Authentic Biochemistry

As an hypothetico-deduction,  Dr. Guerra proposes that the Recombination Activating Gene-RAG System is a Potential Candidate in Age Associated Morbidity. In conjunction with a neutral sphingomyelinase and the subsequent synthesis of diacylglycerol thence promoting activation of a PKC-Zeta, T cell receptor translocation and activation are obtained.  Prior RAG mediated recombination events in CNS-resident lymphocytes, associated microglia and neurons can lead to recombination event epigenomic ontologies that either promote or curtail a resident hyperimmune response   leading to classical neurodegenerative diseases of the elderly. References: J. Biol. Chem. 1998;273:14550-14559 Frontiers in Immunology.2014. 5:100 Front Cell Dev Biol. 2019; 7: 226. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Single-nucleotide polymorphisms and  copy-number variations (CNV’s)  result from genome wide chromosomal abnormalities including large deletions and duplications where the the immune system appears to play a major role in  the accumulation of chromosomal variation. Aging in humans may be linked to immune-mediated epigenomic epistasis as facilitated by Recombination Activating Gene proteins RAG1 & RAG2 that are canonically linked to V(D)J recombination of the T cell receptor and the B cell immunoglobulins. FEBS J. 2017 Jun; 284(11): 1590–1605. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Neuroinflammatory mediators play a critical role in the pathophysiology of brain ischemia, exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair. These processes occur throughout life and involve the immune system, biochemical pathways, cellular turnover and alteration of gene expression. Signal transduction cascades allow for genome editing to epigenomic mediation of metabolic event ontologies. Aging is a process whereby these processes lose specificity and valence, increasingly functioning without appropriate fine control leading to the potential for chronic and more rarely, acute disease states that ultimately result in mortality --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

An Introduction to the theory of immunoepigenetic tailoring of human instanence. Dr. Guerra Authentic Biochemistry Podcast Studios --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

J Immunol August 1, 2017, 199 (3) 874-884 Ann Rev Cell Dev Biol 2018. 34:111-136 Blood. 2016 Apr 14;127(15):1930-9 J BiolChem. 2017 Aug 25; 292(34): 14292–14307 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

What is involved to make a sound decision? Biochemistry is a scientific discipline; one that examines and interprets the foundational structures and functions of living systems. As with any judgment, as there are reasons for believing, there are also reasons for disbelieving, and the freely willed decision to choose which, should involve the discovery of truths to use as exemplars for seeking coherence and foundation to the premises that necessarily and sufficiently support the better argument for that decision Listen to my lecture to learn the details of this unfolding discussion that recombines epistemology with metaphysics as re-purposed to find Authentic Biochemistry. DJGPhD 31 March 2021 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Annual Review of Cell and Developmental Biology Vol. 34:111-136 Journal of Neuroscience 23 October 2019, 39 (43) 8576-8583 Archivum Immunologiae et Therapiae Experimentalis 2013 Apr;61(2):119-25. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

 In this foundational lipid absorption lecture,  Dr. Guerra address the roles of apo- lipoproteins, triacylglycerol and cholesteryl esters with membrane associated caveolae transport in adipocytes, endothelia and skeletal muscle. An Authentic Biochemistry Podcast Production. 25 March 2021. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Electron transport and the anapleurotics of intermediary metabolism. Dr. Daniel J. Guerra Authentic Biochemistry Studios 21.3.21 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

•Impaired immunological responsiveness is common in the elderly •The immunological competence of an individual is determined by the presence of mature lymphocytes formed in primary lymphoid organs, and secondary lymphoid tissues such as the liver, lung and GI tract. •Immunological equilibrium requires steady lymphocyte output, and controlled expansion •Thymic and lymph-node stromal microenvironments thus represent key elements in the development of the adaptive immune system. Consequently, impairment of the lymphoid microenvironment will ultimately lead to insufficient primary and secondary immune responses or to the decline of thymic selection, manifesting in immune senescence accompanied by late-onset autoimmune disorders, often observed in elderly. •Self-tolerant cytotoxic and helper T-lymphocytes, the crucial regulator cells in adaptive immune responses, develop in the specialized epithelial network of the thymus. The thymus, however, gradually loses its capacity to support lymphopoiesis in an involution

•Cytokines regulate the intensity and duration of the immune response, and  they can act as growth factors or stimulants or even inhibitors of T cell amplification and differentiation. •Cytokines are glycoproteins that are synthesized through a dolichol PP mediated pathway in the ER and are thus dependent upon prenyl lipid metabolism Endoplasmic reticulum localized ADPGK serves glycoprotein synthesis and also functions to control glycolytic vs. aerobic bioenergetic intermediary metabolic agency in lymphocytes. Scientific Reports volume 9, Article number: 14248 (2019) --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

1. Glucokinase- GK is in the neuron 2.Control over glycolysis via GK mediates neural transmission 3.  Neuronal GK further functions on  the appetite/satiety axis thus partially regulating the HPA axis 4. Aging and immune associated dysfunction of these glycolytic systems are associated with neurodegeneration and the loss of neuronal action potential mediated learning, memory, and mood. Therefore, metabolic control over the severity of chronological age and the immunosenescence of the CNS can be exacerbated by visceral obesity thus linking CNS decline to the major causes of morbidity and mortality in the aging human population. Curr Opin Lipidol. 2015 Apr; 26(2): 88–95 Am J Physiol Endocrinol Metab. 2016 Jul 1; 311(1): E42–E55 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

