Authentic Biochemistry

1. Corticotropin releasing factor (CRF) or hormone (CRH) is one of several neurohormones synthesized by specific hypothalamic nuclei in the brain and released into the portal system which bathes the anterior pituitary 2. CRF has marked CNS effects by acting at higher centers in the brain: cortical regions where there is a widespread distribution of CRF neurons. 3. Major role of CRF is to prepare the organism for an appropriate response to various stressors such as physical trauma, insults to the immune system and social interactions 4. It is the hyper- or hyposensitivity of the system that can lead to human pathologies such as anxiety, depression and feeding disorders 5. The hypothalamus induced combined pituitary hormone deficiency, which  is responsible for  systemic hypoplasia is the result of a neutral sphingomyelinase (SMPD3)deficiency 6. SMPD3  deficiency triggers acid sphingomyelinase (ASM) plus de novo CER synthesis and salvage CER production  from sphingosine with concomitant alte

Naïve T Cell metabolic regulationinvolves allosteric and kinetic mechanisms for maximum capacity to switch from glucose uptake to fatty acylCoA utilization for bioenergetic demand. Multiple mechanisms of this coordinated regulation involve the fatty acyl CoA concentration modulation by fine tuning cyctosolic fatty acid synthesis from glucose or lactate or amino acids vs. mitochondrial  beta oxidation to drive the ATP concentration to levels necessary to prepare for cell proliferation and evenbtually cytokine synthesis and secretion. Published 06 January 2021. Dr Daniel J. Guerra,  Authentic Biochemistry . --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

There is a requirement of cholesterol  and ceramides for the maintenance of neuronal  and T cell porosome integrity, accompanying  an interaction of phosphatidic acid (PA) and polyphosphoinositide (PI) lipids with syntaxin-1A where these lipids are necessary for neurotransmitter or cytokine secretion in association with calcium channels  modulated by lipid domain formation upon sphingomelinase and fatty acyltransferase activities.  Complex lipid  composition and three dimensional sequence topology  differs between the inner and outer leaflet of the bilayer at descrete lipid raft domains of the endomembraneous and plasmamembrane where these  macromolecular structures contribute to the polarity of transport, access, and differential signaling uniquely essential for cell communication in the CNS and immune synapse. Published on 05 Jan 2021 Authentic Biochemistry Dr Daniel J. Guerra, Ph.D. SUBSCRIBE to my PODCAST, share it with 5 or more  other intelligent individuals

Cellular long chain acyl-CoA concentrations are controlled by multiple networked and coherent  metabolic pathways ( including mitochondrial β-oxidation versus Golgi-ER-PL complex lipid synthesis versus glyceropholipid and sphingolipid hydrolysis), which functionally associate  resident  acyl-CoA in cellular bioenergetic and signaling pathways. Thus, the regulation of PFK-1 by its direct interaction with acyl-CoA generates downstream interconnected alterations in metabolic flux through glycolysis, the OPP and mitochondrially associated oxidative metabolism plus  vesicular trafficking and directed  subcellular localization  associated with porosomes. Biol Open. 2019 Oct 15; 8(10): bio040311. Biochem Soc Trans. 2015 Apr;43(2):193-8.) J of Molecular and  Cellular Medicine 2014. 18: pp.1927 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Naive T lymphocytes, as opposed to memory  T cells(which are more common in aging) carry out homolactate fermentitive glycolysis.  Memory cells are operating under complete aerobic metabolism involving  mitochondrial bioenergetics including the TCA cycle but also fatty acid oxidation as a source for reducing equivelents to drive the electrontransport chain and oxidative phosphorylation. The regulation of these alternative pathways involves allosteric modification of key enymes and trafficking proteins intracellularly. The acid sphingimyelinase and protein palmitoylation enzymatic machinery coordinates this regulation by changing the membrane micro-environment. ********************************************************************************************************************************************************** Please donate to Authentic Biochemistry 2021! We need your  financial support to continue producing this precison content podcast. Subscribe and contribute today and share this pod

