Authentic Biochemistry

Fear-conditioning  learning is a low-threshold  enduring psychiatric  process that prepares a defense against dangerous phenomena and reduces the need to iteratively  relearn the signal. It is a pattern recognition response that can be modulated by experience and the severity of the stress signal and it is  a response that deteriorates in the elderly and in certain neuropsycoses  and anxiety disorders throughout life. Fear conditioning must be fluid  to readjust according to reverse learning.  Persistent fear and avoidance of the potential for fear-associated events are common presentations of social anxiety disorder (SAD) and avoidant behavior  maintains SAD, thus it prevents the reversal of fear in social situations. The best treatment outcomes are CBT including exposure therapy, which leads to  fear extinction. Pharmacotherapy including  antidepressants, benzodiazepines, beta-blockers, anticonvulsants, or neuroleptics, are commonly administered with lo

Homeostatic  chronic  low stress results in low to moderate levels of CRF in the LC in association with  enhanced Extra-Dimensional Shifting and optimal executive decision making. However, acute or chronic severe stress is linked to  high levels of CRF in the LC and this may  contribute to a shift from optimal executive function necessary for goal-directed behavior toward an iterative decision response.  In healthy environments, this variable tonicity is a readout for adaptation  when goal-oriented behavior is relaxed so that the individual uses pro-forma decisions  even when novel environmental stimuli are encountered. During aging these pathways lose flexibility due to a decrease in executive decision making linked to the senescence phenotype that may impair neural circuitry via inflammation, over or under activation and lack of control over  immune cell responses. J Neurosci. 2008 Nov 5; 28(45): 11517–11525. GeroScience. 2017 Feb; 39(1): 61–72. Neuroscience. 201

Adaptation to stress-such as the fear response obtains dopaminergic input to striatum and prefrontal cortex and  is thought to signal unexpected events and facilitate a shift in attention to promote new learning within the contralateral primary somatosensory cortex (SI) which has been associated with the agentic categories of both the quality and quantity of thought event ontology. This process works in conjunction with  the bilateral secondary somatosensory cortex (SII) process  involved in executive  decision making. Where stimulated, the primary sensory motor-neuronal process  is integrated with novel extra-dimensional learning . Recall that this fear stress response can lose functional valency upon immune-regulating, senescent secretory phenotypes.   In the aging brain, where CRF axon terminals are widely distributed, (including within catecholamine and serotonin  nuclei) there are widespread cortical projections into the medial prefrontal cortex; linking  exec

The anti-inflammatory IL-10 pathway in the CNS can lead to Glioblastoma which is a disease presented 3-4 fold higher in people ≥65 years old, and with a mortality rate for the same age group some 7 fold higher. Activation of the IL-10 Receptor bound ligand induces the JAK1 signal transducer and activator of transcription 3 (STAT3) pathway in APCs. This results in the subsequent translocation of STAT3 homodimers into the nucleus. This STAT3 homodimer binds to STAT-binding elements which promotes the expression of the suppressor of cytokine signaling 3 (SOCS-3) and IL-1 receptor antagonist (IL-1RN).  IL-10 reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor alpha) and diminished expression of both major histocompatibility complex II. The anti-inflammatory  MiDAS phenotype can also induce heart failure in the aging population. References: Front Pharmacol. 2019; 10: 200 Aging Cell. 2018 Oct;17(5) Int Heart J. 2018 Jul 31;59(4):837-844 Front. Immunol., 19 March 2018 N

Non-uniform ageing is a major associative risk factor for cancer and degenerative diseases and mitochondrial dysfunction is linked to cellular senescence in association with cell cycle arrest, telomerase decline and nucleic acid/lipid/protein oxidation. Indeed, mitochondrial dysfunction comprises a distinct type of cellular senescence; mitochondrial SIRT3 or SIRT5, can induce Mitochondrial Dysfunction Associated-Senescence (MiDAS) Senescence is a chronological and pathophysiological sequenced event response that restricts mitotic division and thus aberrant proliferation of damaged, infected and/or tumor inducing cells. Because these cells are senescent and exhibit low anabolic currency to present self-produced antigen epitopes as displayed by HLA, they are not targeted by immune responses but rather, may become secretory and induce inflammation by instantiating the Senescence Associated Secretory Phenotype-SASP. Senescence presents with metabolic reprogramming, epigenetic chromatin remodeling, and the secreti

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

•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 multip

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