Authentic Biochemistry

Dr Daniel J. Guerra

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Jan 14, 2021 · 28 min
The stress-induced Neural Network tracks Kantian Epistemology through characteristic action potential and neuromodulator/neurotransmitter phenomenology. Dr Guerra 13 JAN 2021.
LC axonal projections to the mPFC modulate a diversity of cognitive processes, including working memory, sustained attention, and flexible attention and under moderate rates of LC activity and NE release, high-affinity postsvnaptic α2 adrenergic receptors in the PFC are preferentially engaged and promote working memory However, with elevated LC firing and activation of lower affinity α1 adrenergic receptors, working memory is impaired while agentic focused attention becomes prominent so it seems that LC projections to the PFC modulate different cognitive processes in a context-sensitive manner. his latter mechanism could correlate with the experienced rapid response such as in “fight or flee” decision making upon immediate threatening danger. The sensation perception recognition and response behaviour all works sequentially from these neuronal loci post encounter to the stimulus and as such fit well into Kantian epistemology which obtains that the individual is presented with a particular stimulus-sense data or “intuition” that is processed by the faculty of the understanding as a perception of danger in association with a concept-abstracted from previous experience. This representation is then acted upon and the neural network-already poised to respond sequentially follows suit and ultimately directs the motor cortex to act. DONATE TO AUTHENTIC BIOCHEMISTRY TODAY!!!!!!
Jan 13, 2021 · 29 min
Fear and Aging associated with neuronal conditioning and synaptogenesis via corticotropin releasing hormone. Dr. Dan Guerra; Authentic Biochemistry 13 JAN 2021
•Intensive and chronic or excessive stress diminishes intellectual performance and general cognition: this is a form of negative reinforcement and can be related to learning disability and anxiety about future events. Indeed, •Individual responses and the magnitude of stressor as well as its association with self identity and goals will influence endurance, resilience, and self-empowerment vs. dissatisfaction and defeat. •Stresses first become recognized in the developing fetus since the fetal brain attains awareness during the first trimester and maternal stress is well established as an epigenetic mechanism involved in fetal neural development and stress is lifelong , contributing to one’s character and ability to overcome fear and anxiety. •Stress response is an element of the hypothalamic-pituitary-adrenocortical (HPA) axis where Corticotropin-releasing factor (CRF) serves as a gate keeper for fear conditioning playing dual roles as hormone and as neuromodulator. •CRH exerts multiple effects on the adult brain, often spatiotemporal, as shown by secretion site-specific responses in that CRH after binding to its GPCR's: CRHR1 and CRHR2 which subsequently regulates the formation of neuronal dendrites; neurite elongation, synaptogenesis, and circuit integration of adult-born neurons thus organizing and modifying excitatory transmission in a neuronal type-specific manner Transl Psychiatry. 2019; 9: 272. Cell Reports Oct 2019, 29, 932–945
Jan 10, 2021 · 30 min
Fear associated Corticotropin Releasing Factor and the Immune response are linked to CNS neutral Sphingomyelinase I. Dr Dan Guerra 09 January 2021
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 alterations in membrane PLC mediated DAG enrichment of VLCPUFA’s and their SFA counterparts thus diturbing membrane raft-mediated signaling and cell death and an appropriate local immune response thus disturbing glucocorticoid (and a host of other) HPA axis hormones.
Jan 7, 2021 · 29 min
Glycolysis is inhibited in T cells when Glucose 6 P non-competitively inhibits hexokinase after GLUT1 uptake of serum glucose:Setting the stage for lipogenesis.
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 .
Jan 6, 2021 · 29 min
The Porosomal complex and complex lipid interconversions organizing the transport and secretion of cytokines after T cell Receptor Activation by APC's
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 and donate to our casue to bring to you Authentic Biochemistry!
Jan 3, 2021 · 29 min
Inhibitory PFK1 palmitoylation is facillitated by Acid Sphingomyelinase. Daniel J. Guerra, PhD. Authentic Biochemistry Podcast 02 January 2021
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
Jan 1, 2021 · 29 min
T lymphocyte maturation and memory cell accumulation are differentially mediated by sphingomyelinase and protein palmitoylation. Dr Dan Guerra. 01 Jan 2021
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 podcast with anyone who wants to learn Authentic Biochemistry. Grazie! Dr Dan Guerra
Dec 30, 2020 · 29 min
Tumor cells and T lymphocytes carry forward initially similar and subsequently distinct bioenergetic regulation through AMPK. Dr Guerra Authentic Biochemistry 30 Dec. 2020
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 glycolysis and overcoming hypoxia. Hypoxia renders the mitochondrial electron-transport chain-oxidative phosphorylation pathway non-functional as molecular oxygen is the ultimate electron acceptor becoming reduced to water. With depleted oxygen as in stress and in heavy skeletal muscle contraction, glycolysis must be stimulated as AMP levels rise. AMP also controls PFK-1 directly In tumors, the rate of translation of HIF-1a mRNA in cancer cells is dependent upon the activity of the mammalian target of rapamycin (mTOR), which in turn is determined by the activity of upstream tumor suppressor proteins and oncoproteins. HIF-1α plays a key role in stimulating glycolytic enzymes and in blocking mitochondrial activity. LncRNAs can also regulate Akt and AMPK pathways. Akt may increase oxidative phosphorylation by enhancing metabolic coupling between glycolysis and oxidative phosphorylation. Relevant Research References Cell Research volume 30, pages649–659(2020) Molecular Cancer July 2017. 16(1)DOI: 10.1186/s12943-017-0699-3 Genomics, Proteomics & Bioinformatics Volume 14, Issue 1, February 2016, Pages 42-54 J BiolChem. 2011 Apr 8; 286(14): 11937–11950.