 Early stage TCR activated T cells with rampant lactic acid fermentation, fail to  maintain adequate ATP levels , especially when glucose is limiting.This decrease in ATP relative to ADP+AMP results in the activation of AMPK, which inhibits mTOR activity and all subsequent anabolism especially assocaited for  T cell proliferation. Indeed, induced Loss of AMPKα1, will sythetically restore  mTOR signaling and T cell cytokine production, but not proliferation. Although loss of AMPK can restore some functions in glucose-restricted T cells, the cells do not initiate metabolic adaptations necessary to recover ATP levels. In vivo, AMPKα1-deficient T cells have decreased mitochondrial respiration, flux of glutamine into the mitochondria, and ATP:AMP ratios, and therefore fail to proliferate and function effectively. In cardiac and skeletal muscle, AMPK phosphorylates the bifunctional enzyme at a unique SER residue which induces the PFK-2 activation over the phosphatase activity thus stimulating gl

Authentic Biochemistry Podcast 29 December 2020 Daniel J. Guerra Ph.D. •All scientific inquiry should start with dialectical method that uses the current knowledge base to generate various specific Theses and then follow each with the counter-argument by employing the Square of Opposition thus producing Anti-theses and then, making the third movement, which allows for a Synthesis that has the flavor of rejection, acceptance or indifference. *Downstream of co-stimulation and PI3K-AKT, the mammalian target of Rapamycin (mTOR) kinase pathway integrates multiple signals and regulates anabolic metabolic reprogramming in T cells exiting quiescence. mTOR complex 1 (mTORC1) is required for cell cycle entry and coordination of early metabolic changes that occur upon T cell activation. *T cells deficient in Raptor, an essential component of mTORC1, fail to upregulate the expression of Glut1 and other glycolytic enzymes when activated. *Raptor-deficient T cells also exhibit defects in de novo lipid synthesis and oxidat

Human neuroscientific research seeks to uncover patterns of commonality and uniformity to help define mechanisms which reliably result in the experience of thinking and interacting with the world. This scientific mindset is in opposition to real life experience where human bonding is unique to a specific relationship. This may be best understood as a compatibilist approach, where neuroscience may affirm the very real experience of an individual when he makes a judgment or chooses to imagine his next move while the neurocircuitry is providing the means to have that experience without an agentic causal connection. This view as stated is not a contradiction, since it doesn’t assert there is no experience of free will or directed emotion or thought but rather that it is coincidental to the neurophysiology and the grounding provided by neurobiochemical networking. In my view, there is an alternative to this theory; it is based on the principal of “first causes”. Merry Christmas Everyone! --- Send in a voice mes

T cell agency initiates upon the stimulation of the TCR via presentation of cognate peptide-MHC complexes in associative ligand-mediated membrane co-receptor CD28 with co-stimulatory molecules presented on the surface of the APC: this event is called T cell licensure and essentially quits quiescence. The TCR signals through the ERK/MAPK pathways and calcium flux; where as CD28 signaling activates the PI3K-AKT-mTOR axis, and both pathways synergistically engage the NF-κB organon of pleitropic T lymphocyte agency. Merry Christmas from AUTHENTIC BIOCHEMISTRY! Please subscribe and help promote/produce the podcast by donating 10 dollars each this month! Thank You! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

