism.3, 4, 16 Thus porphyrins microarrays can function as a quantal brain modulating extrasensory quantal perception. Porphyrin microarrays can function as a quantal brain in communication with digital world and geomagnetic fields. The dipolar porphyrins in the setting of digoxin induced sodium potassium ATPase inhibition can produce a pumped phonon system mediated Frohlich model superconducting state inducing quantal perception with nanoarchaeal sensed gravity producing the orchestrated reduction of the quantal possibilities to the macroscopic world. ALA can produce sodium potassium ATPase inhibition resulting in a pumped phonon system mediated quantal state involving dipolar porphyrins. Porphyrins by auto-oxidation can generate biophotons and are involved in quantal perception. Biophotons can mediate quantal perception. Porphyrin auto-oxidation is modulated by low level of electromagnetic

fields

and

geomagnetic

fields.

Cellular

porphyrins

photo-oxidation are involved in sensing of earth magnetic fields and low level biomagnetic fields. Porphyrins can thus contribute to quantal perception. Low level electromagnetic fields and light can induce porphyrin synthesis. Low level EMF can produce ferrochelatase inhibition as well as heme oxygenase induction contributing to heme depletion, ALA synthase induction and increased porphyrin synthesis. Light also induces ALA synthase and porphyrin synthesis. The increased porphyrin synthesized can contribute to increased quantal

44


perception and can modulate conscious perception. The human porphyrin microarrays induced biophotons and quantal fields can modulate the source from which low level EMF and photic fields were generated. Thus the porphyrin generated by extraneous low level EMF and photic fields can interact with the source of low level EMF and photic fields modulating it. Thus porphyrins can serve as a bridge between the human brain and the source of low level EMF and photic fields. This serves as a mode of communication between the human brain and digital EMF storage devices like internet. The porphyrins can also serve as the source of communication with the environment. Environmental EMF and chemicals produce heme oxygenase induction and heme depletion increasing porphyrin synthesis, quantal perception and two-way communication. Thus induction of porphyrin synthesis can serve as a mechanism of communication between human brain and the environment by extrasensory perception. Porphyrin microarrays can function as quantal computers storing information and can serve the purpose of extrasensory perception. Porphyrins can serve as a two way communicating bridge between digital information storage systems generating low level electromagnetic fields and human systems. The low level of EMF produced by digital system enhances porphyrin synthesis and serves the purpose of two way extrasensory perception and communication. The human porphyrin quantal computers can in turn by biophoton emission modulate digital information storage system. Low level of electromagnetic fields and its porphyrin messengers can induce the Warburg phenotype. An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described. The archaea can synthesize porphyrins and induce porphyrin synthesis. Porphyrins have been related to schizophrenia, metabolic syndrome x, malignancy, systemic lupus erythematosis, multiple sclerosis and Alzheimer’s diseases. Porphyrins can mediate the effect of low level electromagnetic fields inducing the Warburg


45

phenotype leading to the above mentioned disease states. The Warburg phenotype results in inhibition of pyruvate dehydrogenase and the TCA cycle. The pyruvate enters the GABA shunt pathway where it is converted to succinyl CoA. The glycolytic pathway is upregulated and the glycolytic metabolite phosphoglycerate is converted to serine and glycine. Glycine and succinyl CoA are the substrates for ALA synthesis. The archaea induces the enzyme heme oxygenase. Heme oxygenase converts heme to bilirubin and biliverdin. This depletes heme from the system and results in upregulation of ALA synthase activity resulting in porphyria. Heme inhibits HIF alpha. The heme depletion results in upregulation of HIF alpha activity and further strengthening of the Warburg phenotype. The porphyrin self oxidation results in redox stress which activates HIF alpha and generates the Warburg phenotype. The Warburg phenotype results in channeling acetyl CoA for cholesterol synthesis as the TCA cycle and mitochondrial oxidative phosphorylation are blocked. The archaea uses cholesterol as an energy substrate. Porphyrin and ALA inhibits sodium potassium ATPase. This increases cholesterol synthesis by acting upon intracellular SREBP. The cholesterol is metabolized to pyruvate and then the GABA shunt pathway for ultimate use in porphyrin synthesis. The porphyrins can self organize and self replicate into macromolecular arrays. The porphyrin arrays behave like an autonomous organism and can have intramolecular electron transport generating ATP. The porphyrin macroarrays can store information and can have quantal perception. The porphyrin macroarrays serves the purpose of archaeal energetics and sensory perception. The Warburg phenotype is associated with malignancy, autoimmune disease and metabolic syndrome x. Low level electromagnetic fields can induce the Warburg phenotype contributing to human disease. The role of porphyrins and low level electromagnetic fields in regulation of cell functions and neuro-immuno-endocrine integration is discussed. Low levels

46


of EMF fields can induce digoxin synthesis. Protoporphyrin binds to the peripheral benzodiazepine receptor regulating steroid and digoxin synthesis. Increased porphyrin metabolites can contribute to hyperdigoxinemia. Digoxin can modulate the neuro-immuno-endocrine system. Low level of EMF fields can modulate membrane, nucleic acid and protein structure and function via induction of porphyrin synthesis. Porphyrins can combine with membranes modulating membrane function. Porphyrins can combine with proteins oxidizing their tyrosine, tryptophan, cysteine and histidine residues producing crosslinking and altering protein conformation and function. Porphyrins can complex with DNA and RNA modulating their function. Porphyrin interpolating with DNA can alter transcription and generate HERV expression. Low level of EMF fields through modulation of porphyrin metabolism can produce heme deficiency by inhibiting heme oxygenase and ferrochelatase. Heme deficiency can also result in disease states. Heme deficiency results in deficiency of heme enzymes. There is deficiency of cytochrome C oxidase and mitochondrial dysfunction. The glutathione peroxidase is dysfunctional and the glutathione system of free radical scavenging does not function. The cytochrome P450 enzymes involved in steroid and bile acid synthesis have reduced activity leading to steroid - cortisol and sex hormones as well as bile acid deficiency states. The heme deficiency results in dysfunction of nitric oxide synthase, heme oxygenase and cystathione beta synthase resulting in lack of gasotransmitters regulating the vascular system and NMDA receptor - NO, CO and H2S. Heme has got cytoprotective, neuroprotective, anti-inflammatory and antiproliferative effects. Heme is also involved in the stress response. Heme deficiency leads to metabolic syndrome, immune disease, degenerations and cancer.3-5 Low level electromagnetic fields can modulate cell functions and neuro-immuno-endocrine-genetic integration via induction of porphyrin synthesis.


47

Low level electromagnetic fields via modulating porphyrin metabolism can produce an autonomic neuropathy. Protoporphyrins block acetyl choline transmission producing a vagal neuropathy with sympathetic overactivity. Vagal neuropathy results in immune activation, vasospasm and vascular disease. A vagal neuropathy underlines neoplastic and autoimmune processes as well as metabolic syndrome x. Low level electromagnetic fields by modulating porphyrin metabolism can induce cell death. Porphyrin induced increased NMDA transmission and free radical injury can contribute to neuronal degeneration. Free radicals can produce mitochondrial PT pore dysfunction. This can lead to cytoC leak and activation of the caspase cascade leading to apoptosis and cell death. Altered porphyrin metabolism has been described in Alzheimer’s disease. The increased porphyrin photo-oxidation generated free radicals mediated NMDA transmission can also contribute to epileptogenesis. The protoporphyrins binding to mitochondrial benzodiazepine receptors can regulate brain function and cell death.3, 4, 16 Low level electromagnetic fields by modulating porphyrin metabolism can generate redox stress to regulate cell functions. The porphyrins can undergo photo-oxidation and auto-oxidation generating free radicals. The archaeal porphyrins can produce free radical injury. Free radicals produce NFKB activation, open the mitochondrial PT pore resulting in cell death, produce oncogene activation, activate NMDA receptor and GAD enzyme regulating neurotransmission and generates the Warburg phenotypes activating glycolysis and inhibiting TCA cycle/oxphos. Porphyrins have been related to schizophrenia,

metabolic

syndrome

x,

malignancy,

systemic

lupus

erythematosis, multiple sclerosis and Alzheimer’s diseases. Low level electromagnetic fields by modulating porphyrin metabolism can regulate cell membrane sodium potassium ATPase. The porphyrins can complex and intercalate with the cell membrane producing sodium potassium ATPase

48


inhibition adding on to digoxin mediated inhibition. Porphyrins can complex with proteins and nucleic acid producing biophoton emission. Low level electromagnetic fields by modulating porphyrin metabolism can regulate DNA, RNA and protein structure and function. Porphyrins complexing with proteins can modulate protein structure and function. Porphyrins complexing with DNA and RNA can modulate transcription and translation. Low level electromagnetic fields by modulating porphyrin metabolism can regulate mitochondrial function, peripheral benzodiazepine receptor and steroidogenesis. The porphyrin especially protoporphyrins can bind to peripheral benzodiazepine receptors in the mitochondria and modulate its function, mitochondrial cholesterol transport and steroidogenesis. Peripheral benzodiazepine receptor modulation by protoporphyrins can regulate cell death, cell proliferation, immunity and neural functions. Low level electromagnetic fields by modulating porphyrin metabolism and inducing redox stress can regulate enzyme systems. The porphyrin photo-oxidation generates free radicals which can modulate enzyme function. Redox stress modulated enzymes include pyruvate dehydrogenase, nitric oxide synthase, cystathione beta synthase and heme oxygenase. Free radicals can modulate mitochondrial PT pore function. Free radicals can modulate cell membrane function and inhibit sodium potassium ATPase activity. Thus the porphyrins are key regulatory molecules modulating all aspects of cell function.3-5 Low level of electromagnetic fields by modulating porphyrin metabolism can induce viroidal and HERV expression. There was an increase in free RNA indicating self replicating RNA viroids and free DNA indicating generation of viroid complementary DNA strands by archaeal reverse transcriptase activity. The actinides and porphyrins modulate RNA folding and catalyse its ribozymal action. Digoxin can cut and paste the viroidal strands by modulating RNA splicing generating RNA viroidal diversity. The viroids are evolutionarily escaped archaeal group I introns which have retrotransposition


49

and self splicing qualities. Porphyrin photo-oxidation induced redox stress can produce HDAC inhibition. Archaeal pyruvate producing histone deacetylase inhibition and porphyrins intercalating with DNA can produce endogenous retroviral (HERV) reverse transcriptase and integrase expression. This can integrate the RNA viroidal complementary DNA into the noncoding region of eukaryotic non coding DNA using HERV integrase as has been described for borna and ebola viruses. The archaea and viroids can also induce cellular porphyrin synthesis. Bacterial and viral infections can precipitate porphyria. Thus porphyrins can regulate genomic function. The increased expression of HERV RNA can result in acquired immunodeficiency syndrome, autoimmune disease, neuronal degenerations, schizophrenia and malignancy.14, 15 Low level electromagnetic fields by modulating porphyrin metabolism and generating redox stress can produce immune activation. The porphyrin photo-oxidation can generate free radicals which can activate NFKB. This can produce immune activation and cytokine mediated injury. The increase in archaeal porphyrins can lead to autoimmune disease like SLE and MS. A hereditary form of MS and SLE related to altered porphyrin metabolism has been described. The protoporphyrins binding to mitochondrial benzodiazepine receptors can modulate immune function. Porphyrins can combine with proteins oxidizing their tyrosine, tryptophan, cysteine and histidine residues producing crosslinking and altering protein conformation and function. Porphyrins can complex with DNA and RNA modulating their structure. Porphyrin complexed with proteins and nucleic acids are antigenic and can lead onto autoimmune disease.3,

4

Low level electromagnetic fields by modulating porphyrin

metabolism and inducing redox stress can produce insulin resistance. The porphyrin photo-oxidation mediated free radical injury can lead to insulin resistance and atherogenesis. Thus archaeal porphyrins can contribute to metabolic syndrome x. Glucose has got a negative effect upon ALA synthase

50


activity. Therefore hyperglycemia may be reactive protective mechanism to increased archaeal porphyrin synthesis. The protoporphyrins binding to mitochondrial

benzodiazepine

receptors

can

modulate

mitochondrial

steroidogenesis and metabolism. Altered porphyrin metabolism has been described in the metabolic syndrome x. Porphyrias can lead onto vascular thrombosis.3,

4

Low level electromagnetic fields by modulating porphyrin

metabolism and inducing redox stress/heme deficiency can activate HIF alpha. The porphyrin photo-oxidation can generate free radicals inducing HIF alpha and producing oncogene activation. Heme deficiency can lead to activation of HIF alpha and oncogenesis. This can lead to oncogenesis. Hepatic porphyrias induced

hepatocellular

carcinoma.

The

protoporphyrins

binding

mitochondrial benzodiazepine receptors can regulate cell proliferation.

3, 4

to Low

level electromagnetic fields by modulating porphyrin metabolism can regulate prion protein conformation. The porphyrin can combine with prion proteins modulating their conformation. This leads to abnormal prion protein conformation and degradation. Archaeal porphyrins can contribute to prion disease. Low level electromagnetic fields by modulating porphyrin metabolism can produce redox stress and regulate HERV expression. The porphyrins can also intercalate with DNA producing HERV expression. The HERV particles generated can contribute to the retroviral state. The porphyrins in the blood can combine with bacteria and viruses and the photo-oxidation generated free radicals can kill them. Low level electromagnetic fields by modulating porphyrin metabolism can lead to increase predilection for viral and bacterial infections. The archaeal porphyrins can modulate bacterial and viral infections. The archaeal porphyrins are regulatory molecules keeping other prokaryotes and viruses on check.3, 4 The metal actinides provide radiolytic energy, catalysis for oligomer formation and provide a coordinating ion for metalloenzymes all important in


51

abiogenesis.6 The metal actinide surfaces would by surface metabolism generate porphyrins from simple compounds like succinic acid and glycine. Porphyrins can exist as wave forms and particulate forms and can bridge the dividing line between the quantal world and particulate world. Porphyrin molecules can self organize into organisms with energy transduction, ATP synthesis and information storage with replicating capacity. A self replicating porphyrin microorganism may have played a role in the origin of life. Porphyrins can form templates on which macromolecules like polysaccharides, protein and nucleic acids can form. The macromolecules generated on actinidic porphyrins templates would have contributed to the actinidic nanoarchaea and the original organisms on earth. The data supports the persistence of an actinidic archaeal shadow biosphere which throws light on the actinide based origin of life and porphyrins as the premier prebiotic molecule.17, 18 Porphyrins play an important role in the genesis of the biological universe. The porphyrin macroarrays can form in the interstellar space on its own as porphyrins can exist both as particles and waves. Porphyrins form the bridging connection between the quantal world and the particulate world. The self generated porphyrins from the quantal foam can self organize to form macroarrays, can store information and self replicate. This can be called as an abiotic porphyrin organism. The porphyrin template would have generated nucleic acids, proteins, polysaccharides and isoprenoids. This would have generated actinidic nanoarchaea in the interstellar space. The porphyrins have magnetic properties and the interstellar porphyrin organism can contribute to the interstellar grains and interstellar magnetic fields. The cosmic dust grains of porphyrin macroarrays/nanoarchaeal organism occupy the intergalactic space and are thought to be formed of magnetotactic bacteria identified according to their spectral signatures. According to the Hoyle’s hypothesis, the cosmic dust magnetotactic porphyrin macroarrays/nanoarchaeal organism plays a role in the

52


formation of the intergalactic magnetic field. A magnetic field equal in strength to about one millionth part of the magnetic field of earth exists throughout much of our galaxy. The magnetic files can be used to trace the spiral arms of the galaxy following a pattern of field lines that connect young stars and dust in which new stars are formed at a rapid rate. Studies have shown that a fraction of the dust particles have elongated shape similar to bacilli and they are systematically lined up in our galaxy. Moreover the direction of alignment is such that the long axes of the dust tend to be at right angles to the direction of the galactic magnetic field at every point. Magnetotactic porphyrin macroarrays/nanoarchaeal organisms have the property to affect the degree of alignment that is observed. The fact that the magnetotactic porphyrin macroarrays/nanoarchaeal organisms appear to be connected to the magnetic field lines that thread through the spiral arms of the galaxy connecting one region of star formation to another support a role for them in star formation and in the mass distribution and rotation of stars. The nutrient supply for a population of interstellar porphyrin macroarrays/nanoarchaeal organisms comes from mass flows out of supernovas populating the galaxy. Giants arising in the evolution of such stars experience a phenomenon in which material containing nitrogen, carbon monoxide, hydrogen, helium, water and trace elements essential for life flows continuously outward into space. The interstellar organisms need liquid water. Water exists only as vapour or solid in the interstellar space and only through star formation leading to associated planets and cometary bodies can there be access to liquid water. To control conditions leading to star formation is of paramount importance in cosmic biology. The rate of star formation is controlled by two factors: Too high a rate of star formation produces a destructive effect of UV radiation and destroys cosmic biology. Star formation as stated before produces water crucial for organism growth. Cosmic biology of magnetotactic organisms and star formation are thus


53

closely interlinked. Systems like solar systems do not arise in random condensation of blobs of interstellar gas. Only by a rigorous control of rotation of various parts of the system would galaxies and solar system evolved. The key to maintaining control over rotation seems to lie in the intergalactic magnetic field as indeed the whole phenomena of star formation. The intergalactic magnetic fields owes its origin to the lining up of magnetotactic porphyrin macroarrays/nanoarchaeal organisms and the cosmic biology of interstellar organisms can prosper only by maintaining a firm grip on the interstellar magnetic field and hence on the rate of star formation and type of star system produced. This point to a cosmic intelligence or brain capable of computation, analysis and exploration of the universe at large - of magnetotactic porphyrin macroarrays/nanoarchaeal organism networks. The origin of life on earth according to the Hoyle’s hypothesis would be by seeding of porphyrin macroarrays/nanoarchaeal organism from the outer intergalactic space. The porphyrin organism can also be generated on actinidic surfaces in earth. Comets carrying porphyrin organisms would have interacted with the earth. A thin skin of graphitized material around a single porphyrin macroarrays/nanoarchaeal organism or clumps of organism can shield the interior from destruction by UV light. The sudden surge and diversification of species of plants and animals and their equally sudden extinction has seen from fossil records point to sporadic evolution produced by induction of fresh cometary genes with the arrival of each major new crop of comets. The porphyrin macroarrays organism can have a wave particle existence and bridge the world of bosons and fermions. The porphyrin macroarrays/nanoarchaeal organism can form biofilms and the porphyrin organism can form a molecular quantum computing cloud in the biofilm which forms an interstellar intelligence regulating the formation of star systems and galaxies. The porphyrin macroarrays/nanoarchaeal organism quantal computing cloud can bridge the wave particle world functioning as the

54


anthropic observer sensing gravity which orchestrates the reduction of the quantal world of possibilities in to the macroscopic world. The actinide based porphyrin macroarrays/nanoarchaeal organism regulates the human system and biological universe.19-21 Porphyrins also have evolutionary significance since porphyria is related to Scythian races and contributes to the behavioural and intellectual characteristics of this group of population. Porphyrins can intercalate into DNA and produce HERV expression. HERV RNA can get converted to DNA by reverse transcriptase which can get integrated into DNA by integrase. This tends to increase the length of the non coding region of the DNA. The increase in non coding region of the DNA is involved in primate and human evolution. Thus, increased rates of porphyrin synthesis would correlate with increase in non-coding DNA length. The alteration in the length of the noncoding region of the DNA contributes to the dynamic nature of the genome. Thus genetic and acquired porphyrias can lead to alteration in the non coding region of the genome. The alteration of the length of the non coding region of the DNA contributes to the racial and individual differences in populations. An increased length of non coding region as well as increased porphyrin synthesis leads to increased cognitive and creative neuronal function. Porphyrins are involved in quantal perception and regulation of the thalamo-cortico-thalamic pathway of conscious perception. Thus genetic and acquired porphyrias contribute to higher cognitive and creative capacity of certain races. Porphyrias are common among Eurasian Scythian races who have assumed leadership roles in communities and groups. Porphyrins have contributed to human and primate evolution.3, 4 The increased porphyrin synthesis in the Scythian races contributes to higher level of extrasensory quantal perception in this racial group. This contributes to higher level of cognitive and spiritual function of the brain in this racial group.


55

The porphyrins can contribute to the role of low level electromagnetic fields in the pathogenesis of metabolic syndrome x, malignancy, psychiatric disorders, autoimmune disease, AIDS, prion disease, neuronal degeneration and epileptogenesis. An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states - metabolic syndrome x, malignancy, psychiatric disorders, autoimmune disease, AIDS, prion disease, neuronal degeneration and epileptogenesis is described. Archaeal porphyrin synthesis and induction of endogenous porphyrin synthesis is crucial in the pathogenesis of these disorders. Porphyrins may serve as regulatory molecules modulating immune, neural, endocrine, metabolic and genetic systems. The porphyrins photo-oxidation generated free radicals can produce immune activation, produce cell death, activate cell proliferation, produce insulin resistance and modulate conscious/quantal perception. Porphyrins can regulate hemispheric dominance. The archaeal porphyrins functions as key regulatory molecules with mitochondrial benzodiazepine receptors playing an important role. Thus the porphyrins contributes to the inducing role of low level electromagnetic fields in the pathogenesis of metabolic syndrome x, malignancy, psychiatric disorders, autoimmune disease, AIDS, prion disease, neuronal degeneration and epileptogenesis. Low level electromagnetic fields and its porphyrin messengers can regulate immune, neural, endocrine, metabolic and genetic systems.3, 4 A hypothesis regarding the role of porphyrins and quantal perception as well as the role of porphyrins in environmental communication/modulation of digital information storage/processing system is presented. Thus porphyrin microarrays can function as a quantal computer mediating extrasensory perception. Porphyrin microarrays in human systems and brain owing to the wave particle nature of porphyrins can bridge the quantal world and particulate world. The relationship between low level of electromagnetic fields and human disease is highlighted.

56


The porphyrions are self replicating supramolecular organisms which forms the precursor template on which the viroids, prions and nanoarchaea originate. Stress induced template directed abiogenesis of porphyrions, prions, viroids and archaea is a continuous process and can contribute to changes in brain structure and behavior as well as disease process.

References [1] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [2] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [3] Puy, H., Gouya, L., Deybach, J.C. (2010). Porphyrias. The Lancet, 375(9718), 924-937. [4] Kadish, K. M., Smith, K. M., Guilard, C. (1999). Porphyrin Hand Book. Academic Press, New York: Elsevier. [5] Gavish M., Bachman, I., Shoukrun, R., Katz, Y., Veenman, L., Weisinger, G., Weizman, A. (1999). Enigma of the Peripheral Benzodiazepine Receptor. Pharmacological Reviews, 51(4), 629-650. [6] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [7] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [8] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [9] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press.


57

[10] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [11] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [12] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [13] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [14] Tsagris E. M., de Alba, A. E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [15] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87. [16] Kurup R., Kurup, P.A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [17] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [18] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [19] Tielens A. G. G. M. (2008). Interstellar Polycyclic Aromatic Hydrocarbon Molecules, Annual Review of Astronomy and Astrophysics, 46, 289-337. [20] Wickramasinghe C. (2004). The universe: a cryogenic habitat for microbial life, Cryobiology, 48(2), 113-125. [21] Hoyle F., Wickramasinghe, C. (1988). Cosmic Life-Force. London: J. M. Dent and Sons Ltd.

Chapter 4

Global Warming Induced Extinction of Homo Sapiens and Symbiotic Neanderthalisation Relation to Archaeal Mediated RNA Viroids and Amyloidosis

60




61

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Prion

proteins

have

been

implicated

in

systemic

disorders

like

neurodegenerations, cancer and metabolic syndrome. The beta amyloid in Alzheimer’s disease, alpha synuclein in Parkinson’s disease, the TAR protein in frontotemporal dementia and copper zinc dismutase in motor neuron disease behaves like prion proteins. Prion proteins like behavior is also seen in the tumour suppressor P53 protein in cancer and the islet cell associated amyloid in diabetes mellitus. Prion diseases are conformational diseases. The abnormal prion protein seeded into the system converts the normal proteins with prion like domains to abnormal configuration. This abnormal protein resists digestion by lysosomal enzymes after its half life is over and results in deposition of amyloid plaques. This produces organ dysfunction. Prion phenomena were initially described for Creutzfeldt Jakob’s disease, but now it is found to be wide spread in chronic disease pathogenesis. Ribonucleoproteins are well known to behave like prion proteins and form amyloid. We have demonstrated actinidic archaea which secretes RNA viroids in metabolic syndrome, neurodegenerations, cancer, autoimmune disease, schizophrenia, autism and CJD. The RNA viroids can bind with normal proteins with prion like domains eg., superoxide dismutase and produce a ribonucleoprotein resulting in prion phenomena and amyloidogenesis. The actinidic archaeal growth results in increased digoxin synthesis and phenotypic conversion of homo sapiens to homo Neanderthals as reported earlier. The increased actinidic archaeal growth is due to global warming and this results in Neanderthalisation. Homo neanderthalis tend to have more of civilisational diseases like metabolic syndrome, neurodegenerations, cancer, autoimmune disease, schizophrenia, autism and CJD. Actinidic archaeal secreted RNA viroids may play a crucial role in amyloid formation and pathogenesis of these disorders.1-16

62


Materials and Methods The following groups were included in the study: - Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+cerium 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond. Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: - Cytochrome F420, free RNA, Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of cerium increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of cerium increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in tables 1-2 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time.


63

Results The results show that there was increase in cytochrome F420 in CJD and other disease groups indicating increased archaeal growth. There was also an increase in free RNA indicating self replicating RNA viroids in CJD and other disease groups. The RNA viroid generation was catalysed by actinides. The RNA viroids can bind with proteins having prion like domains forming ribonucleoproteins.

