Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support

Abstract Lethal COVID-19 outcomes are most often attributed to classic cytokine storm and attendant excessive immune signaling. We re-visit this question using RNA sequencing in nasopharyngeal and 40 autopsy samples from COVID-19-positive and negative individuals. In nasal swabs, the top 100 genes which significantly correlated with COVID-19 viral load, include many canonical innate immune genes. However, 22 much less studied "non-canonical" genes are found and despite the absence of viral transcripts, subsets of these are upregulated in heart, lung, kidney, and liver, but not mediastinal lymph nodes. An important regulatory potential emerges for the non-canonical genes for over-activating the renin-angiotensin-activation-system (RAAS) pathway, resembling this phenomenon in hereditary angioedema (HAE) and its overlapping multiple features with lethal COVID-19 infections. Specifically, RAAS overactivation links increased fibrin deposition, leaky vessels, thrombotic tendency, and initiating the PANoptosis death pathway, as suggested in heart, lung, and especially mediastinal lymph nodes, with a tightly associated mitochondrial dysfunction linked to immune responses. For mediastinal lymph nodes, immunohistochemistry studies validate the transcriptomic findings showing abnormal architecture, excess fibrin and collagen deposition, and pathogenic fibroblasts. Further, our findings overlap findings in SARS-CoV-2 infected hamsters, C57BL/6 and BALB/c mouse models, and importantly peripheral blood mononuclear cell (PBMC) and whole blood samples from COVID-19 patients infected with early variants and later SARS-CoV-2 strains. We thus present cytokine storm in lethal COVID-19 disease as an interplay between upstream immune gene signaling producing downstream RAAS overactivation with resultant severe organ damage, especially compromising mediastinal lymph node function.

, Pessoa overlooks continuum effects on nonlinear brain network connectivity by eschewing neural field theories and physiologically derived constructs representative of neuronal plasticity. The absence of this content, which is so very important for understanding the dynamic structure-function embedding and partitioning of brains, diminishes the rich competitive and cooperative nature of neural networks and trivializes Pessoa's arguments, and similar arguments by other authors, on the phylogenetic and operational significance of an optimally integrated brain filled with variable-strength neural connections. Riemannian neuromanifolds, containing limit-imposing metaplastic Hebbian- and antiHebbian-type control variables, simulate scalable network behavior that is difficult to capture from the simpler graph-theoretic analysis preferred by Pessoa and other neuroscientists. Field theories suggest the partitioning and performance benefits of embedded cognitive-emotional networks that optimally evolve between exotic classical and quantum computational phases, where matrix singularities and condensations produce degenerate structure-function homogeneities unrealistic of healthy brains. Some network partitioning, as opposed to unconstrained embeddedness, is thus required for effective execution of cognitive-emotional network functions and, in our new era of neuroscience, should be considered a critical aspect of proper brain organization and operation.