In this episode Dr Guerra provides a concise description of  T lymphocytic fatty acid synthesis from glucose via cytosolic glycolysis,  mitochondrialpyruvate dehydrogenase, pyruvate carboxylase, and citrate synthase and a return to the cytosol for ATP citrate lyase and the homodimeric polyprotein complex FAS to generate palmitoyl-ACP. This ability of  antigen-MHC Antigen Presenting Cell  TCR - activated T lymphocytes to prepare for massive cytokine and chemokine expression requires a biochemical poise to use newly synthesized intracellular triacylglycerol to drive cellular exapnsion and effector-mediated immune responses. Subscribe and Donate! MERRY CHRISTMAS!!! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Metabolic syndrome  (MetSyn)is a dyslipidaemic chronic and aging  linked sedentary life-style constellation of disease presentations including metabolic disorganization, prodromal Type 2 diabetes and a prominent connection to hypertension-most prominently associated with over-eating and obesity. MetSyn is often  prolegomena to middle-age onset CVD, cancer and neurodegeneration. High caloric density soluble carbohydrate nutrition, lack of fasting and the species-specific metabolic inability to convert fatty acids into glucose via gluconeogenesis, provide a pathobiochemical poise toward MetSyn. As Nicotinamide Adenine Dinucleotide (NAD+) levels decline with age and obesity a potential suppression of NAD (H)-dependent enzymes in oxidative phosphorylation, the TCA cycle, and glycolysis resulting in suppressed  ATP production can trigger the AMPK mediated transcriptional activation of the senescence-associated secretory phenotype (SASP) leading to morbidity and mortality in the advanced aged hu

Both the innate and acquired immune systems become senescent during chronological aging. While T cell activation may become disenfranchised from its co-stimulatory control apparatus during aging, the potential for hyper or hypo-immune responses becomes more common. At the same time,   CNS microglia and peripheral resident and circulating macrophages are activated following the stimulation of various pattern recognition or phagocytic receptors.  In the CNS, this activation state is subsequently controlled by proximal neurons, which secrete regulatory ligands. The end result of these interactions is the release of cytokines, neurotoxins, and/or growth factors by microglia/macrophages and  the activation of cellular pathways including phagocytosis. Aberrant function of these pathways can result in significant degeneration during aging.  Cell Rep. 2018 Feb 6; 22(6): 1509–1521. FEBS Journal. 2009.Vol. 276, 1 Pages: 13-26 Experimental & Molecular Medicine volume 51, Article number: 80 (

Dr. Guerra reminds and extends his decade-long hypothesis that The Immune Response could function to generate the networked synaptic connections in the brain during  initiation, development, learning, and aging. The question considered is how do immune cells and immuno-regulatory proteins such as cytokines and chemokines and immunoglobulins recognize certain neurons and not others? The mechanism for maintaining and increasing synaptic strength vs. obsolescence and programmable cell death could be mediated by cellular phenomena known as pattern recognition. The bioenergetics of T lymphocyte activation and subsequent effector mediated inflammatory responses  involves a conversion of glucose to lactate via aerobic glycolysis as coordinated through the early TCR activation stage phosphorylation of pyruvate dehydrogenase via PDHK1 and axial coordination of NAD+ synthesizing LDH. Subscribe to Authentic Biochemistry and donate to our Christmas drive for a more robust AB in 2021! --- Send in a voice mess

Aging  and chronic stress can obtain activation of CNS-resident microglia and astrocytes, that produce  type 1 interferons (T1 IFNs) which signal through the heterodimeric IFN-α/β receptor (IFNAR) where receptor binding of  T1 IFNs activates the JAK/STAT thus inducing  IFN-stimulated genes (ISGs) which mediate both pro- and anti-inflammatory functions depending upon the cellular micro-environment. Now consider how aging is linked to elevated & activated leukocyte counts and it becomes clear that this is a patho-biochemical phenocopy to T cell acute lymphoblastc leukaemia  (T-ALL) where signaling through Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK are shared. IL7-induced glucocorticoid resistance is diagnostic of certain subtypes of T-ALL and this is also associated with the senescence associated secretory phenotype of aging-linked morbidity and mortality. Finally, consider that chronic CNS stress leads to increased  glucocorticoid production leading to  a suppression of cel

In this first pre-Christmas present Authentic Biochemistry Podcast lecture, Dr Guerra examines  the multifactorial expansion of NOTCH signalling through early thymocyte development as regulated by paracrine and endocrine hormonal systems in cooperation with  the exemplary plenum of IL7 cytokine mediated signalling through the phosphatidylinositol and AKT kinase cascades. References J Cell Physiol. 2003 Mar;194(3):237-55 Development 2019 146: dev172148 Int J Mol Sci. 2020 Nov; 21(21): 7972 SUBSCRIBE and give my PODCAST 5 stars and tell a few hundred friends! And by all means donate to my work! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

