Biology subjects

Head, R. D.

Publications and source records attributed to Head, R. D..

4 recordsLinked to original sources

bioRxiv2025

CompBio and MIRaS : A Multi-omic Analysis Platform Built on a Memory-Based Intelligence Engine

As molecular and cellular technologies have advanced, the need to analyze and interpret the resulting, often vast and multi-modal, data into actionable intelligence has become a rate-limiting factor in scientific advancement. While traditional knowledgebase-pathway tools and LLM-based AI tools both provide a degree of support in data interpretation, both exhibit limitations. Presented here is the CompBio multi-omic analysis platform built upon a novel memory-based intelligence engine, MIRaS. The system is not dependent on human-curated pathway knowledgebases, can perform statistical significance analysis, does not suffer from hallucination, and produces traceable results. Furthermore, substantial effort has been placed in the computer-human knowledge transfer components of the system to enable efficient interaction, interpretation, and learning. The system has undergone years of extensive testing, validation, and evolution in omics-based research with dozens of associated publications verifying its effectiveness. A systematic assessment of CompBio and a detailed description of the MIRaS method are provided.

bioinformatics↗

bioRxiv2022

Embryonic Vitamin D Deficiency Programs Hematopoietic Stem Cells to Induce Type 2 Diabetes

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induces diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic subunit alpha and AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

physiology↗

bioRxiv2022

Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small 1intestinal epithelia

Enterotoxigenic E. coli (ETEC), produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and are a common cause of diarrhea in children of resource-poor regions. ETEC have also been linked repeatedly to poorly understood sequelae including enteropathy, malnutrition, and growth impairment. While the cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their potential contribution to subsequent pathology is unclear. LT stimulates cellular cAMP production to activate protein kinase A (PKA) which phosphorylates cellular ion channels that drive export of salt and water into the intestinal lumen resulting in diarrhea. However, as PKA exhibits broad kinase activity and its activated catalytic subunits modulate transcription of many genes, we interrogated the transcriptional profiles of LT-treated small intestinal epithelia. These studies demonstrated toxin-induced changes in hundreds of genes including those required for biogenesis and function of the brush border, the major site absorption of nutrients, and suppression of a key transcription factors, HNF4 and SMAD4, critical to differentiation of intestinal epithelia. Accordingly, LT treatment of intestinal epithelial cells significantly disrupted the absorptive microvillus architecture and altered transport of essential nutrients. In addition, challenge of neonatal mice with LT-producing ETEC recapitulated the architectural derangement of the brush border while maternal vaccination with LT prevented brush border disruption in ETEC-challenged neonatal mice. Finally, mice repeatedly challenged with toxigenic ETEC exhibited impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to mitigate and prevent major sequelae including malnutrition that impact millions of young children.

microbiology↗

bioRxiv2020

Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic protection

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Thus, potently neutralizing mAbs require Fc effector functions for maximal therapeutic benefit during therapy to modulate protective immune responses and mitigate lung disease.

immunology↗