If  γ-aminobutyric acid (GABA) concentration drops significantly in the synaptic cleft, excitotoxicity can obtain, sometimes presenting with epileptic convulsions.This can be reversed by decreasing the concentration of L-glutamate via control over the activity of glutamate dehydrogenase, glutamine synthetase and glutamate transporters or by  the inhibition of  γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter l-glutamic acid. Trends in Cell Biology 2020. 30.6: 440-451. Chem. Rev. 2018. 118. 7: 4037–4070 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

A basic lecture on reactive oxygen synthesis and reduction coupled with glutathione, folic acid and amino acid metabolism. This lecture is foundational for subsequent synthesis with neural transmission, microglial activation and exicitotoxicity leading to neurodegeneration in the aging human CNS. Please subscribe, rate and review, and  contribute to Authentic Biochemistry! djgphd@gmail.com Published 9 March 2021 by Dr Daniel J. Guerra. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

CPS-1 activity is regulated by liver enriched transcription factors as well as Sirtuin-mediated de-acylation. Glutaminase breaks down glutamine into glutamate and ammonia. Glutamate also yields additional NH4+ via the enzyme glutamate dehydrogenase. From here, ammonia is initially incorporated into hepatocyte mitochondria and ultimately results in the formation of urea. Urea subsequently leaves the hepatocyte cytoplasm and is ultimately excreted in urine. Glutaminase-1 (GLS1) is a mitochondrial enzyme found in endothelial cells (ECs) that metabolizes glutamine to glutamate and ammonia and glutaminolysis modulates the function of human umbilical vein endothelia.Glutamine deprivation or GLS1 inhibition also stimulated the production of reactive oxygen species and this was associated with a marked decline in heme oxygenase-1 (HO-1) expression. GLS1 inhibition also sensitized umbilical endothelia to the cytotoxic effect of hydrogen peroxide; a process that is blocked by the overexpression of Heme oxygenase 1. In

Glutaminase breaks down glutamine into glutamate and ammonia. Glutamate also yields additional urea via the enzyme glutamate dehydrogenase. From here, ammonia is initially incorporated into hepatocyte mitochondria and ultimately results in the formation of urea. Urea subsequently leaves the hepatocyte cytoplasm and is ultimately excreted in urine. Sirtuin mediated control over glutamate dehydrogenase and carbamoyl-P synthetase via discrete and potentiating  ADP ribosylation and deacylation is associated with pancreatic insulin secretion, hepatic amino acid utilization and the potential for pathobiochemical sequalae --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

SIRT5 causes deglutarylation and functional activation of glutamate dehydrogenase 1  which is  essential to cellular glutaminolysis.Indeed, SIRT5 supports the anaplerotic transamination entry of glutamine and other amino acids as alpho ketoglutarate into the TCA cycle in malignant phenotypes of colorectal cancer via activation of the glutamate dehydrogenase1. Sirt5 is known to regulate the activity of the urea cycle enzyme, carbamoyl phosphate synthase 1 (CPS1). SIRT5 mediated de-glutarylated CPS1 is elevated in activity to maintain urea cycle competency during active amino acid incorporation into the bioenergetic machinery thus promoting the potentiation of tumorigenesis. Science. 2011 Nov11; 334(6057): 806–809 Cell Metab 2014 Apr 1;19(4):605-17. Nat Commun. 2018 Feb7;9(1):545 Cell. 2006 Sep 8;126(5):941-54 Mol Cell. 2013 Jun 6; 50(5): 686–698 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

The Pyruvate dehydrogenase hydrated E1-E2 interface is  enthalpy driven, while the dehydrated  E3-peripheral subunit binding domain complex is driven by entropy obtaining a favourable  delta G= delta H-T delta S=  -33.4kj mol where the domain interfacial hydration obtains surface  thermal complementarity  and contributes finally to an aggregate  strength of multiple affinities of individual non-covalent binding interactions via enthalpy-driven catalysis. Lipoamidase activity of mitochondrial Sirtuin 4 modulates cellular fate by generating a  debilitating removal of PDH-E2 dihydrolipoyllysine acetyltransferase-bound lipoic acid  thus driving glutaminolysis over glucose oxidation. Cell. 2014 Dec 18; 159(7): 1615–1625. PNAS | August 23, 2016 | vol. 113 | no. 34 Structure VOLUME 13, ISSUE 8, P1119-1130, AUGUST 01, 2005 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

•Free energy change(chemical potential difference) for transporting 1 mole of a substance from region where its concentration is C1 (e.g., Cout) to region where its concentration is C2 (e.g., Cin): ∆G= RTln(C2/C1) (favorable with ∆G< 0 if C2< C1) •Transport of ionsacross membrane (must consider electrical potential in addition to concentration difference): ∆G= RTln(C2/C1) + ZF ∆Y (Z=charge of ion, F=Faraday’s constant, ∆Y=membrane  electrical potential in volts) •Coupled transport (active transport): ∆G= RTln(C2/C1) + ∆G´ (∆G´ of coupled process, such as ATP hydrolysis, may be  negative enough to compensate for unfavorable transport  against concentration gradient when RT ln (C2/C1) > 0) •Diffusional transport: movement of substance from high to low concentration across membrane (down concentration gradient) –Non-facilitated diffusion across lipid bilayer (slow for most biological substances) –Facilitated diffusion (accelerated diffusion by making membrane more permeable to specific tr

Mini Lecture 1 on Membrane Physiological Biochemistry. The amino acid sequence of membrane associated polypeptides obtains secondary structure, glycosylation, acylation and hydropathy which confer functionality (in part) by targeting specific membrane domains. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message