Dec 30, 2020 · 29 min
T cell metabolic Dialectics : deriving bioenergetic supremecy from glycolysis through fatty acid and lipid synthesis to ultimate fatty acid oxidation and ATP generation. Dr Daniel J. Guerra
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 oxidative phosphorylation, suggesting the mTOR pathway is a global regulator of T cell metabolic programs. *mTORC1-mediated signaling is also required for proteomic remodeling of pathways including one-carbon metabolism(SAM and Folic acid), FAO, and the electron transport chain (ETC) that occurs early in activating T cells.
Dec 26, 2020 · 22 min
On the Concept of Neuro-Correlation: A Theoretical Essay. Dr. Daniel J. Guerra . Authentic Biochemistry. 25 December 2020
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!
Dec 23, 2020 · 29 min
T Cell signal transduction involves kinase and transcription factor mediated expression of bioenergetic ensemble gene products. Dr DJ Guerra 23 December 2020
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!
Dec 23, 2020 · 29 min
From Glucose to Triacylglycerol in the developing T lymphocyte. Dr Daniel J. Guerra. Authentic Biochemistry 21 December 2020
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!!!
Dec 17, 2020 · 29 min
The Misguided Linkage of Potentially Ablating Aging -Associated Metabolic Syndrome by tracking NAD+ serum levels. Dr. Daniel Guerra. 17 December 2020.
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 human. However, NAD+ essential DNA Damage Repair and Sirtuin-mediated deacetylation of histone-associated chromatin may exacerbate aging and both neurodegeneration and tumorigenesis. Published and produced by Dr. Daniel J. Guerra, Authentic Biochemistry 17 December 2020. DONATE to Authentic Biochemistry Podcast!!! J Biomed Sci. 2019; 26: 34 Front. Genet., 12 March 2015 BioEssays, 2017. Volume: 39, Issue: 5,
Dec 15, 2020 · 29 min
Intermediary metabolism plays an essential role in immune cell activation that may lead to tissue degeneration, lipid accumulation and oncogenesis in the aging human. Dr. Guerra. 14 December 2020.
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 (2019) Frontiers in Immunology · February 2013 Cell cycle (Georgetown, Tex.) September 2008 7(15):2296-8
Dec 13, 2020 · 29 min
Further Inquiries into The Immune System and The Aging Central Nervous System: The PDH/LDH/PDHK1 Axis. Dr. Dan Guerra 13 December 2020.
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!
Dec 8, 2020 · 29 min
What T -cell Acute Lymphoblastic Leukaemia and Senescing microglial CNS disease have in common relate to Notch and Glucocorticoid signaling. DJGPhD 07 December 2020
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 cell adhesion protein thus corrupting synaptic plasticity, memory re-formation, and cognitive acuity while promoting sarcopenia by stimulating proteasomal removal of contractile proteins and inhibiting the PI3-kinase/Akt pathway. Glucocorticoids also prevent IL-2 synthesis and secretion thus causing immune suppression by blocking T cell activation. J Neuroinflammation. 2019; 16: 236. Cytokine & Growth Factor Reviews, 22 Apr 2017, 35:85-96
Dec 6, 2020 · 29 min
Dr. Guerra interrogates Notch signalling in T lymphocte early development as prolegomena to immunodystrophy obtained with aging. 05 Decemeber 2020
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!
Dec 3, 2020 · 29 min
From Bioenergetics to Cardiac Function and Thymocyte differentiation in the Aging Population. Dr. Daniel J. Guerra 02 December 2020.
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 transcriptionally mediated downregulation of PPARα where this transcription factor normally suppresses PDK4, which allows increased PDH. This suggests that aging correlates with decreasing fatty acid oxidation which is associated with reduced cardiac function. The aged heart relies on lactate, glucose and pyruvate in place of fatty acids and the PDH complex plays a central role in the modulation from fatty acid oxidation to glucose oxidation in the mitochondria to finally anaerobic glycolysis in the aging heart. T lymphocyte maturation and expansion also follows a switch in carbon energy utilization so the two systems function in contrarion regulation, leading to decreased cardiac output with a declining naive T cell population thus losing the regulated induction of inflammation from diverging metabolic sequalae in the aging human. PLoS One. 2013; 8(6): e65532. Int J Mol Sci. 2020 Nov; 21(21): 7972 Please subscribe and donate to Authentic Biochemistry!
Nov 16, 2020 · 29 min
Dr. Guerra herds the Hippo Pathway into T lymphocyte mediated autoimmune disease and cancer in the aging human Authentic Biochemistry 16 November 2020
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
Nov 15, 2020 · 29 min
T cell receptor excision circles (TRECs) are generated in the thymus and are potential indicators of acquired immune disorders in neuropsychiatry and senescence.
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)