These

ribonucleoproteins

can

give

an

abnormal

conformation to the protein resulting in generation of abnormal prions. The abnormal prions can act as a template to convert normal proteins with normal configuration to abnormal conformation. This can result in amyloidogenesis. The abnormal configured proteins will resist lysosomal digestion and accumulate as amyloid. Table 1 Effect of cerium and antibiotics on cytochrome F420. CYT F420 % (Increase with Cerium)


Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

Schizo

23.24

2.01

58.72

7.08

Seizure

23.46

1.87

59.27

8.86

AD

23.12

2.00

56.90

6.94

MS

22.12

1.81

61.33

9.82

NHL

22.79

2.13

55.90

7.29

DM

22.59

1.86

57.05

8.45

AIDS

22.29

1.66

59.02

7.50

CJD

22.06

1.61

57.81

6.04

Autism

21.68

1.90

57.93

9.64

F value

306.749

130.054

P value

< 0.001

< 0.001

Group

64


Table 2 Effect of cerium and antibiotics on free RNA. RNA % change (Increase with Cerium)

RNA % change (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Normal

4.37

0.13

18.38

0.48

Schizo

23.59

1.83

65.69

3.94

Seizure

23.08

1.87

65.09

3.48

AD

23.29

1.92

65.39

3.95

MS

23.29

1.98

67.46

3.96

NHL

23.78

1.20

66.90

4.10

DM

23.33

1.86

66.46

3.65

AIDS

23.32

1.74

65.67

4.16

CJD

23.11

1.52

66.68

3.97

Autism

23.33

1.35

66.83

3.27

F value

427.828

654.453

P value

< 0.001

< 0.001

Group

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. The archaeal origin of the self replicating RNA was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by cerium induced increase in enzyme activities. There was an increase in free RNA indicating self replicating RNA viroids. The actinides modulate RNA folding and catalyse its ribozymal action. Digoxin can cut and paste the viroidal strands by modulating RNA splicing generating RNA viroidal diversity. The viroids are evolutionarily escaped archaeal group I introns which have retrotransposition and self splicing qualities. The RNA viroids can bind with proteins having prion like domains forming ribonucleoproteins. These ribonucleoproteins can give an abnormal conformation to the protein resulting


65

in generation of abnormal prions. The abnormal prions can act as a template to convert normal proteins with normal configuration to abnormal conformation. This can result in amyloidogenesis. The abnormal configured proteins will resist lysosomal digestion and accumulate as amyloid. Amyloidogenesis has been implicated in systemic disorders. The beta amyloid in Alzheimer’s disease, alpha synuclein in parkinson’s disease, the TAR protein in frontotemporal dementia and copper zinc dismutase in motor neuron disease behaves like prion proteins. Prion proteins like behavior is also seen in the tumour suppressor P53 protein in cancer and the islet cell associated amyloid in diabetes mellitus. Prion diseases are conformational diseases. The RNA viroids generated from actinidic archaea can bind to proteins with prion

like

domains

resulting

in

generation

of

ribonucleoproteins.

Ribonucleoproteins with abnormal conformation can act as a template for normal proteins with prion like domains to change to abnormal conformation. This results in generation of prion proteins with abnormal conformation resisting lysosomal digestion and generating amyloid. These systemic diseases are due to actinidic archaeal generated RNA viroid induced prion protein generation and amyloidogenesis. Prion proteins have been implicated in systemic disorders like neurodegenerations, cancer and metabolic syndrome. The beta amyloid in Alzheimer’s disease, alpha synuclein in parkinson’s disease, the TAR protein in frontotemporal dementia and copper zinc dismutase in motor neuron disease behaves like prion proteins. Prion proteins like behavior is also seen in the tumour suppressor P53 protein in cancer and the islet cell associated amyloid in diabetes mellitus. The present study shows that the same prion protein mechanism can operate in schizophrenia, autism and autoimmune diseases. Sporadic CJD is also induced by actinidic archaea induced RNA viroids. Actinidic archaeal induced RNA viroids generated prions can be

66


transferred

between

individuals

indicating

the

infective

nature

of

neurodegenerations, cancer, metabolic syndrome, autoimmune disease and neuropsychiatric diseases. The archaeal porphyrins can modulate amyloid formation. The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide. The pyruvate gets converted to glutamate and ammonia by the GABA shunt pathway. The pyruvate is converted to glutamate by serum glutamate pyruvate transaminase. The glutamate gets acted upon by glutamate dehydrogenase to generate alpha ketoglutarate and ammonia. Alanine is most commonly produced by the reductive amination of pyruvate via alanine transaminase. This reversible reaction involves the interconversion of alanine and

pyruvate,

coupled

to the

interconversion

of

alpha-ketoglutarate

(2-oxoglutarate) and glutamate. Alanine can contribute to glycine. Glutamate is acted upon by Glutamic acid decarboxylase to generate GABA. GABA is converted to succinic semialdehyde by GABA transaminase. Succinic semialdehyde is converted to succinic acid by succinic semialdehyde dehydrogenase. Glycine combines with succinyl CoA to generate delta aminolevulinic acid catalysed by the enzyme ALA synthase. There was upregulated archaeal porphyrin synthesis in the patient population which was archaeal in origin as indicated by actinide catalysis of the reactions. The cholesterol oxidase pathway generated pyruvate which entered the GABA shunt pathway. This resulted in synthesis of succinate and glycine which are substrates for ALA synthase. Glycine and succinyl CoA are the substrates for ALA synthesis. Porphyrin and ALA inhibits sodium potassium ATPase. This increases cholesterol synthesis by acting upon intracellular SREBP. The cholesterol is metabolized to pyruvate and then the GABA shunt pathway for ultimate use in porphyrin synthesis. The porphyrins can self organize and self replicate into macromolecular arrays. The porphyrin arrays behave like an


67

autonomous organism and can have intramolecular electron transport generating ATP. The porphyrin macroarrays can store information and can have quantal perception. The porphyrin macroarrays serves the purpose of archaeal energetics and sensory perception. Protoporphyrine binds to the peripheral benzodiazepine receptor regulating steroid and digoxin synthesis. Increased porphyrin metabolites can contribute to hyperdigoxinemia. Digoxin can modulate the neuro-immuno-endocrine system. The global warming results in increased growth of actinidic archaea and neanderthalisation of the homo sapien species. The actinidic archaea secreted viroids can generate ribonucleoproteins by binding to proteins with prion like domains. This generates amyloidogenesis and systemic diseases like neurodegenerations, cancer, metabolic syndrome, autoimmune disease and neuropsychiatric diseases. The widespread incidence of these systemic diseases leads to extinction of the neanderthalised species.

References [1] Weaver TD, Hublin JJ. Neandertal Birth Canal Shape and the Evolution of Human Childbirth. Proc. Natl. Acad. Sci. USA 2009; 106: 8151-8156. [2] Kurup RA, Kurup PA. Endosymbiotic Actinidic Archaeal Mediated Warburg Phenotype Mediates Human Disease State. Advances in Natural Science 2012; 5(1): 81-84. [3] Morgan E. The Neanderthal theory of autism, Asperger and ADHD; 2007, www.rdos.net/eng/asperger.htm. [4] Graves P. New Models and Metaphors for the Neanderthal Debate. Current Anthropology 1991; 32(5): 513-541. [5] Sawyer GJ, Maley B. Neanderthal Reconstructed. The Anatomical Record Part B: The New Anatomist 2005; 283B(1): 23-31.

68


[6] Bastir M, O’Higgins P, Rosas A. Facial Ontogeny in Neanderthals and Modern Humans. Proc. Biol. Sci. 2007; 274: 1125-1132. [7] Neubauer S, Gunz P, Hublin JJ. Endocranial Shape Changes during Growth in Chimpanzees and Humans: A Morphometric Analysis of Unique and Shared Aspects. J. Hum. Evol. 2010; 59: 555-566. [8] Courchesne E, Pierce K. Brain Overgrowth in Autism during a Critical Time in Development: Implications for Frontal Pyramidal Neuron and Interneuron Development and Connectivity. Int. J. Dev. Neurosci. 2005; 23: 153-170. [9] Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, et al. A Draft Sequence of the Neandertal Genome. Science 2010; 328: 710-722. [10] Mithen SJ. The Singing Neanderthals: The Origins of Music, Language, Mind and Body; 2005, ISBN 0-297-64317-7. [11] Bruner E, Manzi G, Arsuaga JL. Encephalization and Allometric Trajectories in the Genus Homo: Evidence from the Neandertal and Modern Lineages. Proc. Natl. Acad. Sci. USA 2003; 100: 15335-15340. [12] Gooch S. The Dream Culture of the Neanderthals: Guardians of the Ancient Wisdom. Inner Traditions, Wildwood House, London; 2006. [13] Gooch S. The Neanderthal Legacy: Reawakening Our Genetic and Cultural Origins. Inner Traditions, Wildwood House, London; 2008. [14] Kurtén B. Den Svarta Tigern, ALBA Publishing, Stockholm, Sweden; 1978. [15] Spikins P. Autism, the Integrations of ‘Difference’ and the Origins of Modern Human Behaviour. Cambridge Archaeological Journal 2009; 19(2): 179-201. [16] Eswaran V, Harpending H, Rogers AR. Genomics Refutes an Exclusively African Origin of Humans. Journal of Human Evolution 2005; 49(1): 1-18.

Chapter 5

Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Bile Acids from Cholesterol Regulates Cellular Function

70




71

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile as well as organisms like phytoplasmas and viroids have been implicated in the etiology of these diseases.1-4 Bile acids are considered as steroidal hormones with endocrine, metabolic and neuroregulatory functions. Bile acids has been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.4 The possibility of endogenous bile acid synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered.5-8 An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described.7, 9

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10

72


Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420 and bile acids.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in table 1 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time.


73

Table 1 Effect of rutile and antibiotics on cytochrome F420 and archaeal bile acids.

Group



Bile acids % change (Increase with Rutile)

Bile acids % change (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

4.29

0.18

18.15

0.58

Schizo

23.24

2.01

58.72

7.08

23.20

1.87

57.04

4.27

Seizure

23.46

1.87

59.27

8.86

22.61

2.22

66.62

4.99

AD

23.12

2.00

56.90

6.94

22.12

2.19

62.86

6.28

MS

22.12

1.81

61.33

9.82

21.95

2.11

65.46

5.79

NHL

22.79

2.13

55.90

7.29

22.98

2.19

64.96

5.64

DM

22.59

1.86

57.05

8.45

22.87

2.58

64.51

5.93

AIDS

22.29

1.66

59.02

7.50

22.29

1.47

64.35

5.58

CJD

22.06

1.61

57.81

6.04

23.30

1.88

62.49

7.26

Autism

21.68

1.90

57.93

9.64

22.21

2.04

63.84

6.16

EMF

22.70

1.87

60.46

8.06

23.41

1.41

58.70

7.34

F value

306.749

130.054

290.441

203.651

P value

< 0.001

< 0.001

< 0.001

< 0.001

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source.6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15 The archaeal cholesterol hydroxylase activity indicating bile acid synthesis were increased.8 The archaeal bile acids are steroidal hormones which can bind GPCR and modulate D2 regulating the conversion of T4 to T3 which activates uncoupling proteins reducing redox stress. Bile acids can activate the transcription factor NRF ½ inducing NQO1, GST, HOI reducing redox stress. Bile acids are

74


neuroprotective and help to prevent neurodegenerative process. Bile acids can bind FXR regulating insulin receptor sensitivity. Bile acid deficiency leads to insulin resistance and metabolic syndrome x. Bile acids can bind PXR inducing the bile acid shunt pathway of cholesterol detoxification.25 Bile acid deficiency leads to cholesterol toxicity. Bile acid binding to FXR receptor inhibits tissue fibrosis and connective tissue deposition. Bile acid deficiency may play a role in MPS and collagen deposition in EMF, CCP, MNG and mucoid angiopathy. Bile acids can bind macrophage GPCR and VDR producing immunosuppression and inhibiting NFKB. This helps to modulate the archaea and viroid induced chronic immune activation. Bile acid deficiency can contribute to autoimmune disease. The archaeal bile acids are chemically diverse and structurally different from human bile acids. The archaeal bile acids can bind olfactory GPCR receptors and stimulate the limbic lobe producing a sense of social identity. The dominance of archaeal bile acids over human bile acids in stimulating the olfactory GPCR - limbic lobe pathway leads to loss of social identity and schizophrenia / autism. Bile acids tend to have an inhibitory effect on cell proliferation and prevent malignant transformation.16 Archaeal bile acids binding to VDR has a inhibitory effect on cell proliferation. Bile acids thus can modulate cell death and cell proliferation. It can regulate metabolism via modulating mitochondrial uncoupling proteins and via FXR insulin receptor sensitivity. Bile acids can modulate limbic lobe and brain functions via GPCR receptor and olfactory pathways. Bile acids can regulate immune function via macrophage GPCR and VDR. Archaeal bile acids can produce neuro-immuno-endocrine integration. Archaeal bile acids deficiency can contribute to the pathogenesis of endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease,


75

schizophrenia, autism, seizure disorder, Creutzfeldt Jakob disease and acquired immunodeficiency syndrome.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6]

Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84.

[7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand.

76


[12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Lefebvre P., Cariou, B., Lien, F., Kuipers, F., Staels, B. (2009). Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation, Physiol Rev, 89(1), 147-191.

Chapter 6

Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of PAH from Cholesterol Regulates Cell Function

78




79

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile as well as organisms like phytoplasmas and viroids have been implicated in the etiology of these diseases.1-4 Polycyclic aromatic hydrocarbons have been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.4 The possibility of polycyclic aromatic hydrocarbon synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered.5-8 An actinide dependent shadow biosphere of archaea in the above mentioned disease states is described.7,

9

Polycyclic aromatic hydrocarbon

synthesized by endosymbiotic archaea can contribute to global warming. Global warming has been related to the changing patterns of disease and infections.

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of

80


1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10 Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420 and polycyclic aromatic hydrocarbon.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Polycyclic aromatic hydrocarbon was estimated by measuring hydrogen peroxide liberated by using glucose reagent. Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in table 1 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time.


81

Table 1 Effect of rutile and antibiotics on cytochrome F420 and PAH.

Group




PAH % change (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

4.45

0.14

18.25

0.72

Schizo

23.24

2.01

58.72

7.08

23.01

1.69

59.49

4.30

Seizure

23.46

1.87

59.27

8.86

22.67

2.29

57.69

5.29

AD

23.12

2.00

56.90

6.94

23.26

1.53

60.91

7.59

MS

22.12

1.81

61.33

9.82

22.83

1.78

59.84

7.62

NHL

22.79

2.13

55.90

7.29

22.84

1.42

66.07

3.78

DM

22.59

1.86

57.05

8.45

23.40

1.55

65.77

5.27

AIDS

22.29

1.66

59.02

7.50

23.23

1.97

65.89

5.05

CJD

22.06

1.61

57.81

6.04

23.46

1.91

61.56

4.61

Autism

21.68

1.90

57.93

9.64

22.61

1.42

64.48

6.90

EMF

22.70

1.87

60.46

8.06

23.73

1.38

65.20

6.20

F value

306.749

130.054

391.318

257.996

P value

< 0.001

< 0.001

< 0.001

< 0.001

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15 There was also an increase in polycyclic aromatic hydrocarbon synthesis in the system. The PAH synthesis was inhibited by antibiotics and stimulated by addition of cerium. The archaeal endosymbiont can aromatize cholesterol to generate PAH.16 The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.17

82


Archaeal PAH can intercalate with DNA and RNA modulating their function. PAH intercalation of DNA can produce HERV expression. PAH can induce photon mediated redox stress. The PAH induced redox stress can produce histone deacetylase inhibition resulting in endogenous retroviral (HERV) reverse transcriptase and integrase expression. This can integrate the HERV RNA complementary DNA into the noncoding region of eukaryotic non coding DNA using HERV integrase as has been described for borna and ebola viruses.19 The noncoding DNA is lengthened by integrating HERV RNA complementary DNA with the integration going on as a continuing event. The archaea genome can also get integrated into human genome using integrase as has been described for trypanosomes.20 The integrated viroids and archaea can undergo vertical transmission and can exist as genomic parasites.18-20 This increases the length and alters the grammar of the noncoding region producing memes or memory of acquired characters as well as eukaryotic speciation and individuality.21 The HERV RNA complementary DNA can function as jumping genes producing a dynamic genome important in storage of synaptic information, HLA gene expression and developmental gene expression. The HERV RNA can regulate mrna function by RNA interference.18 The phenomena of RNA interference can modulate T cell and B cell function, insulin signaling lipid metabolism, cell growth and differentiation, apoptosis, neuronal transmission and euchromatin/heterochromatin expression. The PAH can also intercalate with RNA modulating its function. The expression of HERV RNA covered with a phospholipid membrane can contribute to the pathogenesis of acquired immunodeficiency syndrome. Archaeal PAH can regulate genomic function. The archaeal PAH intercalating with DNA can induce DNA mutations and oncogene activation contributing to cellular dedifferentitation and proliferation. Archaeal PAH can induce malignant transformation.22


83

The archaeal PAH can regulate the nervous system including the NMDA/GABA 4, 23

perception.

thalamocorticothalamic

pathway

mediating

conscious

NMDA/GABA receptors can be modulated by PAH increasing

NMDA activity and inducing GAD.4 The dipolar PAH and archaeal magnetite in the setting of digoxin induced sodium potassium ATPase inhibition can produce a pumped phonon system mediated frohlich model superconducting state

23

inducing quantal perception with nanoarchaeal sensed gravity producing the orchestrated reduction of the quantal possibilities to the macrosopic world.4, 23 Archaeal PAH can bind membranes, proteins and DNA generating exciplexes and biophoton emission. Biophotons generate a quantal state mediating quantal perception. The archaeal PAH induced NMDA excitotoxicity can contribute to the pathogenesis of schizophrenia and autism. Archaeal PAH induced NMDA excitotoxicity can also contribute to cell death and neuronal degeneration.24 Archaeal PAH induced redox stress can also contribute to neuronal degeneration. Archaeal PAH can induce AHR dependent regulatory T cells (Tregs). The activation of the AHR-Treg pathway suppresses autoimmune disease. PAH by producing redox stress can also generate immune activation. Thus archaeal PAH has a biphasic role in immunoregulation.25, 26 Archaeal PAH can generate insulin resistance and contribute to metabolic syndrome x. Archaeal PAH by photo-oxidation generates redox stress contributing to insulin resistance. Small particulate matter or nanoparticles in the blood generated by PAH can produce vasospasm and cardiovascular/cerebrovascular disease.27, 28 The PAH synthesized by endosymbiotic archaea can contributes to global warming. This may be the main contributory factor for global warming. Archaeal PAH can induce HERV expression and its integration back into the genomic DNA enlarging the noncoding region of the genome. The increase in the length of noncoding region and the differences in it contribute to eukaryotic

84


and primate evolution. It is the increase in noncoding region length that led to the evolution of primates and humans. Pollution and global warming mediated by archaeal PAH is a method of eukaryotic evolution. Global warming increases the carbon dioxide in the atmosphere and contributes to more archaeal growth. The increase in archaeal growth leads to increased synthesis of PAH and increased global warming. Global warming contributes to evolutionary innovation.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249.


85

[10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [18] Tsagris E. M., de Alba, A. E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [19] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87. [20] Hecht M., Nitz, N., Araujo, P., Sousa, A., Rosa, A., Gomes, D. (2010). Genes from Chagas parasite can transfer to humans and be passed on to children. Inheritance of DNA Transferred from American Trypanosomes to Human Hosts, PLoS ONE, 5, 2-10.

86


[21] Flam F. (1994). Hints of a language in junk DNA, Science, 266, 1320. [22] Melendez-Colon, V. J., Luch, A., Seidel, A., Baird, W. M. (1999). Cancer initiation by polycyclic aromatic hydrocarbons results from formation of stable DNA adducts rather than apurinic sites. Carcinogenesis, 20(10), 1885-91. [23] Lockwood, M. (1989). Mind, Brain and the Quantum. Oxford: B. Blackwell. [24] Patri, M., Padmini, A., Babu, P. P. (2009). Polycyclic aromatic hydrocarbons in air and their neurotoxic potency in association with oxidative stress: A brief perspective. Annals of Neurosciences, Volume 16, Issue 1. [25] Benson, J. M., Shepherd, D. M. (2011). Dietary ligands of the aryl hydrocarbon receptor induce anti-inflammatory and immunoregulatory effects on murine dendritic cells. Toxicol Sci, 124(2), 327-38. [26] Kerkvliet, N.I. (2011). TCDD: An Environmental Immunotoxicant Reveals a Novel Pathway of Immunoregulation-A 30-Year Odyssey. Toxicol Pathol, [Epub ahead of print]. [27] Everett, C. J., Frithsen, I., Player, M. (2011). Relationship of polychlorinated biphenyls with type 2 diabetes and hypertension. J Environ Monit, 13, 241-251. [28] Brook, R. D., Franklin, B., Cascio, W., Hong, Y., Howard, G., Lipsett, M., Luepker, R, Mittleman, M., Samet, J., Smith, S. C. Jr, Tager, I. (2004). Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation, 109(21), 2655-71.

Chapter 7

Global Warming Induced Endosymbiontic Actinidic Archaeal Synthesis of Digoxin from Cholesterol Regulates Cellular Function and Contributes to Disease Pathology

88




89

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile, endogenous digoxin as well as organisms like phytoplasmas and viroids have been implicated in the etiology of these diseases.1-4 Endogenous digoxin has been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.4 The possibility of endogenous digoxin synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered.5-8 An actinide dependent shadow biosphere of archaea in the above mentioned disease states is described.7, 9

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10 Aliquots were withdrawn at zero time immediately after mixing and after

90


incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420 and digoxin.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in tables 1-2 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time.


Table 1 Effect of rutile and antibiotics on cytochrome F420. CYT F420 % (Increase with Rutile)


Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

Schizo

23.24

2.01

58.72

7.08

Seizure

23.46

1.87

59.27

8.86

AD

23.12

2.00

56.90

6.94

MS

22.12

1.81

61.33

9.82

NHL

22.79

2.13

55.90

7.29

DM

22.59

1.86

57.05

8.45

AIDS

22.29

1.66

59.02

7.50

CJD

22.06

1.61

57.81

6.04

Autism

21.68

1.90

57.93

9.64

EMF

22.70

1.87

60.46

8.06

F value

306.749

130.054

P value

< 0.001

< 0.001

Group

Table 2 Effect of rutile and antibiotics on digoxin. Digoxin (ng/ml) (Increase with Rutile)

Digoxin (ng/ml) (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Normal

0.11

0.00

0.054

0.003

Schizo

0.55

0.06

0.219

0.043

Seizure

0.51

0.05

0.199

0.027

AD

0.55

0.03

0.192

0.040

MS

0.52

0.03

0.214

0.032

NHL

0.54

0.04

0.210

0.042

DM

0.47

0.04

0.202

0.025

AIDS

0.56

0.05

0.220

0.052

CJD

0.53

0.06

0.212

0.045

Autism

0.53

0.08

0.205

0.041

EMF

0.51

0.05

0.213

0.033

F value

135.116

71.706

P value

< 0.001

< 0.001

Group

91

92


Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15, 16 The archaeal beta hydroxyl steroid dehydrogenase activity indicating digoxin synthesis was increased. 8 The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.17 Archaeal digoxin induced redox stress can produce histone deacetylase inhibition resulting in endogenous retroviral (HERV) reverse transcriptase and integrase expression. Digoxin can cut and paste the HERV RNA by modulating RNA splicing generating RNA viroidal diversity.18 This can also integrate the HERV RNA complementary DNA into the noncoding region of eukaryotic non coding DNA using HERV integrase.19 The noncoding DNA is lengthened by integrating HERV RNA complementary DNA with the integration going on as a continuing event. The archaea genome can also get integrated into human genome using integrase as has been described for trypanosomes.20 The integrated archaea can undergo vertical transmission and can exist as genomic parasites.19, 20 This increases the length and alters the grammar of the noncoding region producing memes or memory of acquired characters as well as eukaryotic speciation and individuality.21 The HERV RNA complementary DNA can function as jumping genes producing a dynamic genome important in storage of synaptic information, HLA gene expression and developmental gene expression. The HERV RNA can regulate mrna function by RNA interference.18 The phenomena of RNA interference can modulate T cell and B cell function,


93

insulin signaling lipid metabolism, cell growth and differentiation, apoptosis, neuronal transmission and euchromatin / heterochromatin expression. The archaeal digoxin can regulate the nervous system including the NMDA/GABA perception.