In today's lecture, Dr Guerra explains how subclinical hypothyroidism obtains increased serum thyrotropin (thyroid stimulating hormone, TSH) with flat levels of of free thyroxin (T4) and biologically active free triiodothyronine (T3) in the elderly;β1 adrenergic receptors, sodium/potassium ATPase, voltage-gated potassium channels, malic enzyme and atrial and brain natriuretic factor all respond favourably to thyroxin and hese proteins form the primary architecture of the cardiomyocyte and determine contractile strength. ATP drives muscle contraction/relaxation thus active  mitochondrial nadh  oxidation is essential for healthy aging. Ketone and free fatty acid oxidation decreases with aging while glucose oxidation reciprocally increases while thyroid hormone levels decline with aging, suggesting that myocardial metabolic pathology is linked phenomenologically to subclinical hypothyroidism. Indeed,thyroid hormone deficiency found in aging populations inhibits fatty acid oxidation through transcriptio

On this 16th of November Authentic Biochemistry Podcast episode acknowledging my sister Carol's birthday, I explain the MST- kinase mediated transcription factor HIPPO pathway and its potentially gravid linkage to aging associated lymphocyte-informed  autoimmune disease, cancer and neurodegeneration. Published by Dr.. Daniel J. Guerra. 2020 References Experimental & Molecular Medicine volume 51, Article number: 80 (2019) Pharmacological Research Volume 143, May 2019, Pages 151-165 Trends in Cancer, May 2019, Vol. 5, No. 5297-307 Nature Reviews Rheumatology volume 13, page389(2017) Adv Immunol . 2019;144:87-119 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

During thymic T lymphocyte recombinatorial self avoidance, the  processing  obtained in T cell receptor excision generates small circular DNA byproducts that may be used as a biomarkers for thymic output and for the relative ability of T lymphocytes to fight infection, tumors, and obesity -linked cardiovascular disease and metabolic disorders  that may become important pathologies in the aging human population. Transcription factors like Nfil3 are important components of this networked  age-related decline called immunosenescence that has the pathobiochemical signatures of SASP , ROS, mutation, epimutation and epigenetic gene expression pathologies. Dr. Daniel J. Guerra Authentic Biochemistry Podcast Publication. 14 November 2020 References Braz J Med Biol Res. 2019; 52(7): e8292 PLoS One. 2016; 11(6): e0157930 Experimental & Molecular Medicine volume 51, Article number: 80 (2019) --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

1.Id proteins are helix-loop-helix (HLH) proteins lacking the basic amino acid domain necessary to bind DNA.and therefore ID  functions in a dominant negative manner by sequestering ubiquitously expressed  or cell- restricted  basic HLH transcription factors: this results in effective blockade of transcription since ID causes a failure  of dimerized basic HLH proteins to bind DNA. 2. Id proteins  regulate transcription factors that are involved in developmental processes such as myogenesis, neurogenesis, bone morphogenesis, lymphopoiesis hematopoiesis, and myeloid differentiation 3. Id2−/− mice lack lymph nodes and Peyer's patches*, *Peyer's patches are discrete masses of lymphatic tissue found throughout the ileum of the mammalian small intestine Oncogene volume 22, pages1–9(2003) PNAS January 15, 2019 116 (3) 890-899 SUBSCRIBE and tell a colleague about Authentic Biochemistry And please Donate to my podcast! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/mess

Since epithelial clock gene and  lymphocyte transcription factor Nfil3 expression is elevated in recombination deficient mice  the potential for  increased bacterial populations lining the gut may induce  an expansion of class 3 innate-like T lymphocytes (ILC3) in the small intestine. thus allowing for circadian clock activity maintenance and effective immune clearance of potential pathogens. This observation may provide a potential pathobiochemical link between obesity and the increasing pathophysiology associated with human aging. Dr. Daniel J. Guerra Authentic Biochemistry Publication 10 November 2020  PLEASE SUBSCRIBE and give a 5 star review for my podcast and DONATE!!! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message