Biology subjects

Head, S. R.

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

5 recordsLinked to original sources

bioRxiv2025

B cell transcriptomics reveals lasting dysregulation and rapid decline of protective memory after hepatitis C cure

O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/664545v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@d12426org.highwire.dtl.DTLVardef@9c54daorg.highwire.dtl.DTLVardef@186d559org.highwire.dtl.DTLVardef@120f2f3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG HighlightsO_LIB cells in CHC patients retained dysregulated transcriptional profiles despite successful DAA treatment C_LIO_LIB cell dysregulation is marked by global B cell hyperactivation and antigen-specific atypical MBC expansion C_LIO_LISustained upregulation of TNF- signaling via NF-{kappa}B (TNF-/NF-{kappa}B) is a central driver of persistent B cell dysregulation and chronic inflammation C_LIO_LIViral clearance leads to restoration of IFN responses and IFN-stimulated gene (ISG) signatures in B cells but not TNF-/NF-{kappa}B C_LIO_LIHCV IGHV1-69 bnAb-producing B cells are enriched within the CD86hi IgG MBC subset before treatment C_LIO_LICD86hi IgG MBC subset contracts rapidly post-cure in parallel with the rapid decline of cross-nAb responses and loss of protective immune memory against HCV reinfection C_LI Chronic hepatitis C (CHC) disrupts host humoral immune response by impairing the timely generation of neutralizing antibody (nAb) and durable immune memory. However, the underlying mechanisms and their reversibility after viral clearance remain poorly defined. Here, through integrated single-cell transcriptomics and antibody repertoire characterization, we show that B cells from CHC patients retain transcriptional dysregulation even after successful antiviral therapy. Sustained TNF- signaling emerged as a central driver of chronic B cell hyperactivation, persistent dysregulation and unresolved inflammation following cure. Furthermore, a CD86hi memory B cell subset, responsible for an IGHV1-69-encoded multi-donor class recall nAb response, declined rapidly following viral clearance, compromising immune memory against reinfection. Together, these findings reveal how CHC imprints lasting B cell dysregulation, impairs nAb memory, and sustains inflammation in the B cell compartment, after viral clearance. The insights underscore the need for strategies aimed at restoring B cell homeostasis to achieve durable immune protection.

immunology↗

bioRxiv2025

Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids

Alzheimers disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimers disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1{Delta}E9/WT, PSEN1M146V/WT, or APPswe/WT. Our CO model reveals time-progressive accumulation of amyloid beta (A{beta}) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau species. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of A{beta} and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/661453v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@12ac9c6org.highwire.dtl.DTLVardef@24eceaorg.highwire.dtl.DTLVardef@3e3238org.highwire.dtl.DTLVardef@1530d1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Catalyzing computational biology research at an academic institute through an interest network

Biology has been transformed by the rapid development of computing and the concurrent rise of data-rich approaches such as -omics or high-resolution imaging. However, there is a persistent computational skills gap in the biomedical research workforce. Inherent limitations of classroom teaching and institutional core support highlight the need for accessible ways for researchers to explore developments in computational biology. An analysis of the Scripps Research Genomics Core revealed an increasingly diverse set of experiments: the share of experiments other than bulk RNA- or DNA-seq increased from 34% to 60% within 10 years, requiring more tailored computational analyses. These challenges were tackled by forming a volunteer-led affinity group of over 300 academic biomedical researchers interested in computational biology referred to as the Computational Biology and Bioinformatics (CBB) affinity group. This adaptive group has provided continuing education and networking opportunities through seminars, workshops and coding sessions while evolving along with the needs of its members. A survey of CBBs impact confirmed the groups events increased the members exposure to computational biology educational and research events (79% respondents) and networking opportunities (61% respondents). Thus, volunteer-led affinity groups may be a viable complement to traditional institutional resources for enhancing the application of computing in biomedical research.

bioinformatics↗

bioRxiv2019

Identification of key determinants of Staphylococcus aureus vaginal colonization

Staphylococcus aureus is an important pathogen responsible for nosocomial and community acquired infections in humans, and methicillin-resistant S. aureus (MRSA) infections have continued to increase despite wide-spread preventative measures. S. aureus can colonize the female vaginal tract and reports have suggested an increase in MRSA infections in pregnant and postpartum women as well as outbreaks in newborn nurseries. Currently, little is known about specific factors that promote MRSA vaginal colonization and subsequent infection. To study S. aureus colonization of the female reproductive tract in a mammalian system, we developed a mouse model of S. aureus vaginal carriage and demonstrated that both hospital-associated and community-associated MRSA isolates can colonize the murine vaginal tract. Immunohistochemical analysis revealed an increase in neutrophils in the vaginal lumen during MRSA colonization. Additionally, we observed that a mutant lacking fibrinogen binding adhesins exhibited decreased persistence within the mouse vagina. To further identify novel factors that promote vaginal colonization, we performed RNA-sequencing to determine the transcriptome of MRSA growing in vivo during vaginal carriage at 5 hours, 1-day, and 3-days post-inoculation. Over 25% of bacterial genes were differentially regulated at all time points during colonization compared to laboratory cultures. The most highly induced genes were those involved in iron acquisition, including the Isd system and siderophore transport systems. Mutants deficient in these pathways did not persist as well during in vivo colonization. These results reveal that fibrinogen binding as well as the capacity to overcome host nutritional limitation are important determinants of MRSA vaginal colonization.\n\nIMPORTANCEStaphylococcus aureus is an opportunistic pathogen able to cause a wide variety of infections in humans. Recent reports have suggested an increasing prevalence of MRSA in pregnant and postpartum women, coinciding with the increased incidence of MRSA infections in the NICU and newborn nurseries. Vertical transmission from mothers to infants at delivery is a likely route of MRSA acquisition by the newborn, however, essentially nothing is known about host and bacterial factors that influence MRSA carriage in the vagina. Here, we established a mouse model of vaginal colonization and observed that multiple MRSA strains can persist in the vaginal tract. Additionally, we determined that MRSA interactions with fibrinogen as well as iron uptake can promote vaginal persistence. This study is the first to identify molecular mechanisms which govern vaginal colonization by MRSA, the critical initial step preceding infection and neonatal transmission.

microbiology↗

bioRxiv2017

A Genome-wide Survey of Mutations in the Jurkat Cell Line

The Jurkat cell line has an extensive history as a model of T cell signaling. But at the turn of the 21st century, some irregularities were observed in Jurkats expression of central regulators of T cell receptor signaling, which raised doubts about how closely the cell line paralleled normal human T cells. While numerous expression deficiencies have been described in Jurkat, genetic explanations have only been provided for a handful of defects. Here, we report a comprehensive catolog of genomic variation in the Jurkat cell line based on whole-genome sequencing. With this list of all detectable, non-reference sequences, we prioritize potentially damaging mutations by mining public databases for functional effects. We confirm the majority of documented mutations in Jurkat and propose links from detrimental gene variants to observed expression abnormalities in the cell line. This work ties together decades of molecular experiments and serves as a resource that will streamline both the interpretation of past research and the design of future Jurkat studies.

genomics↗