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3rdInternational Conference on Hematology & Blood Disorders
November 2-4, 2015 Atlanta, Georgia USA
Biophysical Aspects of the
Robert M. Davidson M.D. Ph.D. FAIS*
Ann Lauritzen, Stephanie Seneff,
Stephen D. Kette, Glyn Wainwright,
Anthony Samsel, and Sydney J. Bush
*Fellow, The American Institute of Stress
Physician and Medical Researcher, Kilgore, Texas, USA
Email: [email protected]
UNIVERSAL NON-SPECIFIC MESENCHYMAL
• The UNMR refers to the different causes of an
acceleration of metabolism of connective tissue of blood
vessels as well as that of all organs studied [Hauss et al.
• Selye (1966) described a local or general intravascular
coagulation that occurs in response to certain toxins or
systemic stress [Selye, Thrombohemorrhagic Phenomena,
Sanarelli-Shwartzman Phenomenon (SSP), a.k.a.
Generalized Shwartzman Reaction (GSR)
• Activation of the coagulation system is thought to be the primary
event in a clinical syndrome involving disseminated intravascular
coagulation (DIC), a consumptive coagulopathy of the
microvasculature, which can be localized or generalized, acute,
subacute, or chronic.
• Fibrinolysis, if it occurs, is thought to be a secondary protective
phenomenon [Bang et al. Thrombosis and Bleeding Disorders, 2014]
The Major “Players" in Our Passion Play
Interfacial water stress
TIME IS OF THE ESSENCE
A prompt response is often required: there’s not much time for de
novo protein synthesis and diffusion of substrates
• In the setting of acute bleeding: to achieve hemostasis and maintain organ
• In the setting of critical care medicine: associated with inflammatory stress,
e.g., ARDS, DIC syndrome, severe trauma, acute coronary and
• In the setting severe infectious disease, e.g. septicemia, Purpura
fulminans, Hemorrhagic Fever viruses (Dengue, Ebola, etc.)
“a rare syndrome of intravascular thrombosis and hemorrhagic
infarction of the skin that is rapidly progressive and is
accompanied by vascular collapse and disseminated intravascular
coagulation. It may be classified as (1) neonatal, (2) idiopathic, or
(3) acute infectious.”
The 4 primary features of acute infectious purpura fulminans are
• Large purpuric skin lesions
• Disseminated intravascular coagulation (DIC)
THE INITIAL COMMON PATHWAY
Exogenous Interfacial Water Stress (EIWS)
Davidson, Robert M.; Seneff, Stephanie. 2012.
Entropy 14, no. 8: 1399-1442.
Davidson, R.M.; Lauritzen, A.; Seneff, S. 2013.
Entropy 15, 3822-3876.
Two Important Characteristics
of Inflammatory States
Low pH: 4.7 - 5.7 Tsai, et al (2014)
trauma (fractures, hematomas)
High oxidative stress: Khansari et al (2009);
Reuter et al (2010); Kim et al (2013)
The Redox Potential of Water is
“The redox potential increases as the pH decreases
(increasing [H+])”. --- Martin Chaplin
Our Proposal for pH Dependent e(aq) Speciation
Mizuse, K. and Fujii, A. (2013). Characterization of a Solvent-Separated Ion-Radical Pair in Cationized Water Networks: Infrared
Photodissociation and Ar-Attachment Experiments for Water Cluster Radical Cations (H2O)n+ (n = 3–8). The Journal of Physical
Chemistry A, 117, 929-938.
Larsen, R.E., Glover, W.J. and Schwartz, B.J. (2010). Does the hydrated electron occupy a cavity? Science, 329, 65-69.
ATP and PAPS are unstable in the setting
• pH instability of ATP in low pH range
“…but is rapidly hydrolysed at extreme pH.”
• pH instability of PAPS in low pH range
“…should be made up in pH 8.0 buffer and stored aliquoted at -70o
• Sulfotransferase (SULT) pH optima are typically neutral pH range
to slightly alkaline
Need for a Universal Sulfurylation Factor
in Inflamed Tissue
• A prompt response is required for the GSP/SSP,
DIC, Purpura Fulminans
• There is not enough time for de novo protein
synthesis and diffusion of substrates, and/or
• To rescue PAPS and ATP from a "hydrolytic fate“
or a recycling, proofreading “mistake”
Our Proposal for a Universal Sulfurylation
WE PROPOSE: 2-O-sulfate L-ascorbate radical plays a central role in the
"universal nonspecific mesenchymal reaction", which has also been referred to as
the Sanarelli-Shwartzman phenomenon.