4, 22

thalamocorticothalamic

pathway

mediating

conscious

NMDA/GABA receptors can be modulated by digoxin induced

calcium oscillations resulting NMDA/GAD activity induction.4 The dipolar PAH and archaeal magnetite in the setting of digoxin induced sodium potassium ATPase inhibition can produce a pumped phonon system mediated frohlich model superconducting state

22

inducing quantal perception with nanoarchaeal

sensed gravity producing the orchestrated reduction of the quantal possibilities to the macroscopic world.4, 22 The higher degree of integration of the archaea into the genome produces increased digoxin synthesis producing right hemispheric dominance and lesser degree producing left hemispheric dominance.4 The increased integration of archaea into the neuronal genome can produce

increased

digoxin

mediated

NMDA

transmission

producing

schizophrenia and autism. Digoxin induced calcium oscillations can activate NFKB producing immune activation and cytokine secretion. The archaeal digoxin induced chronic immune activation can lead on to autoimmune disease.23 Archaeal digoxin can induce the host AKT PI3K, AMPK, HIF alpha and NFKB producing the Warburg metabolic phenotype.24 There is induction of glycolysis, inhibition of PDH activity and mitochondrial dysfunction resulting in inefficient energetics and metabolic syndrome. The archaeal digoxin generated cytokines can lead to TNF alpha induced insulin resistance and metabolic syndrome x. Digoxin induced sodium potassium ATPase inhibition can lead to increase in HMG CoA reductase activity and increased cholesterol synthesis. The increased cholesterol substrate also leads to increased archaeal growth and digoxin synthesis due to metabolic channeling to the mevalonate pathway. Digoxin can produce sodium potassium ATPase inhibition and inward

94


movement of plasma membrane cholesterol. This produces defective SREBP sensing, increased HMG CoA reductase activity and cholesterol synthesis. The digoxin induced inward movement of plasma membrane cholesterol can alter membrane

cholesterol/sphingomyelin

ratio

producing

modified

lipid

microdomains. The digoxin induced lipid microdomain modulation can regulate the GPCR couple adrenaline, noradrenaline, glucagon and neuropeptide receptors as well as protein tyrosine kinase linked insulin receptor. The digoxin mediated inhibition of nuclear membrane sodium potassium ATPase can modulate nuclear membrane lipid microdomains and steroidal/thyroxine DNA receptor function. Thus endogenous digoxin can modulate all the endocrine receptors by regulating lipid microdomains. Hyperdigoxinemia is important in the pathogenesis of atherogenesis and metabolic syndrome x. Digoxin induced sodium potassium ATPase inhibition results in an ATP sparing effect. Eighty percent of the ATP generated is used to run the sodium potassium ATPase pump. The digoxin inhibition of the sodium potassium ATPase spares this ATP which is then used for lipid synthesis. Thus endogenous digoxin and the shadow biosphere generated Warburg phenotype can produce increased lipid synthesis and obesity important in metabolic syndrome x. Fat fuels insulin resistance by binding to the toll receptor and producing immune activation and immune infiltration of the adipose tissue. The archaeal digoxin induced monocyte activation and Warburg phenotype induced increased cholesterol synthesis leads to atherogenesis. The Warburg phenotype induced increased mitochondrial PT pore hexokinase can lead on to malignant transformation. The digoxin induced increased intracellular calcium can lead to PT pore dysfunction, cell death and neuronal degeneration.4 The digoxin mediated transcribed HERV RNA can get encapsulated in microvesicles contributing to the retroviral state. The prion protein conformation is modulated by HERV RNA binding producing prion disease. The archaeal digoxin and rutile induced magnesium depletion can lead


95

MPS deposition and produce EMF, CCP, MNG and mucoid angiopathy.4 Thus the archaeal digoxin can produce neuro-immune-metabolic-endocrine-genetic integration. The increased archaeal cholesterol catabolism and digoxin secretion can lead to diverse pathological states of neuronal degeneration, metabolic syndrome x, autoimmune disease, malignancy and psychiatric disorders.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M.S., Somers, K., Kartha, C.C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249.

96


[10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [18] Tsagris E. M., de Alba, A. E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [19] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87. [20] Hecht M., Nitz, N., Araujo, P., Sousa, A., Rosa, A., Gomes, D. (2010). Genes from Chagas parasite can transfer to humans and be passed on to children. Inheritance of DNA Transferred from American Trypanosomes to Human Hosts, PLoS ONE, 5, 2-10.


97

[21] Flam F. (1994). Hints of a language in junk DNA, Science, 266, 1320. [22] Lockwood, M. (1989). Mind, Brain and the Quantum. Oxford: B. Blackwell. [23] Eberl M., Hintz, M., Reichenberg, A., Kollas, A., Wiesner, J., Jomaa, H. (2010). Microbial isoprenoid biosynthesis and human γδ T cell activation, FEBS Letters, 544(1), 4-10. [24] Wallace D. C. (2005). Mitochondria and Cancer: Warburg Addressed, Cold Spring Harbor Symposia on Quantitative Biology, 70, 363-374.

Chapter 8 Global Warming Induced Endosymbiotic Actinidic Archaeal Generation of Ammonia and Thiocyanate Regulates Cell/Neuro-ImmunoEndocrine System and Provides a Substrate for Archaeal Energetics

100




101

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Actinidic archaea has also been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration. Actinidic archaea use cholesterol as a carbon and energy source.1-9 Archaeal cholesterol catabolism mediated by archaeal cholesterol oxidase can produce cholesterol ring oxidation to generate pyruvate. Pyruvate is converted to glutamate by the enzyme serum glutamate pyruvate transaminase. The glutamate gets acted upon by glutamate dehydrogenase to generate ammonia. Archaeal urease can act upon urea generating ammonia and thiocyanate. Ammonia and thiocyanate serves the purpose of cellular and neuroimmune endocrine regulation. The archaea are ammonia oxidizing and can use ammonia for their energetics.The archaeal urease activity related ammonia and thiocyanate synthesis as well as cholesterol oxidase activity generating pyruvate and ammonia was studied in schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered

102


saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10 Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome

F420, hydrogen peroxide, pyruvate, ammonia, glutamate,

thiocyanate and urease activity.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in tables 1-4 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time. The results show increased archaeal urease activity generating ammonia and thiocyanate in the disease states. It also shows increased cholesterol ring oxidase activity generating pyruvate. The pyruvate is converted by SGPT to glutamate. Glutamate dehydrogenase converts glutamate to ammonia. There is generation of ammonia by archaeal urease and cholesterol oxidase activity.


103

Table 1 Effect of rutile and antibiotics on cytochrome F420. Group Normal Schizo Seizure AD MS NHL DM AIDS CJD Autism EMF F value P value

CYT F420 % (Increase with Rutile) Mean ±SD 4.48 0.15 23.24 2.01 23.46 1.87 23.12 2.00 22.12 1.81 22.79 2.13 22.59 1.86 22.29 1.66 22.06 1.61 21.68 1.90 22.70 1.87 306.749 < 0.001

CYT F420 % (Decrease with Doxy+Cipro) Mean ±SD 18.24 0.66 58.72 7.08 59.27 8.86 56.90 6.94 61.33 9.82 55.90 7.29 57.05 8.45 59.02 7.50 57.81 6.04 57.93 9.64 60.46 8.06 130.054 < 0.001

Table 2 Effect of rutile and antibiotics on pyruvate and glutamate.


Pyruvate % change (Increase with Rutile) Mean ±SD 4.34 0.21 20.99 1.46 20.94 1.54 22.63 0.88 21.59 1.23 21.19 1.61 20.67 1.38 21.21 2.36 21.07 1.79 21.91 1.71 22.29 2.05 321.255 < 0.001

Pyruvate % change (Decrease with Doxy+Cipro) Mean ±SD 18.43 0.82 61.23 9.73 62.76 8.52 56.40 8.59 60.28 9.22 58.57 7.47 58.75 8.12 58.73 8.10 63.90 7.13 58.45 6.66 62.37 5.05 115.242 < 0.001

Glutamate (Increase with Rutile) Mean ±SD 4.21 0.16 23.01 2.61 23.33 1.79 22.96 2.12 22.81 1.91 22.53 2.41 23.23 1.88 21.11 2.25 22.47 2.17 22.88 1.87 21.66 1.94 292.065 < 0.001

Glutamate (Decrease with Doxy+Cipro) Mean ±SD 18.56 0.76 65.87 5.27 62.50 5.56 65.11 5.91 63.47 5.81 64.29 5.44 65.11 5.14 64.20 5.38 65.97 4.62 65.45 5.08 67.03 5.97 317.966 < 0.001

104



Group



Ammonia % (Increase with Rutile) Mean ±SD

Ammonia % (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

Schizo

22.50

1.66

60.21

7.42

22.52

1.90

66.39

4.20

Seizure

23.81

1.19

61.08

7.38

22.83

1.90

67.23

3.45

AD

22.65

2.48

60.19

6.98

23.67

1.68

66.50

3.58

MS

21.14

1.20

60.53

4.70

22.38

1.79

67.10

3.82

NHL

23.35

1.76

59.17

3.33

23.34

1.75

66.80

3.43

DM

23.27

1.53

58.91

6.09

22.87

1.84

66.31

3.68

AIDS

23.32

1.71

63.15

7.62

23.45

1.79

66.32

3.63

CJD

22.86

1.91

63.66

6.88

23.17

1.88

68.53

2.65

Autism

23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

EMF

23.29

1.67

60.52

5.38

22.29

2.05

61.91

7.56

F value

380.721

171.228

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 4 Effect of rutile and antibiotics on archaeal urease and thiocyanate.

Group

Thiocyanate % (Increase with Rutile) Mean ±SD

Thiocyanate % (Decrease with Doxy+Cipro) Mean ±SD

Archaeal urease (Increase with Rutile) Mean ±SD

Archaeal urease (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.40

0.10

18.48

0.39

4.45

0.14

18.25

0.72

Schizo

22.52

1.90

66.39

4.20

23.01

1.69

59.49

4.30

Seizure

22.83

1.90

67.23

3.45

22.67

2.29

57.69

5.29

AD

23.67

1.68

66.50

3.58

23.26

1.53

60.91

7.59

MS

22.38

1.79

67.10

3.82

22.83

1.78

59.84

7.62

NHL

23.34

1.75

66.80

3.43

22.84

1.42

66.07

3.78

DM

22.87

1.84

66.31

3.68

23.40

1.55

65.77

5.27

AIDS

23.45

1.79

66.32

3.63

23.23

1.97

65.89

5.05

CJD

23.17

1.88

68.53

2.65

23.46

1.91

61.56

4.61

Autism

23.20

1.57

66.65

4.26

22.61

1.42

64.48

6.90

EMF

22.29

2.05

61.91

7.56

23.73

1.38

65.20

6.20

F value

372.716

556.411

391.318

257.996

P value

< 0.001

< 0.001

< 0.001

< 0.001


105

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 14-16 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.14-16 The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide.14-16 The pyruvate gets converted to glutamate by serum glutamate pyruvate transaminase. Glutamate is acted upon by glutamate dehydrogenase generating alpha ketoglutarate and ammonia. The archaeal urease acts upon urea as the substrate and generates thiocyanate and ammonia. The archaeal urease and cholesterol oxidase are actinide dependent and activated by rutile. They are suppressed by antibiotics. Ammonia and thiocyanate serves the purpose of cellular and neuro-immuno-endocrine regulation. The archaea are ammonia oxidizing and can use ammonia for their energetics. The archaeal ammonia can regulate brain function. The ammonia can function as a synaptic gasotransmitter. Ammonia can stimulate GABA receptors at high levels and NMDA receptors at low levels. Thus ammonia has a biphasic action in that it can modulate both GABA and NMDA receptors. Thus ammonia can regulate the NMDA/GABA thalamo-cortico-thalamic pathway mediating conscious perception. Ammonia is involved in the pathogenesis of schizophrenia and mood disorders. Ammonia can stimulate membrane sodium potassium ATPase activity. Membrane sodium potassium ATPase when stimulated leads to decrease in intracellular calcium and increase in intracellular magnesium resulting in modulation of multiple neurotransmitter systems. The neurotransmitter release from the presynaptic vesicles is calcium dependent.17-20

106


Membrane sodium potassium ATPase uses 80 percent of the mitochondrial synthesized ATP. Elevated ammonia levels results in a hyperactive membrane sodium potassium ATPase and exhausts all ATP reserves. The mitochondria get fatigued leading on to mitochondrial dysfunction. Ammonia can open the mitochondrial permeability transient, produce cytochrome C release and activate the caspase cascade. Cyanide ion released by urease action can produce cytochrome C oxidase inhibition and mitochondrial dysfunction. Mitochondrial dysfunction can lead onto neuoronal degeneration.17-20 Ammonia inhibits insulin release from beta cells contributing to the diabetic state. The hyperactive membrane sodium potassium ATPase due to increased ammonia levels produces increased ATP usage and mitochondrial fatigue. The mitochondrial PT pore opening produce by ammonia and related mitochondrial dysfunction leads onto inefficient energetics and metabolic syndrome x. The archaeal urease activity generates the thiocyanate ion from urea. Cyanide inhibits mitochondrial cytochrome C oxidase and produces mitochondrial dysfunction. Cyanide toxicity has been related to mucoid angiopathy implicated in coronary artery disease and strokes. Cyanide toxicity leads to pancreatic dysfunction and diabetes mellitus manifesting as chronic calcific pancreatitis. Cyanide toxicity can also lead to multinodular goiter and endomyocardial fibrosis. Thus the generation of thiocyanate from urea by the activity of archaeal urease can contribute to a cardiac endocrine syndrome. Thiocyanate can also modulate protein function and structure by binding to proteins. This produces thiocynalation of proteins. Thus thiocyanate can modulate cell function. 18-23 Ammonia can function as a mutagen and contribute to alteration in DNA function. Ammonia can also modulate immune function. It can alter T cell and B cell function. Ammonia can be immunostimulatory or immunosuppressive


107

depending on its levels. Ammonia can contribute to the genesis of autoimmune disease.24-26 Ammonia can also produce cell proliferation and oncogenic transformation as exemplified in gastric carcinoma and hepatomas. During autophagy, portions of the cytoplasm are sequestered into autophagosomes and digested by lysosomal hydrolases. Massive autophagy can be induced in mammalian tissues in a coordinated fashion through nutrient deprivation, which has prompted the search of soluble metabolites that can stimulate autophagy. Ammonia, which is generated as a by-product of glutaminolysis, has been identified as a diffusible factor that stimulates autophagy. Intriguingly, cancer cells increase the rate glutaminolysis and the interstitial fluid of cancers contains

higher-than-normal

physiological

concentrations

of

ammonia,

suggesting a previously unknown pathway through which tumor cells can condition their microenvironment.27, 28 Thus ammonia and thiocyanate produced by endosymbiotic archaeal metabolism modulate neural transmission, metabolic/mitochondrial function, immunity, cell death, cell proliferation and endocrine/pancreatic function. Thus the archaea can use ammonia as a signaling molecule to produce neuro-immune-metabolic-endocrine integration. The archaea are ammonia oxidizing and can use ammonia for their energetics.29 The archaeal utilization of ammonia as a signalling molecule and for energetics may be a remnant of ammonia based primitive archaeal life forms and metabolism. Liquid ammonia can replace water as a solvent for life to originate.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press.

108


[3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84.


109

[16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Jones EA. (2002). Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy. Metab Brain Dis. 17(4), 275-81. [18] Veauvy CM, Wang Y, Walsh PJ, Pérez-Pinzón MA. (2002). Comparison of the effects of ammonia on brain mitochondrial function in rats and gulf toadfish. Am J Physiol Regul Integr Comp Physiol. 283(3), R598-603. [19] Norenberg MD, Rama Rao KV, Jayakumar AR. (2004) Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr, 36(4): 303-7. [20] Xue Z, Li B, Gu L, Hu X, Li M, Butterworth RF, Peng L. (2010). Increased Na, K-ATPase alpha2 isoform gene expression by ammonia in astrocytes and in brain in vivo. Neurochem Int., 57(4): 395-403. [21] Wu J., Wu G., Wu L. (2008). Thiocyanation of Aromatic and Heteroaromatic Compounds Using Ammonium Thiocyanate and I2O5. ChemInform, 39 (51). [22] Jensen P., Wilson M. T., Aasa R., Malmström B. G. (1984). Cyanide inhibition of cytochrome c oxidase. A rapid-freeze e.p.r. investigation. Biochem J, 224(3), 829-837. [23] Emmanuel B., Thompson J. R., Christopherson R. J., Milligan L. P., Berzins, R. (1982). Interrelationships between urea, ammonia, glucose, insulin and adrenaline during ammonia-urea toxicosis in sheep (Ovis aries). Comparative Biochemistry and Physiology Part A: Physiology, 72(4), 697-702. [24] Liu, C. H., Chen, J. C. (2004). Effect of ammonia on the immune response of white shrimpLitopenaeus vannamei and its susceptibility to Vibrio alginolyticus. Fish & Shellfish Immunology, 16(3), 321-334. [25] Cheng W., Hsiao I. S., Chen J. C. (2004). Effect of ammonia on the immune response of Taiwan abalone Haliotis diversicolor supertexta and its susceptibility to Vibrio parahaemolyticus. Fish & Shellﬁsh Immunology, 17, 193e20.

110


[26] von Borell E, Özpinar A, Eslinger KM, et al. (2007). Acute and prolonged effects of ammonia on hematological variables, stress responses, performance, and behavior of nursery pigs. J Swine Health Prod, 15(3), 137-145. [27] Mariño G., Kroemer G. (2010). Ammonia: A Diffusible Factor Released by Proliferating Cells That Induces Autophagy. Sci. Signal. 3, pe19. [28] Tsujii M, Kawano S, Tsuji S, Takei Y, Tamura K, Fusamoto H, Kamada T. (1995). Mechanism for ammonia-induced promotion of gastric carcinogenesis in rats. Carcinogenesis, 16(3), 563-6. [29] You J., Das A., Dolan E. M., Hu, Z. (2009). Ammonia-oxidizing archaea involved in nitrogen removal. Water Research, 43(7), 1801-1809.

Chapter 9

Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Pyruvate from Cholesterol and the GABA Shunt Pathway Regulates Cell Function

112




113

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile, endogenous digoxin as well as organisms like phytoplasmas and viroids have been implicated in the etiology of these diseases.1-4 Cholesterol catabolism has been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.4 The possibility of cholesterol catabolism synthesis by actinide based primitive organism like archaea generating pyruvate and its subsequent channelling to the GABA shunt pathway was evaluated in these disease states.5-8 An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described.7, 9

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10

114


Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420, hydrogen peroxide, pyruvate, ammonia and glutamate.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.



Table 1 Effect of rutile and antibiotics on cytochrome F420. Group

CYT F420 % (Increase with Rutile) Mean ±SD

CYT F420 % (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.48

0.15

18.24

0.66

Schizo

23.24

2.01

58.72

7.08

Seizure

23.46

1.87

59.27

8.86

AD

23.12

2.00

56.90

6.94

MS

22.12

1.81

61.33

9.82

NHL

22.79

2.13

55.90

7.29

DM

22.59

1.86

57.05

8.45

AIDS

22.29

1.66

59.02

7.50

CJD

22.06

1.61

57.81

6.04

Autism

21.68

1.90

57.93

9.64

EMF

22.70

1.87

60.46

8.06

F value

306.749

130.054

P value

< 0.001

< 0.001

Table 2 Effect of rutile and antibiotics on pyruvate and glutamate. Pyruvate % change Pyruvate % change Glutamate (Increase with (Decrease with (Increase with Rutile) Doxy+Cipro) Rutile)

Glutamate (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.34

0.21

18.43

0.82

4.21

0.16

18.56

0.76

Schizo

20.99

1.46

61.23

9.73

23.01

2.61

65.87

5.27

Seizure

20.94

1.54

62.76

8.52

23.33

1.79

62.50

5.56

AD

22.63

0.88

56.40

8.59

22.96

2.12

65.11

5.91

MS

21.59

1.23

60.28

9.22

22.81

1.91

63.47

5.81

NHL

21.19

1.61

58.57

7.47

22.53

2.41

64.29

5.44

DM

20.67

1.38

58.75

8.12

23.23

1.88

65.11

5.14

AIDS

21.21

2.36

58.73

8.10

21.11

2.25

64.20

5.38

CJD

21.07

1.79

63.90

7.13

22.47

2.17

65.97

4.62

Autism

21.91

1.71

58.45

6.66

22.88

1.87

65.45

5.08

EMF

22.29

2.05

62.37

5.05

21.66

1.94

67.03

5.97

F value

321.255

115.242

292.065

317.966

P value

< 0.001

< 0.001

< 0.001

e < 0.001

Group

115

116



Group

H2O2 % (Increase with Rutile)

H2O2 % (Decrease with Doxy+Cipro)

Ammonia % (Increase with Rutile)

Ammonia % (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

Schizo

22.50

1.66

60.21

7.42

22.52

1.90

66.39

4.20

Seizure

23.81

1.19

61.08

7.38

22.83

1.90

67.23

3.45

AD

22.65

2.48

60.19

6.98

23.67

1.68

66.50

3.58

MS

21.14

1.20

60.53

4.70

22.38

1.79

67.10

3.82

NHL

23.35

1.76

59.17

3.33

23.34

1.75

66.80

3.43

DM

23.27

1.53

58.91

6.09

22.87

1.84

66.31

3.68

AIDS

23.32

1.71

63.15

7.62

23.45

1.79

66.32

3.63

CJD

22.86

1.91

63.66

6.88

23.17

1.88

68.53

2.65

Autism

23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

EMF

23.29

1.67

60.52

5.38

22.29

2.05

61.91

7.56

F value

380.721

171.228

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15, 16 The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide.14 The pyruvate gets converted to glutamate by serum glutamate pyruvate transaminase. Glutamate is acted upon by glutamate dehydrogenase generating alpha ketoglutarate and ammonia. Glutamate can also enter the GABA shunt pathway. The glutamate is converted to GABA by the enzyme


117

glutamic acid decarboxylase. GABA is converted to succinic semialdehyde and then succinic acid. Succinic acid enters the TCA sequence. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.17 Archaeal pyruvate can produce histone deacetylase inhibition resulting in endogenous retroviral (HERV) reverse transcriptase and integrase expression. This can integrate the HERV RNA complementary DNA into the noncoding region of eukaryotic non coding DNA using HERV integrase as has been described for borna and ebola viruses.18, 19 The noncoding DNA is lengthened by integrating HERV RNA complementary DNA with the integration going on as a continuing event. The archaea genome can also get integrated into human genome using integrase as has been described for trypanosomes.20 The integrated HERV RNA complementary DNA and archaea can undergo vertical transmission and can exist as genomic parasites.19, 20 This increases the length and alters the grammar of the noncoding region producing memes or memory of acquired characters as well as eukaryotic speciation and individuality.21 The HERV RNA complementary DNA can function as jumping genes producing a dynamic genome important in storage of synaptic information, HLA gene expression and developmental gene expression. The RNA viroids can regulate mrna function by RNA interference.18 The phenomena of RNA interference can modulate T cell and B cell function, insulin signalling lipid metabolism, cell growth

and

differentiation,

apoptosis,

neuronal

transmission

and

euchromatin/heterochromatin expression. Thus archaeal pyruvate can modulate genomic transmission. The HERV RNA can get encapsulated in microvesicles contributing to the retroviral state. The prion protein conformation is modulated by HERV RNA binding producing prion disease.

118


Archaeal pyruvate can produce histone deacetylase inhibition which is cytoprotective. Archaeal pyruvate can also function as a free radical scavenger. Archaeal pyruvate can protect against neuronal degeneration. The glutamate generated from pyruvate can produce glutamate excitotoxicity and neuronal degeneration.

The

ammonia

generated

by

the

action

of

glutamate

dehydrogenase has got multiple actions. The ammonia increases sodium potassium ATPase activity which increases mitochondrial function, cell exhaustion and cell death. The ammonia has got a biphasic action in that it can stimulate the NMDA receptor producing glutamate excitotoxicity. Ammonia can therefore act as a gasotransmitter. The ammonia generated can play a role in neuronal degeneration. The archaea and viroids can regulate the nervous system including the NMDA/GABA perception.

4, 22


pathway

mediating

conscious

The cholesterol ring oxidase generated pyruvate can be

converted by the GABA shunt pathway to glutamate and GABA. The glutamate dehydrogenase generated ammonia can stimulate both the GABA and NMDA receptor acting as a gasotransmitter. The cholesterol ring oxidase generated H2O2 can increase NMDA transmission and activate GAD generating GABA. Thus the H2O2, ammonia, glutamate and GABA generated by pyruvate metabolism can modulate the thalamo-cortico-thalamic pathway. The dipolar archaeal magnetite in the setting of cholesterol oxidase generated H2O2 and glutamate dehydrogenase generated ammonia induced sodium potassium ATPase inhibition can produce a pumped phonon system mediated frohlich model superconducting state22 inducing quantal perception with nanoarchaeal sensed gravity producing the orchestrated reduction of the quantal possibilities to the macrosopic world.4, 22 The archaeal pyruvate can get converted to acetyl CoA and acetyl choline. Acetyl choline is the principal neurotransmitter mediating memory and cognition. Acetyl choline is also the principal


119

parasympathetic neurotransmitter regulating the visceral system. The higher degree of integration of the archaea into the genome produces increased digoxin synthesis producing right hemispheric dominance and lesser degree producing left hemispheric dominance.4 The increased integration of archaea into the neuronal genome can produce increased cholesterol oxidase mediated NMDA transmission producing schizophrenia and autism. The archaeal pyruvate and alpha ketoglutarate generated by the action of GDH on glutamate can suppress NFKB producing immunosuppression and decrease in cytokine secretion. The succinate generated by the GABA shunt pathway can activate the immune system and increase cytokine secretion. Thus the

metabolites

immunosuppressive

pyruvate/alpha

ketoglutarate

and

immunostimulatory succinate has a regulatory role on the immune system. The disruption of metabolic balance between pyruvate/alpha ketoglutarate and succinate can lead to autoimmune disease. The ammonia generated by the action of GDH is immunosuppressive. The H2O2 generated by action of cholesterol oxidase can activate NFKB. Thus the gasotransmitters NH3 and H2O2 can also regulate the immune system.4, 23 The archaeal pyruvate can get converted to acetyl CoA and acetyl choline. Acetyl choline stimulates the vagal system which is immunosuppressive. Archaea pyruvate gets converted to glutamate. Glutamate gets acted upon by GDH to generate alpha ketoglutarate. Glutamate can enter the GABA shunt pathway generating succinate. Alpha ketoglutarate inhibits the transcription factor HIF alpha. Succinate stimulates the transcription factor HIF alpha. Activation of HIF alpha stimulates glycolysis, inhibits pyruvate dehydrogenase, stimulates heme oxygenase, stimulates VEGF and activates NOS. Thus the activation of HIF alpha by succinate generates the Warburg phenotype with increased glycolysis. This can lead to increased cell proliferation and malignant

120


transformation. The mitochondrial PT pore hexokinase is increased leading onto cell proliferation. The increase in glycolysis can activate glyceraldehyde 3 phosphate dehydrogenase which gets translocated to the nucleus after polyadenylation. This can produce nuclear cell death and neuronal degeneration. The increase in the glycolytic enzyme fructose 1,6 diphosphatase increases the pentose phosphate pathway. This generates NADPH which activates NOX. NOX activation is related to NMDA activation and glutamate excitotoxicity. This leads onto neuronal degeneration. The lymphocytes depend on glycolysis for its energy needs. The increase in glycolysis owing to the induction of Warburg phenotype can lead to immune activation. NOX activation consequent to the generation of the Warburg phenotype also activates the insulin receptor. Pyruvate and succinate can increase insulin secretion from the beta cells of the pancreas. Thus there is a hyperinsulinemic state leading on to metabolic syndrome x. Thus the induction of the Warburg phenotype by succinate generated via the GABA shunt pathway can lead to malignancy, autoimmune disease, metabolic syndrome x, neuropsychiatric disease and neuronal degeneration.24 The accumulated pyruvate enters the GABA shunt pathway and is converted to citrate which is acted upon by citrate lyase and converted to acetyl CoA, used for cholesterol synthesis.24 The pyruvate can be converted to glutamate and ammonia which is oxidised by archaea for energy needs. The increased cholesterol substrate leads to increased archaeal growth and digoxin synthesis leading to metabolic channeling to the mevalonate pathway. Thus there is also an increased cholesterol and lipid synthesis consequent to induction of the Warburg phenotype. The increase in cholesterol synthesis leads to more of archaeal growth.