• Takebayashi, J., Kaji, H., Ichiyama, K., Makino, K., Gohda, E., Yamamoto, I. and Tai, A. (2007). Inhibition of free radical-induced erythrocyte
hemolysis by 2-O-substituted ascorbic acid derivatives. Free Radical Biology and Medicine, 43, 1156-1164.
• Verlangieri, A.J. and Mumma, R.O. (1973). In vivo sulfation of cholesterol by ascorbic acid 2-sulfate. Atherosclerosis,17, 37-48.
• Cabral, J., Haake, P. and Kessler, K. (1998). Rearrangement of 3-Acyl Derivatives of L-Ascorbic Acid. Journal of Carbohydrate Chemistry, 17, 1321-1329.
Need for a Universal Phosphorylation
Factor in Inflamed Tissue
• A great need also exists for an ultimate
phosphorylation factor in inflamed tissue to
(a) rescue ATP from a "hydrolytic fate“, and
(b) rescue DNA/RNA from proofreading
Proposed TBP TS for sulfuryl and phosphoryl
group transfer by Ascorbate derivative radicals
“Flattening” the Free Energy Landscape
for Biological Group Transfers, generally
• Having proposed chemical biological means by which
the Ascorbate radical can catalyze sulfuryl and
phosphoryl group transfer, under conditions of
inflammatory stress, it soon became apparent that:
• Similar chemical biological means might exist by
which the Ascorbate radical can also catalyze
nitrosyl, acyl, and glycosyl group transfer, under
conditions of inflammatory stress
L. Amudat, Ph.D.
A NEW PARADIGM FOR
• Null hypothesis: The Cu1+ Ascorbate radical complex does
NOT directly modulate miRNA synthesis by RNA polymerase III
in human patients with cancer, i.e. under conditions of
inflammatory stress (low pH and high oxidative stress).
• Application: Disproving the null hypothesis would allow us to
assert that the Cu1+ Ascorbate radical complex directly
modulates miRNA synthesis by RNA polymerase III in humans
with cancer, perhaps as a sequela of a proofreading "error" or
a sequela of dysregulating of a mesenchymal stem cell, under
conditions of inflammatory stress.
Fractones have been referred to as stem cell “niches” and they are thought to regulate
cytoskeletal assembly and organize the ECM of the heart, gut, brain, and bone
marrow/RES. They have complex cytoarchitectures consisting of stem cells, progenitor
cells, supporting cells, and laminin-rich basement membranes (Hochman-Mendez et al
Frederic Mercier and his associates have studied neural stem cell niches and described
“particulate extracellular matrix structures that I previously characterized in both the
developing and adult brain”. --- F. Mercier (personal statement)
“In the neural stem cell niche of the adult brain, I have demonstrated that fractone-
associated heparan sulfate proteoglycans serve as captors and activators of growth
factors to regulate neural stem cell proliferation.”
Mercier, F., Kitasako, J.T. and Hatton, G.I. (2002). Anatomy of the brain neurogenic zones revisited: fractones and the
fibroblast/macrophage network. J Comp Neurol, 451, 170-188.
CNS Fractones Need Sulfur
• GAGs and HSPGs need a UNIVERSAL SULFURYLATION
FACTOR, e.g. 2-O-sulfate-L-ascorbate radical might
preempt and supercede PAPS/SULTS
• CNS fractones need BOTH ascorbate and sulfur
• HSPGs have been shown to be low in sulfur at autopsy of
CNS fractones in Autism
Corley et al (2012); Mercier et al (2012); Meyza et al (2012); Pearson et al (2013); Mercier
et al (2011)
High-dose Intravenous Ascorbate
in Critical Care Medicine
• High Dose Intravenous Ascorbate has become
• Evidence now exists to suggest an important role
in both the prevention and management of
critical care disease characterized by endothelial
dysfunction [Oudemans-van Straaten, 2014;
Early Reversal of Endothelial Dysfunction
SOURCE: Oudemans-van Straaten, H.M., Spoelstra-de Man, A.M. and de Waard, M.C. (2014). Vitamin C revisited. Critical
care (London, England), 18, 460.
Ascorbate radical and putative 2-O-substituted L-
Ascorbate derivative radicals,
(a) catalyze group transfer
(b) modulate redox kinetics.
The catalysis and modulation function for Vitamin C has
supramolecular, epigenetic, biophysically-pleiotropic
implications which apply to all aspects of medicine.
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