121

Thus the archaeal cholesterol oxidase generated pyruvate can fuel the GABA shunt pathway generating the Warburg phenotype and contribute to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356.

122


[11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [18] Tsagris E. M., de Alba, A. E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [19] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87. [20] Hecht M., Nitz, N., Araujo, P., Sousa, A., Rosa, A., Gomes, D. (2010). Genes from Chagas parasite can transfer to humans and be passed on to children. Inheritance of DNA Transferred from American Trypanosomes to Human Hosts, PLoS ONE, 5, 2-10. [21] Flam F. (1994). Hints of a language in junk DNA, Science, 266, 1320. [22] Lockwood, M. (1989). Mind, Brain and the Quantum. Oxford: B. Blackwell.


123

[23] Eberl M., Hintz, M., Reichenberg, A., Kollas, A., Wiesner, J., Jomaa, H. (2010). Microbial isoprenoid biosynthesis and human γδ T cell activation, FEBS Letters, 544(1), 4-10. [24] Wallace D. C. (2005). Mitochondria and Cancer: Warburg Addressed, Cold Spring Harbor Symposia on Quantitative Biology, 70, 363-374.

Chapter 10

Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Short Chain Fatty Acid Butyrate and Propionate from Cholesterol Regulates Cellular Function

126




127

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile as well as organisms like phytoplasmas and viroids have been implicated in the etiology of these diseases.1-4 Short chain fatty acids butyrate and propionate has been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.4 The actinidic archaea by cholesterol side chain oxidation generates butyrate and propionate which can regulate immune, metabolic, neural and genomic function. The possibility of short chain fatty acids butyrate and propionate synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered in this study.5-8

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10

128


Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420, butyrate and propionate.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Butyrate and propionate were estimated by HPLC method. Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.



129

Table 1 Effect of rutile and antibiotics on cytochrome F420. Group



Normal

4.48

0.15

18.24

0.66

Schizo

23.24

2.01

58.72

7.08

Seizure

23.46

1.87

59.27

8.86

AD

23.12

2.00

56.90

6.94

MS

22.12

1.81

61.33

9.82

NHL

22.79

2.13

55.90

7.29

DM

22.59

1.86

57.05

8.45

AIDS

22.29

1.66

59.02

7.50

CJD

22.06

1.61

57.81

6.04

Autism

21.68

1.90

57.93

9.64

EMF

22.70

1.87

60.46

8.06

F value

306.749

130.054

P value

< 0.001

< 0.001

Table 2 Effect of rutile and antibiotics on butyrate and propionate generation from cholesterol.

Group

Butyrate% change (Increase with Rutile) Mean ±SD

Butyrate% change (Decrease with Doxy+Cipro) Mean ±SD

Propionate % change (Increase with Rutile) Mean ±SD

Propionate % change (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

Schizo

22.50

1.66

60.21

7.42

22.52

1.90

66.39

4.20

Seizure

23.81

1.19

61.08

7.38

22.83

1.90

67.23

3.45

AD

22.65

2.48

60.19

6.98

23.67

1.68

66.50

3.58

MS

21.14

1.20

60.53

4.70

22.38

1.79

67.10

3.82

NHL

23.35

1.76

59.17

3.33

23.34

1.75

66.80

3.43

DM

23.27

1.53

58.91

6.09

22.87

1.84

66.31

3.68

AIDS

23.32

1.71

63.15

7.62

23.45

1.79

66.32

3.63

CJD

22.86

1.91

63.66

6.88

23.17

1.88

68.53

2.65

Autism

23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

EMF

23.29

1.67

60.52

5.38

22.29

2.05

61.91

7.56

F value

380.721

171.228

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001

130


Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15, 16 There was an increase in cholesterol side chain oxidation by actinidic archaea. This is indicated by the presence of increasing butyrate and propionate in the system. The cholesterol side chain oxidation generating butyrate and propionate is inhibited by antibiotics and stimulated by rutile. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.17 Archaeal butyrate can produce histone deacetylase inhibition resulting in endogenous retroviral (HERV) reverse transcriptase and integrase expression. This can integrate the HERV RNA complementary DNA into the noncoding region of eukaryotic noncoding DNA using HERV integrase as has been described for borna and ebola viruses.19 The noncoding DNA is lengthened by integrating HERV RNA complementary DNA with the integration going on as a continuing event. The archaea genome can also get integrated into human genome using integrase as has been described for trypanosomes.20 The integrated archaea can undergo vertical transmission and can exist as genomic parasites.19,20 This increases the length and alters the grammar of the noncoding region producing memes or memory of acquired characters as well as eukaryotic speciation and individuality.21 The HERV RNA complementary DNA can function as jumping genes producing a dynamic genome important in storage of synaptic information, HLA gene expression and developmental gene expression. The HERV RNA can regulate mRNA function by RNA


131

interference.18 The phenomena of RNA interference can modulate T cell and B cell function, insulin signaling lipid metabolism, cell growth and differentiation, apoptosis, neuronal transmission and euchromatin / heterochromatin expression. Butyrate and propionate are histone deacetylase inhibitors. HDAC inhibitors like butyrate can inhibit cell proliferation. Butyrate is used in the treatment of several malignant neoplasms. Butyrate can also modulate protein folding and function. Butyrate can correct the unfolded protein response. Butyrate is thus used in the treatment of disorders with unfolded protein response. This includes disorders like neuronal degeneration and trinucleotide repeat disease. Butyrate by modulating protein folding is of use in the management of metabolic syndrome x and insulin resistance syndromes. Butyrate and propionate can bind to lymphocyte GPCR receptors. Butyrate and propionate is immunosuppressive and is used in the treatment of autoimmune disease. Archaeal butyrate and propionate deficiency can lead to immune activation and autoimmune disease. Butyrate can be convered to the inhibitory gamma aminobutyric acid or GABA or the excitatory beta hydroxybutyric acid. Thus butyric acid metabolites can regulate the NMDA/GABA thalamocorticothalamic pathway mediating conscious perception. Butyrate coma has been described. Butyrate can also modulate gene expression related to multiple neurotransmitter systems. Butyrate and propionate are involved in the genesis of neuropsychiatric disorders. Intraventricular propionate has been related to autism and schizophrenia.22-28 Thus short chain fatty acids butyrate and propionate can regulate cell death and cell proliferation through modulation of unfold protein response and HDAC inhibition. It can regulate the insulin receptor and protein function by

132


modulating protein folding. Butyrate and propionate via binding to lymphocyte GPCR receptors can regulate immune function. Butyrate can also modulate several neurotransmitter systems including NMDA/GABA. Butyrate by producing HDAC inhibition can regulate gene expression. Thus the archaeal short chain fatty acids butyrate and propionate generated by cholesterol side chain oxidation can regulate the neuro-immune-genetic-endocrine-metabolic system as well as the cell cycle. The archaeal short chain fatty acids may play a role in the pathogenesis of malignancy, degenerations, metabolic syndrome x, autoimmune disease and neuropsychiatric disorders.22-28

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448.


133

[9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [18] Tsagris E. M., de Alba, A. E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [19] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87.

134


[20] Hecht M., Nitz, N., Araujo, P., Sousa, A., Rosa, A., Gomes, D. (2010). Genes from Chagas parasite can transfer to humans and be passed on to children. Inheritance of DNA Transferred from American Trypanosomes to Human Hosts, PLoS ONE, 5, 2-10. [21] Flam F. (1994). Hints of a language in junk DNA, Science, 266, 1320. [22] Meijer, K., de Vos P., Priebe M.G. (2010) Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin Nutr Metab Care, 13(6), 715-21. [23] Chakravortty, D., Koide, N., Kato, Y., Sugiyama, T., Mu, M. M., Yoshida, T., Yokochi T. (2000). The inhibitory action of butyrate on lipopolysaccharide-induced nitric oxide production in RAW 264.7 murine macrophage cells. J Endotoxin Res, 6(3), 243-7. [24] Marks, P. A., Jiang, X. (2005). Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle, 4, 549-551. [25] Insinga, A., Monestiroli, S., Ronzoni, S., Gelmetti, V., Marchesi, F., Viale, A., Altucci, L., Nervi, C., Minucci, S., Pelicci, P. G. (2005). Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med, 11, 71-76. [26] Yam, G. H., Gaplovska-Kysela, K., Zuber, C., Roth, J. (2007). Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilin to rescue cells from endoplasmic reticulum stress and apoptosis. Invest Ophthalmol Vis Sci, 48(4), 1683-90. [27] Kim, P. S., Arvan, P. (1998). Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones. Endocr Rev, 19(2), 173-202. [28] Reger, M. A., Henderson, S. T., Hale, C., Cholerton, B., Baker, L. D. (2004). Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiology of Aging, 25(3), 311-314.

Chapter 11

Global Warming Induced Endosymbiotic Actinidic Archaeal Synthesis of Neurotransmitters by Cholesterol Catabolism Regulates Brain Function

136




137

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis (EMF) along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile as well as organisms like phytoplasmas and viroids have been implicated in the etiology of EMF.1-4 Bacterial synthesis of neurotransmitters plays a role in quorum sensing and motility. The possibility of endogenous neurotransmitter synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered in EMF and systemic diseases like neuoronal degeneration, psychiatric disease, metabolic syndrome x, autoimmune disease and malignancy.5-8 An actinide dependent shadow biosphere of archaea in the above mentioned disease states is described.7, 9


138


incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420, dopamine, serotonin, noradrenaline, acetyl choline and glutamate.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). The statistical analysis was done by ANOVA.



139

Table 1 Effect of rutile and antibiotics on cytochrome F420 and glutamate.

Group



Glutamate% change (Increase with Rutile) Mean ±SD

Glutamate% change (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.48

0.15

18.24

0.66

4.34

0.21

18.43

0.82

Schizo

23.24

2.01

58.72

7.08

20.99

1.46

61.23

9.73

Seizure

23.46

1.87

59.27

8.86

20.94

1.54

62.76

8.52

AD

23.12

2.00

56.90

6.94

22.63

0.88

56.40

8.59

MS

22.12

1.81

61.33

9.82

21.59

1.23

60.28

9.22

NHL

22.79

2.13

55.90

7.29

21.19

1.61

58.57

7.47

DM

22.59

1.86

57.05

8.45

20.67

1.38

58.75

8.12

AIDS

22.29

1.66

59.02

7.50

21.21

2.36

58.73

8.10

CJD

22.06

1.61

57.81

6.04

21.07

1.79

63.90

7.13

Autism

21.68

1.90

57.93

9.64

21.91

1.71

58.45

6.66

EMF

22.70

1.87

60.46

8.06

22.29

2.05

62.37

5.05

F value

306.749

130.054

321.255

115.242

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 2 Effect of rutile and antibiotics on noradrenaline and acetyl choline.

Group

Noradrenaline % (Increase with Rutile) Mean ±SD

Noradrenaline % (Decrease with Doxy+Cipro) Mean ±SD

Acetyl choline % (Increase with Rutile) Mean ±SD

Acetyl choline % (Decrease with Doxy+Cipro) Mean ±SD

Normal

4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

Schizo

22.50

1.66

60.21

7.42

22.52

1.90

66.39

4.20

Seizure

23.81

1.19

61.08

7.38

22.83

1.90

67.23

3.45

AD

22.65

2.48

60.19

6.98

23.67

1.68

66.50

3.58

MS

21.14

1.20

60.53

4.70

22.38

1.79

67.10

3.82

NHL

23.35

1.76

59.17

3.33

23.34

1.75

66.80

3.43

DM

23.27

1.53

58.91

6.09

22.87

1.84

66.31

3.68

AIDS

23.32

1.71

63.15

7.62

23.45

1.79

66.32

3.63

CJD

22.86

1.91

63.66

6.88

23.17

1.88

68.53

2.65

Autism

23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

EMF

23.29

1.67

60.52

5.38

22.29

2.05

61.91

7.56

F value

380.721

171.228

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001

140


Table 3 Effect of rutile and antibiotics on dopamine and serotonin.

Group

DOPAMINE % (Increase with Rutile)

DOPAMINE % (Decrease with Doxy+Cipro)

5 HT % change (Increase with Rutile)

5 HT % change (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.41

0.15

18.63

0.12

4.34

0.15

18.24

0.37

Schizo

21.88

1.19

66.28

3.60

23.02

1.65

67.61

2.77

Seizure

22.29

1.33

65.38

3.62

22.13

2.14

66.26

3.93

AD

23.66

1.67

65.97

3.36

23.09

1.81

65.86

4.27

MS

22.92

2.14

67.54

3.65

21.93

2.29

63.70

5.63

NHL

23.81

1.90

66.95

3.67

23.12

1.71

65.12

5.58

DM

24.10

1.61

65.78

4.43

22.73

2.46

65.87

4.35

AIDS

23.43

1.57

66.30

3.57

22.98

1.50

65.13

4.87

CJD

23.70

1.75

68.06

3.52

23.81

1.49

64.89

6.01

Autism

22.76

2.20

67.63

3.52

22.79

2.20

64.26

6.02

EMF

22.28

1.52

64.05

2.79

22.82

1.56

64.61

4.95

F value

403.394

680.284

348.867

364.999

P value

< 0.001

< 0.001

< 0.001

< 0.001

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15 The archaeal cholesterol oxidase activity results in generation of pyruvate.14 The pyruvate gets converted to glutamate and GABA by the GABA shunt pathway. The pyruvate generated by cholesterol oxidase activity can also get converted to acetyl CoA and acetyl choline. The archaeal aromatization of cholesterol generating norepinephrine,


141

serotonin and dopamine was also detected.16 The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.17 The archaea and viroids can regulate the nervous system including the NMDA/GABA perception.

4, 18


pathway

mediating

conscious

NMDA/GABA receptors can be modulated by cholesterol

catabolism generated glutamate and GABA. The archaea can regulate limbic lobe transmission with archaeal cholesterol aromatase/ring oxidase generated norepinephrine, dopamine, serotonin and acetyl choline.16 The increased integration of archaea into the neuronal genome can produce increased cholesterol oxidase and aromatase mediated monoamine and NMDA transmission producing schizophrenia and autism. The archaeal cholesterol catabolism generated glutamate can produce NMDA excitotoxicity producing neuronal degeneration. The archaeal glutamate and GABA synthesis can play a role in neurodegeneration, autism and schizophrenia. Archaeal cholesterol catabolism generated glutamate and serotonin can produce immune activation and acetyl choline can produce immunosuppression. The

balance

between

the

two

sets

of

immunostimulatory

and

immunosuppressive neurotransmitters can contribute to autoimmune disease. Parasympathetic neuropathy and vagal blockade can lead to autoimmune disease. Immunity is regulated by the vagal reflex. Archaeal cholesterol catabolism generated glutamate and GABA can regulate insulin secretion from the pancreatic beta cells contributing to metabolic syndrome x. Metabolic syndrome x has been attributed to alteration in the sympathetic/parasympathetic balance. There is vagal suppression and sympathetic overactivity. This produces hyperinsulinism, immune activation and metabolic syndrome x. Sympathetic overactivity and vagal blockade can lead to vasospasm, microangiopathy and vascular disease. Sympathetic overactivity and parasympathetic blockade can

142


produce malignant cell proliferation. The Warburg phenotype can be induced by vagal blockade induced immune activation.19 Thus the archaeal synthesis of acetyl choline and catecholamines can regulate the sympathetic and parasympathetic nervous system contributing to metabolic syndrome x, autoimmune disease and malignancy. The archaeal neurotransmitters may control the human nervous system regulating visceral functions and consciousness.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C.E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249.


143

[10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [18] Lockwood, M. (1989). Mind, Brain and the Quantum. Oxford: B. Blackwell. [19] Wallace D. C. (2005). Mitochondria and Cancer: Warburg Addressed, Cold Spring Harbor Symposia on Quantitative Biology, 70, 363-374.

Chapter 12

Global Warming Induced Membrane Sodium Potassium ATPase Inhibition Mediated ATP Synthesis Induced by Digoxin, Photoinduction and Electromagnetic Fields

146




147

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endogenous digoxin, exposure to sunlight and electromagnetic fields can produce membrane sodium potassium ATPase inhibition. Membrane sodium potassium ATPase in the setting of digoxin, photic and electromagnetic field induced inhibition can synthesize ATP. The cellular membrane sodium potassium ATPase mediated synthesis of ATP in response to sunlight, electromagnetic fields and endogenous digoxin induced sodium potassium ATPase inhibition can serve as a nonmitochondrial source of ATP for the purpose of cellular metabolism. The membrane sodium potassium ATPase mediated ATP synthesis can serve as a source for cellular energetics.1 This was studied and reported in this paper.

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. The experimental protocol for the study of membrane sodium potassium ATPase mediated ATP sysnthesis was as follows. Reagents:

148


Phosphate buffer: A) NaH2PO4 0.15 M B) K2HPO4 0.15 M Reagent C) Mix 24ml of A + 76ml B. Adjust the pH to 7.2 Reagent D) Mix equal volume of reagent C + normal saline MgSO4 0.0138 M ADP Na salt 0.0125 M Procedure: Citrated blood 5 ml. Separate the RBC by centrifugation at 1300 rpm at 4°C. Wash with normal saline till supernatant is clear. Suspend the RBC in normal saline. Incubate the suspension at 37°C for 4 hours. Centrifuge and remove the supernatant and suspend the RBC in solution D containing MgSO4 + ADP. Reaction mixture: 1. Mix well allows the system to attain 37°C in a thermostatic water bath. 2. Withdraw an aliquot and deprotenise immediately with 0.8N perchloric acid and neutralize with 1N KOH and estimate the ATP in the supernatant. 3. Incubate the remaining mixture at 37°C for 1hr. Withdraw another aliquot and deprotenise immediately with 0.8 N perchloric acid and neutralize with 1 N KOH and estimate the ATP in the supernatant. Difference in the ATP content is the measure of ATP synthase activity. Three sets of protocols were used (1) Addition of digoxin at a concentration of 1 mg/ml (2) exposure to sunlight of the experimental setup for 1 hour


149

(3) exposure to low intensity electromagnetic field for 1 hour. ATP was estimated by the method described before.2-4 Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results The results of the study showed increased ATP synthesis by RBC membrane sodium potassium ATPase in the presence of added digoxin, exposure to sunlight and low intensity electromagnetic fields. The added digoxin, exposure to sunlight and low intensity electromagnetic fields produce sodium potassium ATPase inhibition. Membrane sodium potassium ATPase in its inhibited state can synthesize ATP. The results are expressed in table 1 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time. There was RBC membrane sodium potassium ATPase mediated ATP synthesis in the patients with schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration in the presence of added digoxin, exposure to sunlight and low intensity electromagnetic fields.

150


Table 1 Sodium potassium ATPase inhibition mediated membrane ATP synthesis. Digoxin induced ATP synthesis % change

Photoinduction induced ATP synthesis % change

EMF induced ATP synthesis % change

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.40

0.11

4.34

0.15

4.48

0.15

Schizo

23.67

1.42

23.81

1.49

22.06

1.61

Seizure

23.09

1.90

22.79

2.20

21.68

1.90

AD

23.58

2.08

22.82

1.56

22.70

1.87

MS

23.52

1.76

23.09

1.81

23.12

2.00

NHL

24.01

1.17

21.93

2.29

22.12

1.81

DM

23.72

1.73

23.02

1.65

23.24

2.01

AIDS

23.15

1.62

22.13

2.14

23.46

1.87

CJD

23.00

1.64

23.12

1.71

22.79

2.13

Autism

22.60

1.64

22.73

2.46

22.59

1.86

EMF

23.37

1.31

22.98

1.50

22.29

1.66

F value

449.503

348.867

306.749

P value

< 0.001

< 0.001

< 0.001

Group

Discussion Membrane sodium potassium ATPase primarily is involved in the generation of the membrane resting potential and the paroxysmal depolarization shift. Membrane sodium potassium ATPase when inhibited can serve as an enzyme mediating ATP synthesis. The membrane sodium potassium ATPase is also inhibited by digoxin, photoexposure and low intensity electromagnetic fields. The study demonstrates that digoxin induced membrane sodium potassium ATPase inhibition can induce membrane sodium potassium ATPase mediated ATP synthesis. Photic and electromagnetic induction of membrane sodium potassium ATPase mediated ATP synthesis is also demonstrated in the study in normal individuals as well as in pathological states.


151

ATP synthesis is usually a mitochondrial function and is subserved by mitochondrial oxidative phosphorylation. ATP synthesis is also mediated by anaerobic glycolysis. These are the two major recognized sources of ATP synthesis. Membrane sodium potassium ATPase is a ubiquitous enzyme and is present in all cell membranes. Membrane sodium potassium ATPase is also seen in organelle membranes especially nuclear membrane and endoplasmic reticular membranes. Membrane sodium potassium ATPase inhibition adds a new dimension to the enzymes function. Membrane sodium potassium ATPase is inhibited by endogenous digoxin, neurotransmitters like glutamate, sunlight, electric fields, magnetic fields and adrenergic hormones. Membrane sodium potassium ATPase when inhibited can catalyse ATP synthesis. Membrane sodium potassium ATPase mediated ATP synthesis in the presence of digoxin, sunlight and electric fields induced inhibition can be a major source of ATP and cellular energetics. The human body can use photoinduction of membrane sodium potassium ATPase inhibition mediated membrane ATP synthesis as a means of garnering solar energy for cellular metabolism. The electromagnetic fields induced membrane sodium potassium ATPase inhibition mediated ATP synthesis is a mechanism by which the human body can utilize electric and magnetic fields for cellular metabolism. The membrane sodium potassium ATPase inhibition mediated ATP synthesis may serve as a major source of cellular energetics. The sunlight induced photic induction of membrane sodium potassium ATPase inhibition mediated ATP synthesis may be a primitive source of cellular energy before the evolution of mitochondrial oxidative phosphorylation. The electromagnetic induction of membrane sodium potassium ATPase inhibition mediated ATP synthesis may also be a similar primitive source of cellular energy. The photic and electromagnetic inductin of membrane sodium potassium ATPase inhibition

152


related ATP synthesis still serves as a major source of cellular energetics despite the presence of mitochondrial oxidative phosphorylation and anaerobic glycolysis. The membrane sodium potassium ATPase inhibition mediated ATP synthesis is increased in pathological states like endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism,

seizure

disorder,

Creutzfeldt

Jakob

disease

and

acquired

immunodeficiency syndrome. This is due to the increased endogenous digoxin synthesis in these disease states. The endogenous digoxin is produced by symbiotic actindic archaea having a mevalonate pathway. The archaeal digoxin induced membrane sodium potassium ATPase inhibition mediated ATP synthesis may serve as a source of ATP for primitive endosymbiotic cellular archaeal cellular metabolism. This may be the major source of cellular energy for endosymbiotic actinidic archaea. Extracellular ATP produces immune activation, cell proliferation, excitatory neurotransmission and cell death contributing to pathological states. ATP is a neurotransmitter in the central and sympathetic nervous system. ATP is stored in and released from synaptic nerve terminals and is known to act postsynaptically via P2X receptors. It promotes calcium signalling. ATP is a co-transmitter

at

noradrenaline,

acetyl

choline

and

GABA

synapse.

Extracellular ATP can inhibit glutamate transmission. It can thus regulate the NMDA/GABA


pathway

mediating

conscious

perception. ATP functions as a fast excitatory neurotransmitter and is involved in the pathogenesis of schizophrenia. It also plays a role in the pathogenesis of depression.

Purinergic

receptors

regulate

cell

proliferation

and

cell

differentitation. They also play a role in organ development and regeneration.


153

Thus extracelluar ATP may play a role in oncogenesis. Extra cellular ATP and purinergic receptors can mediate cell death. They can initiate neurodegenerative process. They are important in the pathogenesis of Alzheimer’s disease and Parkinson’s disease. Extracellular ATP and purinergic receptors are involved in immune activation and can initiate autoimmune disease. 5’AMP is immunosuppressive, inhibits NFKB and reduces cytokine secretion. ATP is immunostimulatory, activates NFKB and promotes cytokine secretion. Thus the ectoATPases can regulate the 5’AMP/ATP ratio and regulate immune signaling. Extracellular ATP can modulate the response to bacterial and viral infection. Extracellular ATP is involved in the signaling pathway of HIV infection and are important cell fusion and HIV replication. Extracellular ATP and purinergic receptors are also involved in lipopolysaccharide signaling. The ectoATPase acts upon ATP to generate 5’AMP. 5’AMP activates 5’AMP activated protein kinase.

5'AMP-activated protein kinase

or

AMPK or 5' adenosine

monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells. The C. elegans homologue of AMPK, aak-2, has been shown by Ristow and colleagues to be required for extension of life span in states of glucose restriction mediating a process named mitohormesis. 5’AMP can reversibly inhibit mitochondrial oxidative phosphorylation and produce cell hibernation. Purinergic receptors are involved in regulating pancreatic insulin and glucagon secretion. Extracellular ATP may play a role in the development of metabolic syndrome x.5-13

154


References [1] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [2] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [3] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [4] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [5] Skaper S. D., Debetto P., Giusti P. (2010). The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J, 24(2), 337-45. [6] Burnstock G. (2008). Purinergic signalling and disorders of the central nervous system. Nature Reviews Drug Discovery, 7, 575-590. [7] White N., Burnstock, G. (2006). P2 receptors and cancer. Trends in Pharmacological Sciences, 27(4), 211-217. [8] Junger W. G. (2011). Immune cell regulation by autocrine purinergic signaling. Nature Reviews Immunology, 11, 201-212. [9] Séror C., Melki M. T., Subra F., Raza S. Q., Bras M., Saï di H., Nardacci R., Voisin L., Paoletti A., et al. (2011). Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. J Exp Med, 208(9), 1823-34. [10] Guerra A. N., Fisette P. L., Pfeiffer Z. A., Quinchia-Rios, B.H., Prabhu U., Aga M., Denlinger L. C., Guadarrama A. G., Abozeid S., Sommer J. A., Proctor R. A., Bertics P. J. (2003). Purinergic receptor regulation of LPS-induced signaling and pathophysiology. J Endotoxin Res. 9(4), 256-63. [11] Winder W. W., Hardie, D. G. (1999). AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol, 277 (1 Pt 1), E1-10. [12] Stapleton D., Mitchelhill, K. I., Gao G., Widmer J., Michell B. J., Teh T., House C. M., Fernandez C. S., Cox T., Witters L.A., Kemp B.E. (1996). Mammalian AMP-activated protein kinase subfamily. J Biol Chem, 271 (2), 611-4.


155

[13] Petit P., Loubatières-Mariani M. M., Keppens S., Sheehan, M. J. (1996). Purinergic receptors and metabolic function. Drug Development Research, 39(3-4), 413-425.

Chapter 13 Global Warming Induced Endosymbiotic Actinidic Archaeal Digoxin Inhibited Sodium Potassium ATPase Mediated ATP Synthesis and Archaeal Ectoatpases Produce Neuro-ImmunoMetabolic-Endrocrine/Cell Cycle Regulation

158




159

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Actinidic archaea has also been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration. Archaea have got ectoATPases. EctoATPases convert ATP to ADP and AMP. ATP functions as purinergic neurotransmitter regulating multiple cell functions. 5'AMP activates the metabolic gauge AMP kinase. Archaeal digoxin produces membrane sodium potassium ATPase inhibition. Membrane sodium potassium ATPase in the setting of digoxin induced inhibition can synthesize ATP. This ATP can serve as a substrate for ectoATPase. This ATP can serve as a substrate for ectoATPase and functions as an archaeal signalling molecule. The RBC membrane sodium potassium ATPase mediated ATP synthesis and archaeal ectoATPase activity was assessed in the above mentioned disorders.1-9

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of

160


1 mg/ml. Cholesterol substrate was prepared as described by Richmond.10 Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following three estimations were carried out: - Cytochrome F420 and ectoATPase activity. RBCs from the patient’s blood were separated within 1 hour of collection of blood and ATP synthesis activity was assessed in the presence of added digoxin to produce a concentration 12.2 ng/dl.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.

Results Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in tables 1-3 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time. There was RBC membrane sodium potassium ATPase mediated ATP synthesis and serum archaeal ectoATPase activity in the patients with schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.




Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

Schizo

23.24

2.01

58.72

7.08

Seizure

23.46

1.87

59.27

8.86

AD

23.12

2.00

56.90

6.94

MS

22.12

1.81

61.33

9.82

NHL

22.79

2.13

55.90

7.29

DM

22.59

1.86

57.05

8.45

AIDS

22.29

1.66

59.02

7.50

CJD

22.06

1.61

57.81

6.04

Autism

21.68

1.90

57.93

9.64

EMF

22.70

1.87

60.46

8.06

F value

306.749

130.054

P value

< 0.001

< 0.001

Group

Table 2 Effect of rutile and antibiotics on archaeal EctoATPase activity. EctoATPase activity % change (Increase with Rutile)

EctoATPase activity % change (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Normal

4.34

0.15

18.24

0.37

Schizo

23.02

1.65

67.61

2.77

Seizure

22.13

2.14

66.26

3.93

AD

23.09

1.81

65.86

4.27

MS

21.93

2.29

63.70

5.63

NHL

23.12

1.71

65.12

5.58

DM

22.73

2.46

65.87

4.35

AIDS

22.98

1.50

65.13

4.87

CJD

23.81

1.49

64.89

6.01

Autism

22.79

2.20

64.26

6.02

EMF

22.82

1.56

64.61

4.95

F value

348.867

364.999

P value

< 0.001

< 0.001

Group

161

162


Table 3 RBC membrane ATP synthesis in the presence of digoxin. Group

RBC membrane ATP synthesis % Mean

±SD

Normal

4.40

0.11

Schizo

23.67

1.42

Seizure

23.09

1.90

AD

23.58

2.08

MS

23.52

1.76

NHL

24.01

1.17

DM

23.72

1.73

AIDS

23.15

1.62

CJD

23.00

1.64

Autism

22.60

1.64

EMF

23.37

1.31

F value

449.503

P value

< 0.001

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source.14-16 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.14-16 There was increased actinide dependent ectoATPase activity. The ectoATPase activity was stimulated by rutile and inhibited by antibiotics. The ectoATPase can convert extracellular ATP into ADP and 5'AMP. There was also evidence of RBC membrane ATP synthesis mediated by digoxin inhibted RBC membrane sodium potassium ATPase. The membrane sodium potassium ATPase in the setting of digoxin mediated inhibition can synthesize ATP. This extracellular ATP serves as a


163

substrate for archaeal ectoATPases to generate AMP and ADP. The archaeal digoxin inhibits membrane sodium potassium ATPase and the inhibited enzyme synthesizes ATP which functions as a signaling molecule. The archaea regulates the neuro-immuno-metabolic-endocrine system using extracellular ATP. ATP is a neurotransmitter in the central and sympathetic nervous system. ATP is stored in and released from synaptic nerve terminals and is known to act postsynaptically via P2X receptors. It promotes calcium signalling. ATP is a cotransmitter at noradrenaline, acetyl choline and GABA synapse. Extracellular ATP can inhibit glutamate transmission. It can thus regulate the NMDA/GABA thalamo-cortico-thalamic pathway mediating conscious perception. ATP functions as a fast excitatory neurotransmitter and is involved in the pathogenesis of schizophrenia. It also plays a role in the pathogenesis of depression.17-18 Purinergic receptors regulate cell proliferation and cell differentitation. They also play a role in organ development and regeneration. Thus extracelluar ATP may play a role in oncogenesis. Extra cellular ATP and purinergic receptors can mediate cell death. They can initiate neurodegenerative process. They are important in the pathogenesis of Alzheimer’s disease and Parkinson’s disease.18, 19 Extracellular ATP and purinergic receptors are involved in immune activation and can initiate autoimmune disease. 5'AMP is immunosuppressive, inhibits NFKB and reduces cytokine secretion. ATP is immunostimulatory, activates NFKB and promotes cytokine secretion. Thus the ectoATPases can regulate the 5'AMP/ATP ratio and regulate immune signaling. Extracellular ATP can modulate the response to bacterial and viral infection. Extracellular ATP is involved in the signalling pathway of HIV infection and are important cell fusion and HIV replication. Extracellular ATP and purinergic receptors are also involved in lipopolysaccharide signalling.20-22

164


The ectoATPase acts upon ATP to generate 5'AMP. 5'AMP activates 5'AMP activated protein kinase. 5'AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells. The C. elegans homologue of AMPK, aak-2, has been shown by Ristow and colleagues to be required for extension of life span in states of glucose restriction mediating a process named mitohormesis. 5'AMP can reversibly inhibit mitochondrial oxidative phosphorylation and produce cell hibernation. Purinergic receptors are involved in regulating pancreatic insulin and glucagon secretion. Extracellular ATP may play a role in the development of metabolic syndrome x.23-25 Thus the archaeal digoxin can mediate sodium potassium ATPase mediated extracellular ATP synthesis. The extracellular ATP is an archaeal signalling molecule. The extracellular ATP gets acted upon by actinide dependent archaeal ectoATPases to generate ADP and AMP. ATP can act upon purinergic receptors regulating neurotransmission, cell death, cell proliferation, cell differentiation, immunity, endocrine function and metabolism. 5'AMP can activate AMPK the principal metabolic gauge of the body.

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335.


165

[2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52.

166


[15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Skaper S. D., Debetto P., Giusti P. (2010). The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J, 24(2), 337-45. [18] Burnstock G. (2008). Purinergic signalling and disorders of the central nervous system. Nature Reviews Drug Discovery, 7, 575-590. [19] White N., Burnstock, G. (2006). P2 receptors and cancer. Trends in Pharmacological Sciences, 27(4), 211-217. [20] Junger W.G. (2011). Immune cell regulation by autocrine purinergic signaling. Nature Reviews Immunology, 11, 201-212. [21] Séror C., Melki M. T., Subra F., Raza S. Q., Bras M., Saï di H., Nardacci R., Voisin L., Paoletti A., et al. (2011). Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. J Exp Med, 208(9), 1823-34. [22] Guerra A. N., Fisette P. L., Pfeiffer Z. A., Quinchia-Rios, B. H., Prabhu U., Aga M., Denlinger L. C., Guadarrama A. G., Abozeid S., Sommer J. A., Proctor R. A., Bertics P. J. (2003). Purinergic receptor regulation of LPS-induced signaling and pathophysiology. J Endotoxin Res. 9(4), 256-63. [23] Winder W. W., Hardie, D. G. (1999). AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol, 277 (1 Pt 1), E1-10. [24] Stapleton D., Mitchelhill, K. I., Gao G., Widmer J., Michell B. J., Teh T., House C. M., Fernandez C. S., Cox T., Witters L. A., Kemp B.E. (1996). Mammalian AMP-activated protein kinase subfamily. J Biol Chem, 271 (2), 611-4. [25] Petit P., Loubatières-Mariani M. M., Keppens S., Sheehan, M. J. (1996). Purinergic receptors and metabolic function. Drug Development Research, 39(3-4), 413-425.

Chapter 14

Global Warming Induced Endosymbiotic Actinidic Archaeal Mediated Warburg Phenotype Mediates Human Disease State

168




169

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Endomyocardial fibrosis along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile as well as organisms like phytoplasmas and viroids have been implicated in the etiology of these diseases.1-4 The Warburg phenotype has been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.4 The possibility of Warburg phenotype induced by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered in this paper.5-8 An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described.7, 9


170


incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420 and hexokinase.11-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.





Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

Schizo

23.24

2.01

58.72

7.08

Seizure

23.46

1.87

59.27

8.86

AD

23.12

2.00

56.90

6.94

MS

22.12

1.81

61.33

9.82

NHL

22.79

2.13

55.90

7.29

DM

22.59

1.86

57.05

8.45

AIDS

22.29

1.66

59.02

7.50

CJD

22.06

1.61

57.81

6.04

Autism

21.68

1.90

57.93

9.64

EMF

22.70

1.87

60.46

8.06

F value

306.749

130.054

P value

< 0.001

< 0.001

Group

Table 2 Effect of rutile and antibiotics on hexokinase. Hexokinase % change (Increase with Rutile)

Hexokinase % change (Decrease with Doxy+Cipro)

Mean

±SD

Mean

±SD

Normal

4.21

0.16

18.56

0.76

Schizo

23.01

2.61

65.87

5.27

Seizure

23.33

1.79

62.50

5.56

AD

22.96

2.12

65.11

5.91

MS

22.81

1.91

63.47

5.81

NHL

22.53

2.41

64.29

5.44

DM

23.23

1.88

65.11

5.14

AIDS

21.11

2.25

64.20

5.38

CJD

22.47

2.17

65.97

4.62

Autism

22.88

1.87

65.45

5.08

EMF

21.66

1.94

67.03

5.97

F value

292.065

317.966

P value

< 0.001

< 0.001

Group

171

172


Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 6, 14 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.15,

16

The archaeal glycolytic

hexokinase activity were increased. The part of the increased glycolytic hexokinase activity detected is human. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.17 Archaea can induce the host AKT PI3K, AMPK, HIF alpha and NFKB producing the Warburg metabolic phenotype.18 The increased glycolytic hexokinase activity indicates the generation of the Warburg phenotype. The generation of the Warburg phenotype is due to activation of HIF alpha. This stimulates anaerobic glycolysis, inhibits pyruvate dehydrogenase, inhibits mitochondrial

oxidative

phosphorylation,

stimulates

heme

oxygenase,

stimulates VEGF and activates nitric oxide synthase. This can lead to increased cell proliferation and malignant transformation. The mitochondrial PT pore hexokinase is increased leading onto cell proliferation. There is induction of glycolysis, inhibition of PDH activity and mitochondrial dysfunction resulting in inefficient energetics and metabolic syndrome. The archaea and viroid generated cytokines can lead to TNF alpha induced insulin resistance and metabolic syndrome x. The increase in glycolysis can activate glyceraldehyde 3 phosphate dehydrogenase which gets translocated to the nucleus after polyadenylation. The PARP enzyme is activated by glycolysis mediated redox stress. This can produce nuclear cell death and neuronal degeneration. The increase in the glycolytic enzyme fructose 1,6 diphosphatase increases the


173

pentose phosphate pathway. This generates NADPH which activates NOX. NOX activation is related to NMDA activation and glutamate excitotoxicity. This leads onto neuronal degeneration.18 The increase in glycolysis activates the enzyme fructose 1,6 diphosphatase which activates the pentose phosphate pathway liberating NADPH. This increases NOX activity generating free radical stress and H2O2. Free radical stress is related to insulin resistance and metabolic syndrome x. Free radicals can activate NFKB producing immune activation and autoimmune disease. Free radicals can open the mitochondrial PT pore, produce release of cyto C and activate the caspase cascade. This produces cell death and neuronal degeneration. The free radicals can activate NMDA receptor and induce the enzyme

GAD generating GABA.

This activates the NMDA/GABA

thalamo-cortico-thalamic pathway mediating conscious perception. Increased free radical generation can also intitiate schizophrenia. Free radicals can also produce oncogene activation and malignant transformation. Free radicals can produce HDAC inhibition and HERV generation. The encapsulation of HERV particles in phospholipids vesicles can mediate the generation of the acquired immunodeficiency syndrome. Free radicals can also promote atherogenesis.18 The lymphocytes depend on glycolysis for its energy needs. The increase in glycolysis owing to the induction of Warburg phenotype can lead to immune activation. Immune activation can lead to autoimmune disease. TNF alpha can activate the NMDA receptor leading to glutamate excitotoxicity and neuronal degeneration. TNF alpha activating NMDA receptor can contribute to schizophrenia. TNF alpha can induce expression of HERV particles contributing to generation of acquired immunodeficiency syndrome. Immune activation has also been related to malignant transformation mediated by NFKB. TNF alpha can also act upon the insulin receptor producing insulin resistance.

174


NOX activation consequent to the generation of the Warburg phenotype also activates the insulin receptor. Thus there is a hyperinsulinemic state leading on to metabolic syndrome x.18 Thus the induction of the Warburg phenotype can lead to malignancy, autoimmune disease, metabolic syndrome x, neuropsychiatric disease and neuronal degeneration. The Warburg phenotype leads to inhibition of pyruvate dehydrogenase and accumulation of pyruvate. The accumulated pyruvate enters the GABA shunt pathway and is converted to citrate which is acted upon by citrate lyase and converted to acetyl CoA, used for cholesterol synthesis. The pyruvate can be converted to glutamate and ammonia which is oxidised by archaea for energy needs. The increased cholesterol substrate leads to increased archaeal growth and further induction of the Warburg phenotype.18

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84.


175

[7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [10] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [11] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [12] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [13] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [14] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [15] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [16] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [17] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [18] Wallace D. C. (2005). Mitochondria and Cancer: Warburg Addressed, Cold Spring Harbor Symposia on Quantitative Biology, 70, 363-374.

Chapter 15

Global Warming Induced Endosymbiotic Actinidic Archaeal Cholesterol Catabolic Syndrome - Hypocholesterolemia and Human Diseases

178




179

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Actinidic archaea have also been implicated in the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.1-9 Actinide based primitive organism like archaea have a mevalonate pathway and cholesterol catabolism. Cholesterol catabolism by actinidic archaea can lead to cholesterol depletion and a hypocholesterolemic state contributing to the pathogenesis of these disorders.10-17 Archaea can use cholesterol as a carbon and energy source. Archaeal cholesterol catabolism can lead to multiple systemic disease. Low cholesterol values in populations have been related to high mortality. The archaeal cholesterol catabolizing enzymes were studied and the results in presented in this paper. This can be described as the endosymbiotic actinidic archaeal cholesterol catabolic syndrome.10-17

Materials and Methods The following groups were included in the study: - endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob’s disease and acquired immunodeficiency syndrome. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml,

180


(IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.18 Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420, polycyclic aromatic hydrocarbon, digoxin, bile acid, cholesterol oxidase activity measured by hydrogen peroxide liberation, pyruvate, butyrate and propionate were estimated.19-21 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Polycyclic aromatic hydrocarbon was estimated by measuring hydrogen peroxide liberated by using glucose reagent. Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The statistical analysis was done by ANOVA.



181

Table 1 Effect of rutile and antibiotics on cytochrome F420 and PAH.


CYT F420 % (Increase with Rutile) Mean ±SD 4.48 0.15 23.24 2.01 23.46 1.87 23.12 2.00 22.12 1.81 22.79 2.13 22.59 1.86 22.29 1.66 22.06 1.61 21.68 1.90 22.70 1.87 306.749 < 0.001

CYT F420 % (Decrease with Doxy+Cipro) Mean ±SD 18.24 0.66 58.72 7.08 59.27 8.86 56.90 6.94 61.33 9.82 55.90 7.29 57.05 8.45 59.02 7.50 57.81 6.04 57.93 9.64 60.46 8.06 130.054 < 0.001

PAH % change (Increase with Rutile) Mean ±SD 4.45 0.14 23.01 1.69 22.67 2.29 23.26 1.53 22.83 1.78 22.84 1.42 23.40 1.55 23.23 1.97 23.46 1.91 22.61 1.42 23.73 1.38 391.318 < 0.001

PAH % change (Decrease with Doxy+Cipro) Mean ±SD 18.25 0.72 59.49 4.30 57.69 5.29 60.91 7.59 59.84 7.62 66.07 3.78 65.77 5.27 65.89 5.05 61.56 4.61 64.48 6.90 65.20 6.20 257.996 < 0.001

Table 2 Effect of rutile and antibiotics on butyrate and propionate generation from cholesterol.

Group

Butyrate % change (Increase with Rutile) Mean ±SD

Butyrate % change (Decrease with Doxy+Cipro) Mean ±SD

Propionate % change (Increase with Rutile) Mean ±SD

Propionate % change (Decrease with Doxy+Cipro) Mean ±SD

Normal 4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

Schizo

22.50

1.66

60.21

7.42

22.52

1.90

66.39

4.20

Seizure 23.81

1.19

61.08

7.38

22.83

1.90

67.23

3.45

AD

22.65

2.48

60.19

6.98

23.67

1.68

66.50

3.58

MS

21.14

1.20

60.53

4.70

22.38

1.79

67.10

3.82

NHL

23.35

1.76

59.17

3.33

23.34

1.75

66.80

3.43

DM

23.27

1.53

58.91

6.09

22.87

1.84

66.31

3.68

AIDS

23.32

1.71

63.15

7.62

23.45

1.79

66.32

3.63

CJD

22.86

1.91

63.66

6.88

23.17

1.88

68.53

2.65

Autism 23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

EMF

1.67

60.52

5.38

22.29

2.05

61.91

7.56

23.29

F value 380.721

171.228

372.716

556.411

P value < 0.001

< 0.001

< 0.001

< 0.001

182


Table 3 Effect of rutile and antibiotics on digoxin and bile acids.

Group

Digoxin (ng/ml) (Increase with Rutile) Mean ±SD

Digoxin (ng/ml) (Decrease with Doxy+Cipro) Mean ±SD

Bile Acids % change (Increase with Rutile) Mean ±SD

Bile Acids % change (Decrease with Doxy+Cipro) Mean ±SD

Normal

0.11

0.00

0.054

0.003

4.29

0.18

18.15

0.58

Schizo

0.55

0.06

0.219

0.043

23.20

1.87

57.04

4.27

Seizure

0.51

0.05

0.199

0.027

22.61

2.22

66.62

4.99

AD

0.55

0.03

0.192

0.040

22.12

2.19

62.86

6.28

MS

0.52

0.03

0.214

0.032

21.95

2.11

65.46

5.79

NHL

0.54

0.04

0.210

0.042

22.98

2.19

64.96

5.64

DM

0.47

0.04

0.202

0.025

22.87

2.58

64.51

5.93

AIDS

0.56

0.05

0.220

0.052

22.29

1.47

64.35

5.58

CJD

0.53

0.06

0.212

0.045

23.30

1.88

62.49

7.26

Autism

0.53

0.08

0.205

0.041

22.21

2.04

63.84

6.16

EMF

0.51

0.05

0.213

0.033

23.41

1.41

58.70

7.34

F value

135.116

71.706

290.441

203.651

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 4 Effect of rutile and antibiotics on pyruvate and hydrogen peroxide.

Group





Normal

4.34

0.21

18.43

0.82

4.43

0.19

18.13

0.63

Schizo

20.99

1.46

61.23

9.73

22.50

1.66

60.21

7.42

Seizure

20.94

1.54

62.76

8.52

23.81

1.19

61.08

7.38

AD

22.63

0.88

56.40

8.59

22.65

2.48

60.19

6.98

MS

21.59

1.23

60.28

9.22

21.14

1.20

60.53

4.70

NHL

21.19

1.61

58.57

7.47

23.35

1.76

59.17

3.33

DM

20.67

1.38

58.75

8.12

23.27

1.53

58.91

6.09

AIDS

21.21

2.36

58.73

8.10

23.32

1.71

63.15

7.62

CJD

21.07

1.79

63.90

7.13

22.86

1.91

63.66

6.88

Autism

21.91

1.71

58.45

6.66

23.52

1.49

63.24

7.36

EMF

22.29

2.05

62.37

5.05

23.29

1.67

60.52

5.38

F value

321.255

115.242

380.721

171.228

P value

< 0.001

< 0.001

< 0.001

< 0.001


183

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source. 22-24 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.22-24 The archaeal beta hydroxyl steroid dehydrogenase activity indicating digoxin synthesis and archaeal cholesterol hydroxylase activity indicating bile acid synthesis were increased.22-24 The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide.22-24 The pyruvate gets converted to glutamate and ammonia by the GABA shunt pathway. The archaeal aromatization of cholesterol generating PAH was also detected.22-24 This indicates archaeal cholesterol aromatase activity. The archaeal cholesterol side chain oxidase activity generates butyrate and propionate. Thus archaeal cholesterol oxidase, cholesterol aromatase, cholesterol side chain oxidase, cholesterol hydroxylase and beta hydroxyl steroid dehydrogenase activity were detected in high levels in the patient population of endomyocardial fibrosis, Alzheimer’s disease, multiple sclerosis, non-Hodgkin’s lymphoma, metabolic syndrome x with cerebrovascular thrombosis and coronary artery disease, schizophrenia, autism, seizure disorder, Creutzfeldt Jakob disease and acquired immunodeficiency syndrome. The archaeal cholesterol catabolizing enzymes were actinide dependent. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms. 25 This leads to a cholesterol depleted state and hypocholesterolemic syndrome in patients with schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration.

184


Low cholesterol has been related to multiple systemic diseases. Low cholesterol is detected in patients with autism and schizophrenia. Low cholesterol is also associated with neuronal degenerations like Alzheimer’s disease and Parkinson’s disease. Cholesterol is required for the formation of synaptic connectivity in neuronal cultures. Depletion of cholesterol from the brain results in loss of synaptic connectivity in multiple neuronal circuits contributing to neuropsychiatric disorders and neuronal degeneration. Low cholesterol has also been related to malignancy. Cholesterol is required for contact inhibition. Absence of cholesterol results in loss of contact inhibition and uncontrolled cell proliferation. Low cholesterol has been related to autoimmune disease.10-17 The gut endotoxins and lipopolysaccharides are absorbed along with fat producing the syndrome of metabolic endotoxaemia. The endotoxins and lipopolysaccharides can combine with lipoproteins and are detoxified. Metabolic endotoxaemia produces chronic immune activation and generation of superantigens. This has been related to the genesis of autoimmune disease. Metabolic endotoxaemia results in immune activation and generation of TNF alpha which modulates the insulin receptor producing insulin resistance. Insulin resistance is related to metabolic syndrome x and vascular thrombosis. Metabolic endotoxaemia has been related to neuronal degenerations like Alzheimer’s disease and Parkinson’s disease. Metabolic endotoxaemia related chronic immune activation drives the retroviral state. Metabolic endotoxaemia can induce NFKB which can drive malignant cell transformation. Thus hypocholesterolemia

leads

to

non-detoxification

of

endotoxins

and

lipopolysaccharides resulting in metabolic syndrome x, neuronal degnerations and autoimmune disease.10-17


185

Infections have been related to schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration. H. pylori infection and nocardiosis has been related to Parkinson’s disease. Chlamydial infection and actinomycosis has been related to Alzheimer’s disease. Clostridial infection has been related to motor neuron disease. Atypical mycobacterial infection had been related to malignancy like lymphoma. Staphylococal infections have been related to carcinoma of the breast. Gut bacterial infections had been related to rheumatoid disease. Toxoplasmosis has been related to schizophrenia. Gut bacteria with increase in gut firmicutes and decrease in bacteroides have been related to metabolic syndrome x. Chlamydial infections have been related to vascular disease. Low cholesterol leads to lack of lipoprotein binding to endotoxins.10-17 The endotoxins and lipopolysaccharides are not detoxified. Viral diseases have been related to the pathogenesis of schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration. The virus binds to lipid microdomains in the cell membrane. Cholesterol depletion leads to alteration in lipid microdomains and increased entry of virus in the cell. Herpes virus infection and borna virus disease leads to schizophrenia. Enterovirus infection has been associated with motor neuron disease. Corona virus infection predisposes to Parkinson’s disease. Herpes virus infection is implicated in Alzheimer’s disease. Herpes virus infection and EBV infections predisposed to SLE. Retroviral infection - exogenous and endogenous have been related to schizophrenia, malignancy, metabolic syndrome x, autoimmune disease and neuronal degeneration. CMV infection and herpes infection has been related to atherogenesis. Prion disease has been related to alterations in cholesterol metabolism. Thus a cholesterol depleted state can lead to increased predilection to viral infection and systemic disease.10-17

186


The actinidic archaea uses cholesterol catabolism to generate energy. The cholesterol catabolizing enzymes of the archaea are dependent on actinides. The archaeal cholesterol catabolism leads to a cholesterol depleted state and systemic disease. Cholesterol depleted state have been related to high mortality. This can be described as the endosymbiotic actinidic archaeal cholesterol catabolic syndrome.10-17

References [1] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [2] Valiathan M. S., Somers, K., Kartha, C.C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [3] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [4] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [7] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [8] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [9] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249.


187

[10] Marini, A., Carulli, G., Azzarà, A., Grassi, B., Ambrogi, F. (1989). Serum cholesterol and triglycerides in hematological malignancies. Acta Haematol, 81(2), 75-9. [11] Jacobs, D., Blackburn, H., Higgins, M. (1992). Report of the Conference on Low Blood Cholesterol: Mortality Associations. Circulation, 86(3), 1046-60. [12] Suarez, E. C. (1999). Relations of trait depression and anxiety to low lipid and lipoprotein concentrations in healthy young adult women. Psychosom Med, 61 (3), 273-9. [13] Woo, D., Kissela, B. M., Khoury, J. C. (2004). Hypercholesterolemia, HMG-CoA reductase inhibitors, and risk of intracerebral hemorrhage: a case-control study. Stroke, 35(6), 1360-4. [14] Schatz, I. J., Masaki, K., Yano, K., Chen, R., Rodriguez, B. L., Curb, J. D. (2001). Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet, 358 (9279), 351-5. [15] Onder, G., Landi, F., Volpato, S., (2003). Serum cholesterol levels and in-hospital mortality in the elderly. Am J Med, 115(4), 265-71. [16] Gordon, B. R., Parker, T. S., Levine, D. M. (2001). Relationship of hypolipidemia to cytokine concentrations and outcomes in critically ill surgical patients. Crit Care Med, 29(8), 1563-8. [17] Jacobs, Jr., D. R., Iribarren, C. (2000). Low Cholesterol and Nonatherosclerotic Disease Risk: A Persistently Perplexing Question. American Journal of Epidemiology, Vol. 151, No. 8. [18] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [19] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [20] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [21] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press.

188


[22] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [23] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [24] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [25] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35.

Chapter 16

Global Warming Induced Endosymbiotic Actinidic Archaea and Viroids - Role in Metabolic/Endocrine Regulation

190




191

continuous process and can contribute to changes in brain structure and behavior as well as disease process. The human body synthesises an endogenous sodium potassium ATPase inhibitor digoxin which plays a role in neuro-immuno-endocrine integration as well as in cardiovascular / metabolic disorders. Endomyocardial fibrosis (EMF) along with the root wilt disease of coconut is endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile producing intracellular magnesium deficiency due to rutile-magnesium exchange sites in the cell membrane has been implicated in the etiology of EMF.1 Endogenous digoxin, a steroidal glycoside which functions as a membrane sodium potassium ATPase inhibitor has also been related to its etiology due to the intracellular magnesium deficiency it produces.2 Organisms like phytoplasmas and viroids have also been demonstrated to play a role in the etiology of these diseases.3,

4

Endogenous digoxin has been related to the pathogenesis of type 2 diabetes mellitus, coronary artery disease and cerebrovascular disease.2 The possibility of endogenous digoxin synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered.5-8 An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described.6 The intracellular endosymbionts archaea and their intron derived viroids constitute the third element regulating the human body. A hypothesis regarding the role of endosymbiotic actinidic archaea and viroids in metabolic/endocrine regulation is put forward.

Materials and Methods Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The following groups were included in the study: -

192


type 2 diabetes mellitus, coronary artery disease - acute coronary syndrome and acute cerebrovascular thrombotic stroke. The coronary artery disease and cerebrovascular disease patients chosen for the study did not have type 2 diabetes mellitus as a risk factor. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.9 Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420, free RNA, free DNA, polycyclic aromatic hydrocarbon, hydrogen peroxide, pyruvate, ammonia, glutamate, hexokinase, ATP synthase, HMG CoA reductase, digoxin and bile acids.10-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Polycyclic aromatic hydrocarbon was estimated by measuring hydrogen peroxide liberated by using glucose reagent. The statistical analysis was done by ANOVA.

Results The parameters checked as indicated above were: - cytochrome F420, free RNA, free DNA, muramic acid, polycyclic aromatic hydrocarbon, hydrogen peroxide, serotonin, pyruvate, ammonia, glutamate, cytochrome C, hexokinase, ATP synthase, HMG CoA reductase, digoxin and bile acids. Plasma of control subjects showed increased levels of the above mentioned parameters with after


193

incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are expressed in tables 1-6 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time. Table 1 Effect of rutile and antibiotics on cytochrome F420. CYT F420 % (Increase with rutile)

CYT F420 % (Decrease with Doxy)

Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

DM

22.59

1.86

57.05

8.45

CAD

22.76

2.26

60.49

6.86

CVA

21.01

2.29

62.37

8.01

F value

306.749

130.054

P value

< 0.001

< 0.001

Group

Table 2 Effect of rutile and antibiotics on free DNA and RNA. DNA % change (Increase with Rutile)

DNA % change (Decrease with Doxy)

RNA % change (Increase with Rutile)

RNA % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.37

0.15

18.39

0.38

4.37

0.13

18.38

0.48

DM

23.01

1.67

65.35

3.56

23.33

1.86

66.46

3.65

CAD

23.12

1.71

65.12

5.58

24.01

1.17

66.66

3.84

CVA

22.51

1.85

63.56

5.29

22.95

1.90

66.39

3.83

F value

337.577

356.621

427.828

654.453

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group

194


Table 3 Effect of rutile and antibiotics on HMG CoA reductase and PAH.

Group

HMG CoA R % change (Increase with Rutile)

HMG CoA R % change (Decrease with Doxy)


PAH % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.30

0.20

18.35

0.35

4.45

0.14

18.25

0.72

DM

23.06

1.65

62.25

6.24

23.40

1.55

65.77

5.27

CAD

23.63

1.58

61.19

7.03

22.22

2.33

61.73

6.33

CVA

22.51

2.47

60.77

5.89

23.87

1.64

66.01

5.78

F value

319.332

199.553

391.318

257.996

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 4 Effect of rutile and antibiotics on digoxin and bile acids. Digoxin (ng/ml) (Increase with Rutile)


Bile acids % change Bile acids % (Increase with change (Decrease Rutile) with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

0.11

0.00

0.054

0.003

4.29

0.18

18.15

0.58

DM

0.47

0.04

0.202

0.025

22.87

2.58

64.51

5.93

CAD

0.49

0.07

0.202

0.021

22.22

2.44

63.47

6.98

CVA

0.51

0.07

0.195

0.023

22.33

2.18

62.20

6.33

F value

135.116

71.706

290.441

203.651

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group

Table 5 Effect of rutile and antibiotics on pyruvate and hexokinase. Pyruvate % change (Increase with Rutile)

Pyruvate % change (Decrease with Doxy)

Hexokinase % change (Increase with Rutile)

Hexokinase % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.34

0.21

18.43

0.82

4.21

0.16

18.56

0.76

DM

20.67

1.38

58.75

8.12

23.23

1.88

65.11

5.14

CAD

20.16

1.07

57.08

9.83

21.88

2.11

65.02

4.40

CVA

20.60

1.81

58.97

7.03

21.98

2.12

65.78

6.08

F value

321.255

115.242

292.065

317.966

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group


195

Table 6 Effect of rutile and antibiotics on ATP synthase and hydrogen peroxide. ATP synthase %

ATP synthase %

H2O2 %

H2O2 %


(Decrease with Doxy)


(Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.40

0.11

18.78

0.11

4.43

0.19

18.13

0.63

DM

23.72

1.73

66.25

3.69

23.27

1.53

58.91

6.09

CAD

23.78

1.20

66.90

4.10

23.24

1.85

57.08

7.42

CVA

23.47

1.60

66.27

3.88

23.32

1.60

61.45

7.01

F value

449.503

673.081

380.721

171.228

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group

Abbreviations DM: Type 2 diabetes mellitus CAD: Coronary artery disease CVA: Cerebrovascular thrombosis

Discussion There was increase in cytochrome F420 indicating archaeal growth in type 2 diabetes mellitus, coronary artery disease and cerebrovascular disease. The archaea can synthesise and use cholesterol as a carbon and energy source.14, 15 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.16 There was also an increase in archaeal HMG CoA reductase activity indicating increased cholesterol synthesis by the archaeal mevalonate pathway. The archaeal beta hydroxyl steroid dehydrogenase activity indicating digoxin

196


synthesis and archaeal cholesterol hydroxylase activity indicating bile acid synthesis were increased.7 The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide.15 The pyruvate gets converted to glutamate and ammonia by the GABA shunt pathway. The archaeal aromatization of cholesterol generating PAH, serotonin and dopamine was also detected.17 The archaeal glycolytic hexokinase activity and archaeal extracellular ATP synthase activity were increased. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.18 There was an increase in free RNA indicating self replicating RNA viroids and free DNA indicating generation of viroid complementary DNA strands by archaeal reverse transcriptase activity. The actinides modulate RNA folding and catalyse its ribozymal action. Digoxin can cut and paste the viroidal strands by modulating RNA splicing generating RNA viroidal diversity. The viroids are probably escaped archaeal group I introns which have retrotransposition and self splicing qualities.19 The decrease in free self replicating RNA and DNA with the addition of antibiotics indicates that the RNA viroids are derived from archaeal introns. Archaeal pyruvate can produce histone deacetylase inhibition resulting in endogenous retroviral (HERV) reverse transcriptase and integrase expression. This can integrate the RNA viroidal complementary DNA into the noncoding region of eukaryotic non coding DNA using HERV integrase as has been described for borna and ebola viruses.20-22 The RNA viroids can regulate mRNA function by RNA interference.19 The phenomena of RNA interference can modulate euchromatin/heterochromatin expression. RNA viroidal mRNA interference plays a role in the pathogenesis of type 2 diabetes mellitus, coronary artery disease and cerebrovascular disease. Viroidal RNA mediated mRNA interference can modulate lipid metabolism triggering of dyslipidemias important in atherogenesis. The viroidal RNA modulation of T cell and B cell


197

function by mRNA interference can lead to immune activation. Monocytic infiltration of the vascular wall is important in atherogenesis. Insulin resistance due to TNF alpha modulation of the insulin receptor can contribute to type 2 diabetes mellitus. The viroidal RNA mediated mRNA interference can also modulate insulin signalling and secretion leading onto type 2 diabetes mellitus.23-32 Archaea and RNA viroid can bind the TLR receptor induce NFKB producing immune activation and cytokine TNF alpha secretion. The archaeal DXP and mevalonate pathway metabolites can bind  TCR and digoxin induced calcium signalling can activate NFKB producing chronic immune activation or systemic inflammatory reaction.2,

33

The archaea and viroid induced chronic immune

activation and generation of superantigens. Immune activation results in induction of NADPH oxidase which generates hydrogen peroxide. Cholesterol oxidase activity also generates hydrogen peroxide. Hydrogen peroxide can increase protein tyrosine kinase activity and suppress protein phosphatase activity increasing insulin receptor function. Immune activated NOX and bacterial cholesterol oxidase can thus regulate insulin receptor function. Immune activation can also produce insulin resistance. TNF alpha produced by chronic immune activation can modulate the insulin receptor producing insulin resistance.30 Chronic immune activation and cholesterol oxidase generated hydrogen peroxide can induce neutral sphingomyelinase generating ceramide producing insulin resistance.34 Immune activation and NFKB induction can suppress the nuclear receptors LXR, PXR and FXR. LXR suppression by NFKB stimulates HMG CoA reductase activity and suppresses cholesterol 7 alpha hydroxylase activity.3,

5

This stimulates cholesterol synthesis and

inhibits its degradation via the bile acid pathway. PXR suppression by NFKB prevents cholesterol detoxification via the bile acid shunt pathway.36 Thus LXR and PXR suppression by NFKB produces acute cholesterol toxicity. This NFKB

198


induced suppression of LXR and PXR can contribute to increased lipid and cholesterol synthesis contributing to obesity. FXR suppression can also lead to insulin resistance, dyslipidemias and increased connective tissue MPS deposition in vessel wall and atherogenesis. The cholesterol toxicity can lead to lipoprotein and cholesterol uptake by monocytes in the vessel wall producing atherogenesis. The archaea and viroid induced chronic immune activation can lead to monocyte infiltration of the vessel wall. This sets the stage for the atherogenetic process.29 The increased cholesterol synthesis is important in stimulating archaeal growth which uses cholesterol as a carbon and energy source. Archaea, viroids and digoxin can induce the host AKT PI3K, AMPK, HIF alpha and NFKB producing the Warburg metabolic phenotype.37 The increased glycolytic hexokinase activity, decrease in blood ATP, leakage of cytochrome C, increase in serum pyruvate and decrease in acetyl CoA indicates the generation of the Warburg phenotype. There is induction of glycolysis, inhibition of PDH activity and mitochondrial dysfunction resulting in inefficient energetics. Inefficient energetics owing to the Warburg’s phenotype can contribute to metabolic syndrome x. The accumulated pyruvate enters the GABA shunt pathway and is converted to citrate which is acted upon by citrate lyase and converted to acetyl CoA, used for cholesterol synthesis.37 The pyruvate can be converted to glutamate and ammonia which is oxidised by archaea for energy needs. Ammonia can stimulate membrane sodium-potassium ATPase increasing ATP utilisation, produce mitochondrial transmembrane potential changes and produce mitochondrial dysfunction important in type 2 diabetes mellitus. The increased cholesterol substrate also leads to increased archaeal growth and digoxin synthesis due to metabolic channelling to the mevalonate pathway.


199

Digoxin can produce sodium potassium ATPase inhibition and inward movement of plasma membrane cholesterol. This produces defective SREBP sensing, increased HMG CoA reductase activity and cholesterol synthesis.28 The digoxin induced inward movement of plasma membrane cholesterol can alter membrane

cholesterol/sphingomyelin 38

microdomains.

ratio

producing

modified

lipid

The digoxin induced lipid microdomain modulation can

regulate the GPCR couple adrenaline, noradrenaline, glucagon and neuropeptide receptors as well as protein tyrosine kinase linked insulin receptor. The digoxin mediated inhibition of nuclear membrane sodium potassium ATPase can modulate nuclear membrane lipid microdomains and steroidal/thyroxine DNA receptor function. Thus endogenous digoxin can modulate all the endocrine receptors by regulating lipid microdomains. Hyperdigoxinemia is important in the pathogenesis of atherogenesis and metabolic syndrome X. Digoxin induced sodium potassium ATPase inhibition results in an ATP sparing effect.39 Eighty percent of the ATP generated is used to run the sodium potassium ATPase pump. The digoxin inhibition of the sodium potassium ATPase spares this ATP which is then used for lipid synthesis. Thus endogenous digoxin and the shadow biosphere generated Warburg phenotype can produce increased lipid synthesis and obesity important in metabolic syndrome x. Fat fuels insulin resistance by binding to the toll receptor and producing immune activation and immune infiltration of the adipose tissue. Digoxin can also increase lymphocytic intracellular calcium which leads on to induction of NFKB and immune activation.2 The archaeal cholesterol catabolism can deplete the lymphocytic cell membranes of cholesterol resulting in alteration of lymphocytic cell membrane microdomains related receptors producing immune activation. The archaeal bile acids are steroidal hormones.40 The archaeal bile acids can bind GPCR and modulate D2 regulating the conversion of T4 to T3. T3 activates uncoupling proteins reducing redox stress. Bile acids can also activate

200


NRF ½ inducing NQO1, GST, HOI reducing redox stress. Bile acids can bind FXR regulating insulin receptor sensitivity and bind PXR inducing the bile acid shunt pathway of cholesterol detoxification. Bile acids can bind macrophage GPCR and VDR producing immunosuppression and inhibiting NFKB. This helps to modulate the archaea and viroid induced chronic immune activation. Thus the archaeal bile acids have a role opposite to digoxin and help to increase insulin sensitivity. The cholesterol ring oxidase generated pyruvate can be converted by the GABA shunt pathway to glutamate. Glutamatergic transmission can lead to immune activation, atherogenesis and increased insulin signalling/release. The archaeal cholesterol aromatase can generate PAH.17 The PAH can also lead to insulin resistance and atherogenesis. Particulate pollution has been related to metabolic syndrome x, type 2 diabetes mellitus and vascular thrombosis. The higher degree of integration of the archaea into the genome produces increased digoxin synthesis producing right hemispheric dominance and lesser degree producing left hemispheric dominance.2 Right hemispheric dominance can lead to type 2 diabetes mellitus and vascular thrombosis. Thus the actinide, viroid and mevalonate pathway bacteria induced metabolic, genetic, immune and neuronal transmission changes can lead onto metabolic syndrome x and atherogenesis. An actinide dependent shadow biosphere of archaea and viroids is described in type 2 diabetes mellitus, coronary artery disease - acute coronary syndrome and acute cerebrovascular thrombosis contributing to their pathogenesis. The archaea secreted digoxin and archaeal viroid serves as a messenger regulating metabolic and endocrine systems.


201

References [1] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [2] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [3] Hanold D., Randies, J. W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [4] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [5] Eckburg P. B., Lepp, P.W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596. [6] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [7] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [8] Davies P.C.W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [9] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [10] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [11] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [12] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press.

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[13] Maarten A. H., Marie-Jose, M., Cornelia, G., van Helden-Meewsen, Fritz, E., Marten, P. H. (1995). Detection of muramic acid in human spleen, Infection and Immunity, 63(5), 1652-1657. [14] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [15] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [16] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [17] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870. [18] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [19] Tsagris E. M., de Alba, A. E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [20] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87. [21] Hecht M., Nitz, N., Araujo, P., Sousa, A., Rosa, A., Gomes, D. (2010). Genes from Chagas parasite can transfer to humans and be passed on to children. Inheritance of DNA Transferred from American Trypanosomes to Human Hosts, PLoS ONE, 5, 2-10. [22] Flam F. (1994). Hints of a language in junk DNA, Science, 266, 1320. [23] Horbach S., Sahm, H., Welle, R. (1993). Isoprenoid biosynthesis in bacteria: two different pathways? FEMS Microbiol Lett, 111, 135-140.


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[24] Gupta R.S. (1998). Protein phylogenetics and signature sequences: a reappraisal of evolutionary relationship among archaebacteria, eubacteria, and eukaryotes, Microbiol Mol Biol Rev, 62, 1435-1491. [25] Hanage W., Fraser, C., Spratt, B. (2005). Fuzzy species among recombinogenic bacteria, BMC Biology, 3, 6-10. [26] Webb J.S., Givskov, M., Kjelleberg, S. (2003). Bacterial biofilms: prokaryotic adventures in multicellularity, Curr Opin Microbiol, 6(6), 578-85. [27] Whitchurch C. B., Tolker-Nielsen, T., Ragas, P. C., Mattick, J. S. (2002). Extracellular DNA Required for Bacterial Biofilm Formation. Science, 295(5559), 1487. [28] Chen Y., Cai, T., Wang, H., Li, Z., Loreaux, E., Lingrel, J.B. (2009). Regulation of intracellular cholesterol distribution by Na/K-ATPase, J Biol Chem, 284(22), 14881-90. [29] Khovidhunkit W., Kim, M. S., Memon, R. A., Shigenaga, J. K., Moser, A. H., Feingold, K. R. (2004). Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host. J Lip Res, 45(7), 1169-1196. [30] Cani P.D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 56, 1761-1772. [31] Poole A. M. (2006). Did group II intron proliferation in an endosymbiont-bearing archaeon create eukaryotes? Biol Direct, 1, 36-40. [32] Villarreal L. P. (2006). How viruses shape the tree of life, Future Virology, 1(5), 587-595. [33] Eberl M., Hintz, M., Reichenberg, A., Kollas, A., Wiesner, J., Jomaa, H. (2010). Microbial isoprenoid biosynthesis and human γδ T cell activation, FEBS Letters, 544(1), 4-10. [34] Memon R. A., Holleran, W. M., Moser, A. H., Seki, T., Uchida, Y., Fuller, J. (1998). Endotoxin and Cytokines Increase Hepatic Sphingolipid Biosynthesis and

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Produce Lipoproteins Enriched in Ceramides and Sphingomyelin. Arterioscler Thromb Vasc Biol, 18(8), 1257-1265. [35] Carayol N., Chen, J., Yang, F., Jin, T., Jin, L., States, D. (2006). A dominant function of IKK/NF-kB signaling in global LPS-induced gene expression. J Biol Chem, 10, 1074. [36] Kliewer S. A. (2005). Cholesterol detoxification by the nuclear pregnane X receptor. Proc Natl Acad Sci USA, 102(8), 2675-6. [37] Wallace D.C. (2005). Mitochondria and Cancer: Warburg Addressed, Cold Spring Harbor Symposia on Quantitative Biology, 70, 363-374. [38] Paila Y. D., Tiwari, S., Chattopadhyay, A. (2009). Are specific nonannular cholesterol binding sites present in G-protein coupled receptors? Biochim Biophys Acta, 1788(2), 295-302. [39] Ebensperger G., Ebensperger, R., Herrera, E. A., Riquelme, R. A., Sanhueza, E. M., Lesage, F. (2005). Fetal brain hypometabolism during prolonged hypoxaemia in the llama. J Physiol, 567(3), 963-975. [40] Lefebvre P., Cariou, B., Lien, F., Kuipers, F., Staels, B. (2009). Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation, Physiol Rev, 89(1), 147-191.

Chapter 17

Global Warming Induced Stem Cell Conversion Produces an Epidemic Benjamin Buttons Reverse Aging Syndrome

206




207

continuous process and can contribute to changes in brain structure and behavior as well as disease process. The global warming produces increased acidity and atmospheric carbon dioxide resulting in extremophilic archaeal symbiosis in humans. The archaeal symbiosis results in neanderthalisation of humans. The archaea induced uncoupling proteins producing the primitive Warburg phenotype and stem cell metabolonomics. The archaeal metabolites of cholesterol digoxin, bile acids and short chain fatty acids induce uncoupling proteins. The lysosomal enzymes a marker of stem cell conversion are markedly increased along with genesis of the archaeal phenotype in metabolic syndrome x, degenerations, autoimmune diseases, cancer, schizophrenia and autism. In all these systemic diseases there is somatic cell transformation to stem cell and lose of function. The neurons become immature and lose their dendritic spines and connectivity. This results in loss of neuronal function and reversion to archaeal magnetite mediated extrasensory perception of low level of EMF. Exposure to low level of EMF results in brain changes. This results in prefrontal cortex atrophy. The primitive brain areas of cerebellum and brain stem become hypertrophic. The somatic and neuronal cell proliferates and there is neanderthalisation of the brain and body.1-17 The idea of goodness is based on reason and logic. Reason judgment and logic is a function of the cerebral cortex especially the prefrontal lobe. Prefrontal lobe function needs dynamic synaptic connectivity which is produced by jumping genes mediated by human endogenous retroviral sequences. Goodness is correlated with heaven. The idea of evil is based on the unconscious and the impulsive behavior related to subcortical areas especially the cerebellum. The cerebellum is the site of impulsive behavior and the unconscious behavior. The cerebellar and subcortical brain connections are predominantly archaeal colony networks. The idea of evil is related to hell. The

208


idea of conscious judgmental acts and unconscious impulsive acts, heaven and hell, goodness and evil are juxtapositions. The global warming and exposure to low level of EMF leads to actinidic archaeal growth in the brain and increased archaeal magnetite mediated perception of low level of EMF. This leads to prefrontal cortex atrophy and cerebellar dominance. The conscious becomes minimal and unconscious brain takes over. The study assessed archaeal growth as assessed by cytochrome F420 activity and stem cell type metabolonomics in systemic diseases, neuropsychiatric disorders and normal individuals with differing psychological profile - prisoners, creative individuals and common sense modulated business men.1-17 The results are presented in this paper.

Materials and Methods The blood samples were drawn from four groups of psychological different population spiritually inclined, criminal prisoners, creative artists and business men. There were 15 members in each group. The blood samples were also drawn from 15 cases each of metabolic syndrome, degenerations - Alzheimer’s disease, autoimmune disease - SLE, cancer - brain glioma, schizophrenia and autism. The estimations done in the blood samples collected include cytochrome F420 activity. Blood lactate, pyruvate, hexokinase, cytochrome C, cytochrome F420, digoxin, bile acids, butyrate and propionate were estimated.

Results The results showed that the spiritual, artistic creative individuals and criminal prisoners had increased cytochrome F420 activity and RBC digoxin levels. The results showed that the businessmen had decreased cytochrome F420 activity and RBC digoxin levels. The blood samples of Alzheimer’s disease,


209

autoimmune disease - SLE, cancer - brain glioma, schizophrenia and autism had increased blood lactate and pyruvate, increased RBC hexokinase, increased serum cytochrome C and serum cytochrome F420, increased serum digoxin, bile acids, butyrate and propionate. The disease state had increased cytochrome F420 activity. The serum cytochrome C levels in the blood were increased. This suggested mitochondrial dysfunction. There was an increased in glycolysis as suggested by increased RBC hexokinase activity and lactic acidosis. Owing to the mitochondrial dysfunction and pyruvate dehydrogenase inhibition there was pyruvate accumulation. The pyruvate was converted to lactate by the Cori cycle and also to glutamate and ammonia. This metabolism is suggestive of the Warburg phenotype and stem cell conversion. The stem cells depend on Warburg anaerobic glycolysis for energetics and have a mitochondrial dysfunction. The lysosomal enzyme beta galactosidase activity was increased in the disease group and in creative artists and criminals suggesting stem cell conversion. This suggests that artistic creative, criminal prisoners as well as spiritual individuals tend to have stem cell metabolonomics and stem cell conversion.

210


Table 1

Group

Cytochrome Serum Cyto C Lactate F 420 (ng/ml) (mg/dl)

Pyruvate (umol/l)

RBC Hexokinase (ug glu phos / hr/mgpro)

Mean ±SD

Mean

±SD

Mean ±SD Mean

±SD Mean ±SD

Normal population

1.00

0.00

2.79

0.28

7.38

40.51

1.42

1.66

0.45

Spiritual

4.00

0.00

12.39

1.23

25.99 8.10

100.51

12.32 5.46

2.83

Acquisitive capitalist

0.00

0.00

1.21

0.38

2.75

0.41

23.79

2.51

0.23

Artistic

4.00

0.00

12.84

0.74

23.64 1.43

96.19

12.15 10.12 1.75

Criminality

4.00

0.00

12.72

0.92

25.35 5.52

103.32

13.04 9.44

3.40

Schizo

4.00

0.00

11.58

0.90

22.07 1.06

96.54

9.96

7.69

3.40

Seizure

4.00

0.00

12.06

1.09

21.78 0.58

90.46

8.30

6.29

1.73

HD

4.00

0.00

12.65

1.06

24.28 1.69

95.44

12.04 9.30

3.98

AD

4.00

0.00

11.94

0.86

22.04 0.64

97.26

8.26

8.46

3.63

MS

4.00

0.00

11.81

0.67

23.32 1.10

102.48

13.20 8.56

4.75

SLE

4.00

0.00

11.73

0.56

23.06 1.49

100.51

9.79

8.02

3.01

NHL

4.00

0.00

11.91

0.49

22.83 1.24

95.81

12.18 7.41

4.22

Glio

4.00

0.00

13.00

0.42

22.20 0.85

96.58

8.75

7.82

3.51

DM

4.00

0.00

12.95

0.56

25.56 7.93

96.30

10.33 7.05

1.86

CAD

4.00

0.00

11.51

0.47

22.83 0.82

97.29

12.45 8.88

3.09

CVA

4.00

0.00

12.74

0.80

23.03 1.26

103.25

9.49

7.87

2.72

AIDS

4.00

0.00

12.29

0.89

24.87 4.14

95.55

7.20

9.84

2.43

CJD

4.00

0.00

12.19

1.22

23.02 1.61

96.50

5.93

8.81

4.26

Autism

4.00

0.00

12.48

0.79

21.95 0.65

92.71

8.43

6.95

2.02

DS

4.00

0.00

12.79

1.15

23.69 2.19

91.81

4.12

8.68

2.60

Cerebral Palsy

4.00

0.00

12.14

1.30

23.12 1.81

95.33

11.78 7.92

3.32

CRF

4.00

0.00

12.66

1.01

23.42 1.20

97.38

10.76 7.75

3.08

Cirr/Hep Fail

4.00

0.00

12.81

0.90

26.20 5.29

97.77

13.24 8.99

3.27

Low level background radiation

4.00

0.00

12.26

1.00

23.31 1.46

103.28

11.47 7.58

3.09

F value

0.001

445.772

162.945

154.701

18.187

P value

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

0.31

0.68


211

Table 2

Group

Normal population Spiritual Acquisitive capitalist Artistic

±SD

RBC Digoxin (ng/ml RBC Susp) Mean ±SD

Beta galactosidase activity in serum (IU/ml) Mean ±SD

50.60

1.42

0.58

0.07

17.75

0.72

0.32

93.43

4.85

1.41

0.23

55.17

5.85

0.16

0.02

23.92

3.38

0.18

0.05

8.70

0.90

Glutamate ACOA (mg/dl) (mg/dl)

Se. Ammonia (ug/dl)

Mean

±SD

Mean ±SD

Mean

8.75

0.38

0.65

0.03

2.51

0.36

3.19

16.49

0.89

2.51

0.42

3.11

0.36

92.40

4.34

1.40

0.32

46.37

4.87

Criminality

2.19

0.19

3.27

0.39

95.37

5.76

1.51

0.29

47.47

4.34

Schizo

2.51

0.57

3.41

0.41

94.72

3.28

1.38

0.26

51.17

3.65

Seizure

2.15

0.22

3.67

0.38

95.61

7.88

1.23

0.26

50.04

3.91

HD

1.95

0.06

3.14

0.32

94.60

8.52

1.34

0.31

51.16

7.78

AD

2.19

0.15

3.53

0.39

95.37

4.66

1.10

0.08

51.56

3.69

MS

2.03

0.09

3.58

0.36

93.42

3.69

1.21

0.21

47.90

6.99

SLE

2.54

0.38

3.37

0.38

101.18 17.06

1.50

0.33

48.20

5.53

NHL

2.30

0.26

3.48

0.46

91.62

3.24

1.26

0.23

51.08

5.24

Glio

2.34

0.43

3.28

0.39

93.20

4.46

1.27

0.24

51.57

2.66

DM

2.17

0.40

3.53

0.44

93.38

7.76

1.35

0.26

51.98

5.05

CAD

2.37

0.44

3.61

0.28

93.93

4.86

1.22

0.16

50.00

5.91

CVA

2.25

0.44

3.31

0.43

103.18 27.27

1.33

0.27

51.06

4.83

AIDS

2.11

0.19

3.45

0.49

92.47

3.97

1.31

0.24

50.15

6.96

CJD

2.10

0.27

3.94

0.22

93.13

5.79

1.48

0.27

49.85

6.40

Autism

2.42

0.41

3.30

0.32

94.01

5.00

1.19

0.24

52.87

7.04

DS Cerebral Palsy CRF Cirr/Hep Fail Low level background radiation F value

2.01

0.08

3.30

0.48

98.81

15.65

1.34

0.25

47.28

3.55

2.06

0.35

3.24

0.34

92.09

3.21

1.44

0.19

53.49

4.15

2.24

0.32

3.26

0.43

98.76

11.12

1.26

0.26

49.39

5.51

2.13

0.17

3.25

0.40

94.77

2.86

1.50

0.20

46.82

4.73

2.14

0.19

3.47

0.37

102.62 26.54

1.41

0.30

51.01

4.77

1871.04

200.702

61.645

60.288

194.418

P value

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

212


Discussion The systemic diseases and neuropsychiatric disorders tend to have a predominant anaerobic glycolytic metabolism and mitochondrial oxidative phosphorylation is suppressed. The metabolism is similar to the metabolism of the stem cell. The pyruvate and lactate levels are increased with a decrease in acetyl coenzyme A and ATP. The glycolytic pathway and hexokinase is increased. This indicates a Warburg phenotype depending upon anaerobic glycolysis for energetics. The lysosomal enzymes beta galactosidase a stem cell marker is increased. The cytochrome F420 is also increased as well as the archaeal catabolite digoxin which suppresses sodium potassium ATPase. Bacteria and archaea are supposed to induce stem cell transformation. The induction of uncoupling proteins leads to stem cell transformation. The uncoupling proteins inhibit oxidative phosphorylation and the substrates are directed to anaerobic glycolysis. Digoxin by inhibiting sodium potassium ATPase can increase intracellular calcium, induce mitochondrial permeability transient pore function and uncouple oxidative phosphorylation. The side chain of cholesterol is catabolized by archaea to butyric acid and propionic acid which uncouple oxidative phosphorylation. The archaeal side chain hydroxylase convert cholesterol to bile acids which uncouple oxidative phosphorylation. Thus archaeal symbiosis in the cell results in cholesterol catabolism and the catabolites digoxin, bile acids and short chain fatty acids uncouple oxidative phosphorylation, inhibit mitochondrial function and promote anaerobic glycolysis. The conversion of somatic cells to stem cell helps in archaeal persistence within the cell and symbiosis. Mycobacterium leprae infection can convert Schwann cells to stem cells. Archaeal infection produces somatic cell conversion to stem cells for archaeal persistence. The conversion to stem cell results in proliferation and loss of function resulting in systemic disease and


213

neuropsychiatric disorders. Stem cell conversion of neurons and loss of function results in development of a new psychological phenotype.1-17 The systemic and neuronal cell in metabolic syndrome x, cancer, autoimmune disease, degenerations, schizophrenia and autism behaves like the stem cell. It is plausible to hypothesise a somatic cell conversion to stem cell in these disorders. The differentiated cells by archaeal induction get converted to stem cell. The stem cell is a immature cell with loss of function. The neurons lose their dendritic spines and loss of connectivity. The brain function becomes primitive. The neurons are adendritic and disconnected. This results in complex brain structures like the modern cerebral cortex and prefrontal cortex atrophy. The primitive parts of the brain the brain stem and cerebellum hypertrophies. This results in neanderthalisation of the brain with a prominent occipital bun and atrophied prefrontal cortex. The prefrontal cortex atrophy results in loss of logic, judgment, reasoning and executive functions. The hypertrophy of the cerebellum and brain stem results in dominance of impulsive behavior. The difference between reality and dreams is lost. The brain is ruled by the senses and impulses. The brain becomes dysfunctional with more of violent, aggressive and cannibalistic behavior. The art becomes more abstract and related to the unconscious. The world of the unconscious brain with its archetypes takes over. There is loss of the world of reasoning, logic and judgment. It is a world of impulsiveness in which primitive tendencies with relation to the unconscious becomes dominant. This produces more of ritualized behavior, violent and aggressive tendencies, terrorism, war, sexual obscenities and alternate sexuality. It is a world of the senses. It is also intensely evil as well as spiritual. The inhibition of the conscious due to loss of cortical functions and the dominance of the unconscious leads to mystical experience. There is a overflowing of spirituality. The paradoxical side of this behavior also dominates. The violence, aggression, obsessive sexuality, magic realism in literature,

214


abstract painting, rock music and dance and modern poetry as well as literature produces transcedence of a different kind. This results in surrealism and syntheism. The loss of function of the neurons results in schizophrenia, autism and degenerations. The increased archaeal induced proliferation of stem cells results in a big sized brain and trunk as in Neanderthals. This archaeal symbiosis produces neanderthalisation and a stem cell syndrome. This produces reverse aging which can be called as an epidemic Benjamin Button syndrome. The lymphocytic stem cells have uncontrolled proliferation and results in autoimmune diseases. The stem cell proliferation results in oncogenesis. The stem cell metabolonomics with inhibited mitochondrial function and anaerobic glycolysis results in metabolic syndrome x. Stem cell markers are increased in schizophrenia and autism and the neurons lack dendritic spines. Stem cell markers are also increased in autoimmune disease. The diabetic metabolism is akin to stem cell metabolism. The cancer cell behaves like the stem cell.1-17 In the metaphysics of evil the unconscious dominates and the behavior is impulsive dictated by primitive thoughts. The unconscious modulated by the cerebellum is responsible for automatic acts producing what is called as psychic automatism. The unconscious parallels what Jung described as the archetypes of the collective unconscious. The metaphysics of evil leads to a syntheistic brain with the dominance of the willpower. The primitive archetypes produce concepts of abstract painting, psychedelic music and dance and postmodern literature or magical realism. All these are modes of connecting with the unconscious. The unconscious produces primitive selfish tendencies leading to individualism and capitalism. The unconscious helps to transcend taboos and creates the surrealistic world. The collective unconscious also produces a sense of spirituality and oneness. It is an impulsive brain with fixations and primitive obsessions. There is cerebellar psychic automatism. This leads to ritualized behaviours. The dominance of the collective unconscious results in ritualized


215

behaviors characteristic of religious worship. The collective unconscious also leads to the creation of obscene art and literature as well as violence which is a form of trancedence. Coprolalic religious ritual ceremonies had been described in some parts of the world. Terrorism and acts of violence are also a type of transcedence. The same phenomena occur in ritual sacrifices in religion, the violence of war and the acquisitiveness of capitalism. The primitive unconscious leads to the will to power. This produces greedy capitalism, dictatorship and fascism. The will to power results in worship of the powerful. It is an individualistic, anarchic, selfish world. The cerebellar world is the primitive world of archetypes in the collective unconscious. The abstract paintings have links with the collective unconscious. The rock music or modern music contains rhythmic primitive chaotic sounds coming out the collective unconscious. The primitive collective unconscious links up post modern literature or magic realism with violence, love, hate, evil, obscenities and death. Thus literature, music, dance and painting helps to overcome reality and rationality producing transcendence. The unconscious brain is formed of an archaeal colony network and is adynamic and inflexible. There is an epidemic of autism and schizophrenia. The loss of function of neurons leads to increased extrasensory perception via archaeal magnetite. This can lead to the lack of development of speech and ritualized behaviours of autism. This also produces the thought disorder, hallucinations and delusions of schizophrenia. It looks like an epidemic cerebellar cognitive, affective disorder.1-17 The goodness is related to conscious brain localized in the cortical areas. The cortical areas mediate moralistic, functionally atheistic, civil society behavior. The civil society depends upon common good. The cortical world is a world of morality, rationality, altruism, civility and decencies. This needs inhibitory power of the cerebral cortex. Such a society is non-capitalistic and works for the common good. It tends to be non creative. The primitive collective spirituality

216


and oneness is lost. It is replaced by goodness based on judgment, reasoning and morality. It is a moralistic world where taboos are banned. This requires synaptic plasticity and is modulated by HERV mediated jumping genes. This needs a dynamic brain and the human cerebral cortex evolved due to the jumping genes generated from human endogenous retroviral sequences. The cerebellar world comparatively is impulsive, criminal, violent, terroristic with love of war, selfish, acquisitive, spiritual, autistic, obsessive, schizophrenic, obscene, evil, ritualized, artistic, illogical and cruel. It is mediated by the archaeal colony network. The stem cell transformation of somatic cells results in HERV resistance and retroviral resistance. Archaeal digoxin inhibits reverse transcriptase by producing magnesium deficiency as well as modulates RNA viral editing inhibiting retroviral replication. This produces lack of HERV jumping genes in this stem cell brain and lack of synaptic plasticity and dynamicity. The stem cell syndrome is characterized by retroviral resistance. Archaeal symbiosis inhibits retroviral infection. The homo sapiens with less of archaeal symbiosis becomes susceptible to retroviral and other RNA viral infection and gets wiped out. The homo neo-neanderthalis are resistance to retroviral and other RNA viral infection and persists. The homo neo-neanderthalis dominates all over the world. But the homo neo-neanderthalis are prone to civilisational disease like malignancy, autoimmune disease, neurodegeneration, metabolic syndrome and neuropsychiatric disorders. The homo neo-neanderthalis becomes extinct after a period of time.1-17 The archaeal induced stem cell syndrome or neanderthalisation is due to global warming and acid rains resulting in increased extremophilic archaeal symbiosis. The archaea catabolizes cholesterol and generates digoxin, bile acids and short chain fatty acids which produce induction of uncoupling proteins. This produces mitochondrial dysfunction and the cell obtains its energetics from glycolysis. Archaeal digoxin produces membrane sodium potassium ATPase


217

inhibition which also contributes to stem cell conversion. The whole body somatic and brain undergoes stem cell conversion and becomes a stem cell phenotype with Warburg metabolic phenotype. The generalized acidity due to global warming and increased atmospheric carbon dioxide also facilitates archaeal growth and stem cell transformation. The acidic pH due to the Warburg phenotype and increased atmospheric carbon dioxide also results in stem cell conversion. The somatic differentiated cell getting converted to stem cells lose their function and become dysfunctional metabolically, neurologically, immunologically and endocrine-wise. This produces the epidemic Benjamin button syndrome and the human species becomes neanderthalic and a collection of immature stem cells. This results in epidemic metabolic syndrome x, degenerations, cancer, autoimmune disease, autism and schizophrenia. The brain becomes converted to a collection of stem cells which are dedifferentiated with loss of function and is like an archaeal colony network. The perception becomes extrasensory and quantal depending on archaeal magnetite. The increased amount of low level EMF perception results in prefrontal cortical atrophy. It also produces cerebellar hypertrophy and the cerebellar cognitive function takes over. This also results in societal changes where evil and spirituality dominates. The world of the logical civil society of the Christian world comes to end and paganistic behavior takes over. The society becomes selfish and dominated by impulsive consumerism and acquisitive capitalism. The world becomes cruel, violent, aggressive and terroristic. Art becomes chaotic and abstract in line with the senses and unconscious. There is a predominance of obsessive and alternate sexuality. Criminal behavior and cruelty dominates. The world is impulsive psychopathic, creative autistic with features of idiotic savants, ritualistic, chaotic, sexual, ugly, anarchic, violent, evil, paganistic, obscene, atheistically spiritual as well as selfish. It mimics the Niezteschean world, the deconstructed world of Derrida, the surrealistic world

218


of Bataille and the nihilistic, anarchic world. There is the death of the individual and life becomes a social value. It is an acephalistic world of Freud and Jung. The art is abstract, the literature is magically real, the music is rock and the dance chaotic. All these results from the extinction of rationality and the dominance of primitive impulsive behavior. A civilization of the senses dominated by the unconscious takes over. The will to goodness given by the cerebral cortex is lost. This results in development of a new homo neo-neanderthal human species with its dominant evilly spiritual cerebellar brain. It produces a surrealistic evil brain with realm of the senses, archetypes, evil spirituality and impulsiveness taking over. It is a kingdom of the collective unconscious and selfish capitalism with the will to power and the realm of the senses.1-17

References [1] Weaver TD, Hublin JJ. Neandertal Birth Canal Shape and the Evolution of Human Childbirth. Proc. Natl. Acad. Sci. USA 2009; 106: 8151-8156. [2] Kurup RA, Kurup PA. Endosymbiotic Actinidic Archaeal Mediated Warburg Phenotype Mediates Human Disease State. Advances in Natural Science 2012; 5(1): 81-84. [3] Morgan E. The Neanderthal theory of autism, Asperger and ADHD; 2007, www.rdos.net/eng/asperger.htm. [4] Graves P. New Models and Metaphors for the Neanderthal Debate. Current Anthropology 1991; 32(5): 513-541. [5] Sawyer GJ, Maley B. Neanderthal Reconstructed. The Anatomical Record Part B: The New Anatomist 2005; 283B(1): 23-31. [6] Bastir M, O’Higgins P, Rosas A. Facial Ontogeny in Neanderthals and Modern Humans. Proc. Biol. Sci. 2007; 274: 1125-1132.


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[7] Neubauer S, Gunz P, Hublin JJ. Endocranial Shape Changes during Growth in Chimpanzees and Humans: A Morphometric Analysis of Unique and Shared Aspects. J. Hum. Evol. 2010; 59: 555-566. [8] Courchesne E, Pierce K. Brain Overgrowth in Autism during a Critical Time in Development: Implications for Frontal Pyramidal Neuron and Interneuron Development and Connectivity. Int. J. Dev. Neurosci. 2005; 23: 153-170. [9] Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, et al. A Draft Sequence of the Neandertal Genome. Science 2010; 328: 710-722. [10] Mithen SJ. The Singing Neanderthals: The Origins of Music, Language, Mind and Body; 2005, ISBN 0-297-64317-7. [11] Bruner E, Manzi G, Arsuaga JL. Encephalization and Allometric Trajectories in the Genus Homo: Evidence from the Neandertal and Modern Lineages. Proc. Natl. Acad. Sci. USA 2003; 100:15335-15340. [12] Gooch S. The Dream Culture of the Neanderthals: Guardians of the Ancient Wisdom. Inner Traditions, Wildwood House, London; 2006. [13] Gooch S. The Neanderthal Legacy: Reawakening Our Genetic and Cultural Origins. Inner Traditions, Wildwood House, London; 2008. [14] Kurtén B. Den Svarta Tigern, ALBA Publishing, Stockholm, Sweden; 1978. [15] Spikins P. Autism, the Integrations of ‘Difference’ and the Origins of Modern Human Behaviour. Cambridge Archaeological Journal 2009; 19(2): 179-201. [16] Eswaran V, Harpending H, Rogers AR. Genomics Refutes an Exclusively African Origin of Humans. Journal of Human Evolution 2005; 49(1): 1-18. [17] Ramachandran V. S. The Reith lectures, BBC London. 2012.

Chapter 18

Global Warming Induced Endosymbiotic Actinidic Archaea and Viroids - Role in Genomic Regulation

222




223

continuous process and can contribute to changes in brain structure and behavior as well as disease process. A hypothesis regarding the role of endosymbiotic actinidic archaea and viroids in genomic regulation is put forward. Endomyocardial fibrosis (EMF) along with the root wilt disease of coconut is also endemic to Kerala with its radioactive actinide beach sands. Actinides like rutile producing intracellular magnesium deficiency due to rutile-magnesium exchange sites in the cell membrane has been implicated in the etiology of EMF.1 Endogenous digoxin, a steroidal glycoside which functions as a membrane sodium-potassium ATPase inhibitor has also been related to its etiology due to the intracellular magnesium deficiency it produces.2 Organisms like phytoplasmas and viroids have also been demonstrated to play a role in the etiology of these diseases.3,

4

Endogenous digoxin has been related to the pathogenesis of Huntington’s disease and trisomy 21.2 The possibility of endogenous digoxin synthesis by actinide based primitive organism like archaea with a mevalonate pathway and cholesterol catabolism was considered.5-8 The role of archaeal viroids was also studied. An actinide dependent shadow biosphere of archaea and viroids in the above mentioned disease states is described.6

Materials and Methods Informed consent of the subjects and the approval of the ethics committee were obtained for the study. The following groups were included in the study: Huntington’s disease and trisomy 21. There were 10 patients in each group and each patient had an age and sex matched healthy control selected randomly from the general population. The blood samples were drawn in the fasting state before treatment was initiated. Plasma from fasting heparinised blood was used and the experimental protocol was as follows (I) Plasma+phosphate buffered

224


saline, (II) same as I+cholesterol substrate, (III) same as II+rutile 0.1 mg/ml, (IV) same as II+ciprofloxacine and doxycycline each in a concentration of 1 mg/ml. Cholesterol substrate was prepared as described by Richmond.9 Aliquots were withdrawn at zero time immediately after mixing and after incubation at 37°C for 1 hour. The following estimations were carried out: Cytochrome F420, free RNA, free DNA, polycyclic aromatic hydrocarbon, hydrogen peroxide, pyruvate, glutamate, hexokinase, ATP synthase, HMG CoA reductase, digoxin and bile acids.10-13 Cytochrome F420 was estimated flourimetrically (excitation wavelength 420 nm and emission wavelength 520 nm). Polycyclic aromatic hydrocarbon was estimated by measuring hydrogen peroxide liberated by using glucose reagent. The statistical analysis was done by ANOVA.

Results The parameters checked as indicated above were: - cytochrome F420, free RNA, free DNA, polycyclic aromatic hydrocarbon, hydrogen peroxide, pyruvate, glutamate, cytochrome C, hexokinase, ATP synthase, HMG CoA reductase, digoxin and bile acids. Plasma of control subjects showed increased levels of the above mentioned parameters with after incubation for 1 hour and addition of cholesterol substrate resulted in still further significant increase in these parameters. The plasma of patients showed similar results but the extent of increase was more. The addition of antibiotics to the control plasma caused a decrease in all the parameters while addition of rutile increased their levels. The addition of antibiotics to the patient’s plasma caused a decrease in all the parameters while addition of rutile increased their levels but the extent of change was more in patient’s sera as compared to controls. The results are


225

expressed in tables 1-6 as percentage change in the parameters after 1 hour incubation as compared to the values at zero time. Table 1 Effect of rutile and antibiotics on cytochrome F 420 and ATP synthase. CYT F420 % (Increase with Rutile)

CYT F420 % (Decrease with Doxy)

ATP synthase % (Increase with Rutile)

ATP synthase % (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.48

0.15

18.24

0.66

4.40

0.11

18.78

0.11

HD

21.68

1.90

57.93

9.64

22.60

1.64

66.86

4.21

Trisomy 21 22.78

2.19

58.97

8.84

23.34

1.58

65.76

3.91

Group

F value

306.749

130.054

449.503

673.081

P value

< 0.001

< 0.001

< 0.001

< 0.001

Table 2 Effect of rutile and antibiotics on free DNA and RNA. DNA % change (Increase with Rutile)

DNA % change (Decrease with Doxy)

RNA % change (Increase with Rutile)

RNA % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.37

0.15

18.39

0.38

4.37

0.13

18.38

0.48

HD

22.12

2.44

63.69

5.14

23.33

1.35

66.83

3.27

Trisomy 21

23.49

1.19

64.63

6.58

23.22

1.35

66.42

4.21

F value

337.577

356.621

427.828

654.453

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group

Table 3 Effect of rutile and antibiotics on HMG CoA reductase and PAH.

Group

HMG CoA R % change (Increase with Rutile)

HMG CoA R % change (Decrease with Doxy)


PAH % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.30

0.20

18.35

0.35

4.45

0.14

18.25

0.72

HD

22.72

1.89

64.51

5.73

22.61

1.42

64.48

6.90

Trisomy 21 23.82

1.78

61.63

7.96

24.06

1.50

63.01

7.76

F value

319.332

199.553

391.318

257.996

P value

< 0.001

< 0.001

< 0.001

< 0.001

226


Table 4 Effect of rutile and antibiotics on digoxin and bile acids. Digoxin (ng/ml) (Increase with Rutile)


Bile acids % change (Increase with Rutile)

Bile acids % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

0.11

0.00

0.054

0.003

4.29

0.18

18.15

0.58

HD

0.53

0.08

0.205

0.041

22.21

2.04

63.84

6.16

Trisomy 21

0.52

0.08

0.208

0.031

21.65

2.37

65.91

4.82

F value

135.116

71.706

290.441

203.651

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group

Table 5 Effect of rutile and antibiotics on pyruvate and hexokinase. Pyruvate % change (Increase with Rutile)

Pyruvate % Hexokinase % change (Decrease change (Increase with Doxy) with Rutile)

Hexokinase % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.34

0.21

18.43

0.82

4.21

0.16

18.56

0.76

HD

21.91

1.71

58.45

6.66

22.88

1.87

65.45

5.08

Trisomy 21

20.95

1.35

60.24

7.16

22.88

1.98

65.45

5.49

F value

321.255

115.242

292.065

317.966

P value

< 0.001

< 0.001

< 0.001

< 0.001

Group

Table 6 Effect of rutile and antibiotics on hydrogen peroxide and glutamate.

Group

H2O2 % change (Increase with Rutile)

H2O2 % change (Decrease with Doxy)

Glutamate % change (Increase with Rutile)

Glutamate % change (Decrease with Doxy)

Mean

±SD

Mean

±SD

Mean

±SD

Mean

±SD

Normal

4.43

0.19

18.13

0.63

4.40

0.10

18.48

0.39

HD

23.52

1.49

63.24

7.36

23.20

1.57

66.65

4.26

Trisomy 21

23.76

1.48

62.14

6.76

23.41

1.55

66.36

4.31

F value

380.721

171.228

372.716

556.411

P value

< 0.001

< 0.001

< 0.001

< 0.001


227

Abbreviation HD - Huntington’s disease

Discussion There was increase in cytochrome F420 indicating archaeal growth. The archaea can synthesize and use cholesterol as a carbon and energy source.14, 15 The archaeal origin of the enzyme activities was indicated by antibiotic induced suppression. The study indicates the presence of actinide based archaea with an alternate actinide based enzymes or metalloenzymes in the system as indicated by rutile induced increase in enzyme activities.16 There was also an increase in archaeal HMG CoA reductase activity indicating increased cholesterol synthesis by the archaeal mevalonate pathway. The archaeal beta hydroxyl steroid dehydrogenase activity indicating digoxin synthesis and archaeal cholesterol hydroxylase activity indicating bile acid synthesis were increased.7 The archaeal cholesterol oxidase activity was increased resulting in generation of pyruvate and hydrogen peroxide.15 The pyruvate gets converted to glutamate and ammonia by the GABA shunt pathway. The archaeal aromatization of cholesterol generating PAH was also detected.17 The archaeal glycolytic hexokinase activity and archaeal extracellular ATP synthase activity were increased. The archaea can undergo magnetite and calcium carbonate mineralization and can exist as calcified nanoforms.18 There was an increase in free RNA indicating self replicating RNA viroids and free DNA indicating generation of viroid complementary DNA strands by archaeal reverse transcriptase activity. The actinides modulate RNA folding and catalyse its ribozymal action. Digoxin can cut and paste the viroidal strands by modulating RNA splicing generating RNA viroidal diversity. The viroids are

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evolutionarily escaped archaeal group I introns which have retrotransposition and self splicing qualities.19 Archaeal pyruvate can produce histone deacetylase inhibition resulting in endogenous retroviral (HERV) reverse transcriptase and integrase expression. This can integrate the RNA viroidal complementary DNA into the noncoding region of eukaryotic non coding DNA using HERV integrase as has been described for borna and ebola viruses.20 The noncoding DNA is lengthened by integrating RNA viroidal complementary DNA with the integration going on as a continuing event. The archaea genome can also get integrated into human genome using integrase as has been described for trypanosomes.21 The integrated viroids and archaea can undergo vertical transmission and can exist as genomic parasites.20, 21 This increases the length and alters the grammar of the noncoding region producing memes or memory of acquired characters.22 The viroidal complementary DNA can function as jumping genes producing a dynamic genome important in storage of synaptic information, HLA gene expression and developmental gene expression. The RNA viroids can regulate mrna function by RNA interference.19 The phenomena of RNA interference can modulate T cell and B cell function, insulin signaling lipid metabolism, cell growth and differentiation, apoptosis, neuronal transmission and euchromatin/ heterochromatin expression. The integration of archaea and RNA viroid complementary DNA can modulate the genomic structure. The integration of nanoarchaea and viroids in to the eukaryotic and human genome produces a chimera which can multiply producing biofilm like multicellular structures having a mixed archaeal, viroidal, prokaryotic and eukaryotic characters which is a regression from the multicellular eukaryotic tissue. This results in a new genotype leading to human diseases like Huntington’s disease and trisomy 21. The microchimeras formed can lead to polyploidy and trisomy 21. The microchimera develops proof reading errors leading to the formation of trinucleotide repeats. DNA


229

polymerase is the proof reading enzyme of the DNA. In the presence of endogenous digoxin there is sodium potassium ATPase inhibition and intracellular magnesium depletion leading on to defects in proof reading function of DNA polymerase in the nucleus during DNA replication. Defective function of DNA polymerase and the proof reading defects leads to generation of trinucleotide repeats. Intracellular magnesium depletion results in defective phosphorylation of MAP (microtubule associated protein). This results in defective microtubule related spindle fiber function and chromosomal non disjunction contributing to trisomy 21. The integrated viroidal RNA complementary DNA can form jumping genes producing defects in gene coding for different proteins and genetic disease. The HERV genes can also function as jumping genes producing defects coding genes as seen in Lesch nyhan syndrome, neurofibromatosis and genetic hyperlipidemias. Thus the integrated actinidic archaea and viroidal RNA complementary DNA can regulate genomic DNA and RNA function.

References [1] Valiathan M. S., Somers, K., Kartha, C. C. (1993). Endomyocardial Fibrosis. Delhi: Oxford University Press. [2] Kurup R., Kurup, P. A. (2009). Hypothalamic digoxin, cerebral dominance and brain function in health and diseases. New York: Nova Science Publishers. [3] Hanold D., Randies, J.W. (1991). Coconut cadang-cadang disease and its viroid agent, Plant Disease, 75, 330-335. [4] Edwin B. T., Mohankumaran, C. (2007). Kerala wilt disease phytoplasma: Phylogenetic analysis and identification of a vector, Proutista moesta, Physiological and Molecular Plant Pathology, 71(1-3), 41-47. [5] Eckburg P. B., Lepp, P. W., Relman, D. A. (2003). Archaea and their potential role in human disease, Infect Immun, 71, 591-596.

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[6] Adam Z. (2007). Actinides and Life’s Origins, Astrobiology, 7, 6-10. [7] Schoner W. (2002). Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem, 269, 2440-2448. [8] Davies P. C. W., Benner, S. A., Cleland, C. E., Lineweaver, C. H., McKay, C. P., Wolfe-Simon, F. (2009). Signatures of a Shadow Biosphere, Astrobiology, 10, 241-249. [9] Richmond W. (1973). Preparation and properties of a cholesterol oxidase from nocardia species and its application to the enzymatic assay of total cholesterol in serum, Clin Chem, 19, 1350-1356. [10] Snell E. D., Snell, C. T. (1961). Colorimetric Methods of Analysis. Vol 3A. New York: Van Nostrand. [11] Glick D. (1971). Methods of Biochemical Analysis. Vol 5. New York: Interscience Publishers. [12] Colowick, Kaplan, N. O. (1955). Methods in Enzymology. Vol 2. New York: Academic Press. [13] Maarten A. H., Marie-Jose, M., Cornelia, G., van Helden-Meewsen, Fritz, E., Marten, P.H. (1995). Detection of muramic acid in human spleen, Infection and Immunity, 63(5), 1652-1657. [14] Smit A., Mushegian, A. (2000). Biosynthesis of isoprenoids via mevalonate in Archaea: the lost pathway, Genome Res, 10(10), 1468-84. [15] Van der Geize R., Yam, K., Heuser, T., Wilbrink, M. H., Hara, H., Anderton, M. C. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages, Proc Natl Acad Sci USA, 104(6), 1947-52. [16] Francis A. J. (1998). Biotransformation of uranium and other actinides in radioactive wastes, Journal of Alloys and Compounds, 271(273), 78-84. [17] Probian C., Wülfing, A., Harder, J. (2003). Anaerobic mineralization of quaternary carbon atoms: Isolation of denitrifying bacteria on pivalic acid (2,2-Dimethylpropionic acid), Applied and Environmental Microbiology, 69(3), 1866-1870.


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[18] Vainshtein M., Suzina, N., Kudryashova, E., Ariskina, E. (2002). New Magnet-Sensitive Structures in Bacterial and Archaeal Cells, Biol Cell, 94(1), 29-35. [19] Tsagris E. M., de Alba, A. E., Gozmanova, M., Kalantidis, K. (2008). Viroids, Cell Microbiol, 10, 2168. [20] Horie M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes, Nature, 463, 84-87. [21] Hecht M., Nitz, N., Araujo, P., Sousa, A., Rosa, A., Gomes, D. (2010). Genes from Chagas parasite can transfer to humans and be passed on to children. Inheritance of DNA Transferred from American Trypanosomes to Human Hosts, PLoS ONE, 5, 2-10. [22] Flam F. (1994). Hints of a language in junk DNA, Science, 266, 1320.

Chapter 19

Global Warming Induced Neo-neanderthalisation and Metabolic Syndrome - Type 2 Diabetes Mellitus with Coronary Artery Disease and Stroke

234




235

continuous process and can contribute to changes in brain structure and behavior as well as disease process. Actinidic archaea has also been related to global warming and human diseases especially metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The growth of endosymbiotic actinidic archaea in relation to climate change and global warming leads to neanderthalisation of the human mind-body system. Neanderthal anthropometry and metabolonomics has been described in metabolic syndrome - type 2 diabetes mellitus, CVA and CAD especially the Warburg phenotype and hyperdigoxinemia. Digoxin produced by archaeal cholesterol catabolism produces Neanderthalisation. Prefrontal cortical atrophy and cerebellar hyperplasia has been related to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD in this communication. This leads on to dysautonomia with sympathetic hyperactivity and parasympathetic neuropathy in these disorders. Actinidic archaeal related cerebellar dominance leads to changes in brain function. The data is described in this paper.1-16

Materials and Methods Fifteen cases, each of metabolic syndrome - type 2 diabetes mellitus, CVA and CAD as well as internet addicts were selected for the study. Each case had an age and sex matched control. Neanderthal anthropometric and phenotypic measurements which included protruding supra-orbital ridges, dolichocephalic skull, small mandible, prominent mid face and nose, short upper and lower limbs, prominent trunk, low index finger-ring finger ratio and fair complexion were evaluated in the cases study. Autonomic function tests were done to assess the sympathetic and parasympathetic system in each case. CT scan of the head was done to have a volumetric assessment of the prefrontal cortex and

236


cerebellum.

Blood

cytochrome

F420

activity

was

assessed

by

spectrophotometric measurement.

Results All the case groups studied had higher percentage of Neanderthal anthropometric and phenotypic measurements. There was low index finger-ring finger ratio suggestive of high testosterone levels in all the patient population studied. In all the case groups studied, there also was prefrontal cortex atrophy and cerebellar hyperplasia. Similarly in the all the case groups studied, there was dysautonomia with sympathetic overactivity and parasympathetic neuropathy. Cytochrome F420 was detected in the entire case group studied showing endosymbiotic archaeal overgrowth. Table 1 Neanderthal phenotype and systemic disease. Disease

Cyt F420 Neanderthal phenotype

Low index finger-ring finger ratio

Diabetes mellitus 65%

72%

72%

CAD

75%

85%

74%

CVA

80%

75%

75%

Internet users

65%

72%

69%

Table 2 Neanderthal phenotype and brain dysfunction. Disease

Dysautonomia Prefrontal cortex atrophy Cerebellar hypertrophy

Diabetes mellitus 64%

84%

69%

CAD

75%

73%

72%

CVA

69%

74%

76%

Internet users

74%

84%

82%


237

Discussion Neanderthal metabolonomics contribute to the pathogenesis of these disorders. There were Neanderthal phenotypic features in all the case groups studied as well as low index finger-ring finger ratios suggestive of increased testosterone levels. Neanderthalisation of the mind-body system occurs due to increased growth of actinidic archaea as a consequence of global warming. Neanderthalisation of the mind leads to cerebellar dominance and prefrontal cortex atrophy. This leads to dysautonomia with parasympathetic neuropathy and sympathetic hyperactivity. This can lead to the pathogenesis of type 2 diabetes mellitus with CAD and CVA. Global warming and the ice age produces increased growth of extremophiles. This leads to increased growth of actinidic archaeal endosymbiosis in humans. There is archaeal proliferation in the gut which enters the cerebellum and brain stem by reverse axonal transport via the vagus. The cerebellum and brain stem can be considered as an archaeal colony. The archaea are cholesterol catabolising and use cholesterol as a carbon and energy source. The actinidic archaea activates the toll receptor HIF alpha inducing the Warburg phenotype resulting in increased glycolysis with generation of glycine as well as pyruvate dehydrogenase suppression. The accumulated pyruvate enters the GABA shunt generating of succinyl CoA and glycine. The archaeal catabolism of cholesterol produces ring oxidation and generation of pyruvate which also enters the GABA shunt scheme producing glycine and succinyl CoA. This leads to increased synthesis of porphyrins. In the setting of digoxin induced sodium potassium ATPase inhibition the dipolar porphyrins produce a pumped phonon system resulting in the Frohlich model Bose-Einstein condensate and quantal perception of low level EMF. Low level EMF pollution is common with internet usage. Perception of low level of EMF leads to neanderthalisation of

238


the brain with prefrontal cortex atrophy and cerebellar hyperplasia. The archaea which reaches the cerebellum from the gut via the vagus nerve proliferates and makes the cerebellum dominant with resultant suppression and atrophy of the prefrontal cortex. This leads to wide spread autistic and schizophrenic traits in population. The actinidic archaea induces the Warburg phenotype with increased glycolysis, PDH inhibition and mitochondrial suppression. This produces Neanderthalisation of the mind-body system. This leads to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The actinidic archaea secretes RNA viroids which block HERV expression by RNA interference. The HERV suppression contributes to the inhibition of prefrontal cortex development in Neanderthals and cerebellar dominance. Archaeal digoxin produces sodium potassium ATPase inhibition and magnesium depletion causing reverse transcriptase inhibition and decreased generation of HERV. The HERV contributes to the dynamicity of the genome and are required for the development of the prefrontal cortex. The HERV suppression contributes to retroviral resistance in Neanderthals. The actinidic archaea catabolizes cholesterol leading to cholesterol depleted state. Cholesterol depletion also leads to poor synaptic connectivity and decreased development of prefrontal cortex. This is not genetic change but a form of symbiotic change with endosymbiotic actinidic archaeal growth in the body and brain. This brain change leads to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. Internet use and low level EMF pollution is common in this century. This results in increased low level EMF perception by the brain by the digoxin-porphyrin mediated pumped phonon system created Bose-Einstein condensates contributing to prefrontal cortex atrophy and cerebellar dominance. Cerebellar dominance leads to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The porphyrin mediates extrasensory perception of low level


239

EMF. This can also contributes to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD in Neanderthals. The modern population is a hybrid of homo sapiens and homo neanderthalis. The extrasensory/quantal perception due to dipolar porphyrins and digoxin induced sodium potassium ATPase inhibition and the generated pumped phonon system mediated quantal perception of low level EMF. This leads to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The archaeal cholesterol catabolism leads to increased synthesis of digoxin which can modulate glucose transport into the cell and insulin sensitivity. Digoxin promotes tryptophan transport over tyrosine. Tyrosine deficiency leads to dopamine deficiency and morphine deficiency. This leads to a morphine deficiency syndrome in Neanderthals. This contributes to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. This can also contribute to addiction and eating behaviour in metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The Neanderthals were essentially meat eaters taking a ketogenic diet. The acetoacetic acid is converted to acetyl CoA which enters the TCA cycle. When the Neanderthal hybrids consume a glucogenic diet owing to the spread of settled civilisation it produces pyruvate accumulation owing to PDH suppression in Neanderthals. The increased archaeal growth activates the toll receptor and induces HIF alpha resulting in increased glycolysis, PDH suppression and mitochondrial dysfunction - the Warburg phenotype. The pyruvate enters the GABA shunt pathway producing glutamate, ammonia and porphyrins resulting in metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. Neanderthals consuming a ketogenic diet produces more of GABA an inhibitory neurotransmitter. There is less production of glutamate the predominant excitatory neurotransmitter of the prefrontal cortex and consciousness pathways. This leads onto dominance of cerebellar function. The

240


Neanderthal hybrids have cerebellar dominance and less of conscious behaviour. The predominant homo sapiens had prefrontal cortex dominance over the cerebellum resulting in more of conscious behaviour. This leads to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The Neanderthals consuming a glucogenic diet produces increased glycolysis in the setting of PDH inhibition. This produces the Warburg phenotype. The predominance of glycolysis and suppression of mitochondrial function results in glycemia and metabolic syndrome - type 2 diabetes mellitus with CAD and CVA. The increased mitochondrial PT pore hexokinase leads to mitochondrial dysfunction resulting in metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The glycolytic intermediate 3-phosphoglycerate is converted to glycine resulting in NMDA excitotoxicity and metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The cerebellar hyperplasia results in sympathetic hyperactivity and parasympathetic neuropathy. Vagal neuropathy and sympathetic over activity can contribute to glycogenolysis and lipolysis resulting in metabolic syndrome x. Vagal neuropathy and sympathetic over activity can contribute to metabolic syndrome x, CVA and CAD. Cerebellar dominance and cerebellar cognitive affective dysfunction can contribute to metabolic syndrome x, CVA and CAD. The increased porphyrin synthesis resulting from succinyl CoA generated by GABA shunt and glycine generated by glycolysis contributes to increased extrasensory perception of low level EMF important in metabolic syndrome type 2 diabetes mellitus, CVA and CAD. The archaeal cholesterol catabolism generates digoxin which produces sodium potassium ATPase inhibition and increase in intracellular calcium and decrease in intracellular magnesium. The increase in intracellular calcium opens the mitochondrial PT pore resulting in mitochondrial dysfunction and metabolic


241

syndrome - type 2 diabetes mellitus, CVA and CAD. The increase in intracellular calcium can modulate the neurotransmitter release from presynaptic vesicles. This can modulate neurotransmission. Digoxin induced magnesium depletion can remove the magnesium block on the NMDA receptor resulting in NMDA excitotoxicity. Digoxin induced magnesium depletion can inhibit reverse transcriptase activity and HERV generation modulating the dynamicity of the genome. Digoxin induced intracellular calcium accumulation and magnesium depletion can modulate G-protein and protein tyrosine kinase dependent neurotransmitter and endocrine receptors. This can produce digoxin induced neuro-immuno-endocrine integration. Digoxin functions as a Neanderthal master hormone. This leads to metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The actinidic archaea are cholesterol catabolising and leads to low levels of testosterone and estrogen. The Neanderthals consume a low fibre diet with low lignan content. The actinidic archaea has cholesterol catabolizing enzymes generating more of testosterone than estrogens. This contributes to estrogen deficiency and testosterone overactivity. The Neanderthal population is hypermales with concomitant right hemispheric dominance and cerebellar dominance. Testosterone suppresses left hemispheric function. The high testosterone levels in Neanderthals contribute to a bigger brain. The Neanderthals males as well as females had a higher level of testosterone contributing to gender equality and gender neutral states. There was group identity and group motherhood with no differences between roles of both males and females. This also resulted in matrilinearity. The higher testosterone levels in males as well as females led to alternate type of sexuality and aberrant behaviour. The homo sapiens eat a high fibre diet with low cholesterol and high lignan content contributing to estrogen dominance, left hemispheric dominance and cerebellar hypoplasia. Homo sapiens had higher reproductive rates and overtook the

242


Neanderthal population resulting in its extinction. This leads to a higher incidence of metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The homo sapien population was conservative with normal sexual mores, family values and patriarchal type of behaviour. The role of females the homo sapien community was inferior to males. The increasing generation of Neanderthal hybrids due to climate change mediated archaeal overgrowth leads to gender equality and equidominance of male and female in this century and higher incidence of metabolic syndrome - type 2 diabetes mellitus, CVA and CAD. The cholesterol catabolism results in cholesterol depletion and bile acid deficiency. Bile acids bind to FXR, LXR and PXR modulating lipid and carbohydrate metabolism. This leads to metabolic syndrome - type 2 diabetes mellitus in the presence of bile acid deficiency. Bile acid uncouples oxidative phosphorylation and its deficiency leads to obesity of metabolic syndrome x. Cholesterol depletion also leads to vitamin D deficiency. Vitamin D binds to VDR and produces immunomodulation. Vitamin D deficiency can also produce rickets and contribute to the phenotypic features of Neanderthals. Vitamin D deficiency can contribute to brain development resulting in macrocephaly. Vitamin D deficiency contributes to insulin resistance and truncal obesity of Neanderthals. Vitamin D deficiency contributes to the fairness of the Neanderthal skin as a phenotypic adaptation. The Neanderthal phenotypic features are due to vitamin D deficiency and insulin resistance. Thus global warming and increased endosymbiotic actinidic archaeal growth leads to cholesterol catabolism and generation of the Warburg phenotype resulting in increased porphyrin synthesis, extrasensory low EMF perception, prefrontal cortex atrophy, insulin resistance and cerebellar dominance. This leads on to neanderthalisation of the body and brain and higher incidence of metabolic syndrome - type 2 diabetes mellitus, CVA and CAD.


243

References [1] Weaver TD, Hublin JJ. Neandertal Birth Canal Shape and the Evolution of Human Childbirth. Proc. Natl. Acad. Sci. USA 2009; 106: 8151-8156. [2] Kurup RA, Kurup PA. Endosymbiotic Actinidic Archaeal Mediated Warburg Phenotype Mediates Human Disease State. Advances in Natural Science 2012; 5(1): 81-84. [3] Morgan E. The Neanderthal theory of autism, Asperger and ADHD; 2007, www.rdos.net/eng/asperger.htm. [4] Graves P. New Models and Metaphors for the Neanderthal Debate. Current Anthropology 1991; 32(5): 513-541. [5] Sawyer GJ, Maley B. Neanderthal Reconstructed. The Anatomical Record Part B: The New Anatomist 2005; 283B(1): 23-31. [6] Bastir M, O’Higgins P, Rosas A. Facial Ontogeny in Neanderthals and Modern Humans. Proc. Biol. Sci. 2007; 274: 1125-1132. [7] Neubauer S, Gunz P, Hublin JJ. Endocranial Shape Changes during Growth in Chimpanzees and Humans: A Morphometric Analysis of Unique and Shared Aspects. J. Hum. Evol. 2010; 59: 555-566. [8] Courchesne E, Pierce K. Brain Overgrowth in Autism during a Critical Time in Development: Implications for Frontal Pyramidal Neuron and Interneuron Development and Connectivity. Int. J. Dev. Neurosci. 2005; 23: 153-170. [9] Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, et al. A Draft Sequence of the Neandertal Genome. Science 2010; 328: 710-722. [10] Mithen SJ. The Singing Neanderthals: The Origins of Music, Language, Mind and Body; 2005, ISBN 0-297-64317-7. [11] Bruner E, Manzi G, Arsuaga JL. Encephalization and Allometric Trajectories in the Genus Homo: Evidence from the Neandertal and Modern Lineages. Proc. Natl. Acad. Sci. USA 2003; 100: 15335-15340.

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[12] Gooch S. The Dream Culture of the Neanderthals: Guardians of the Ancient Wisdom. Inner Traditions, Wildwood House, London; 2006. [13] Gooch S. The Neanderthal Legacy: Reawakening Our Genetic and Cultural Origins. Inner Traditions, Wildwood House, London; 2008. [14] Kurtén B. Den Svarta Tigern, ALBA Publishing, Stockholm, Sweden; 1978. [15] Spikins P. Autism, the Integrations of ‘Difference’ and the Origins of Modern Human Behaviour. Cambridge Archaeological Journal 2009; 19(2): 179-201. [16] Eswaran V, Harpending H, Rogers AR. Genomics Refutes an Exclusively African Origin of Humans. Journal of Human Evolution 2005; 49(1): 1-18.

Climate Change and Human Metabolonomic Evolution

Climate Change and Human Metabolonomic Evolution

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