Biology subjects

Ryan, E.

Publications and source records attributed to Ryan, E..

8 recordsLinked to original sources

bioRxiv2026

Phenuivirus glycoprotein Gc domain is a conserved target of cross-functional monoclonal antibodies

Phenuiviruses which include Rift Valley Fever Virus (RVFV), classified by WHO as one of the top priority pathogens with outbreak potential, are emerging arthropod-borne viruses that pose an increasing threat to public health. In line with the prototype pathogen framework advanced by the NIAID, the sandfly-transmitted Toscana virus (TOSV) has been adopted as a prototype to advance understanding of relevant phenuiviruses and inform the development of broadly applicable medical countermeasures. In this study, we sought to isolate and characterize monoclonal antibodies (mAbs) elicited by natural TOSV infection to identify shared antigenic determinants. By employing the conserved envelope Gc glycoprotein as bait for antigen-specific B cell sorting, we recovered more than 1,450 memory B cells and identified 112 Gc-specific neutralizing mAbs. Over one-third of these mAbs exhibited cross-reactivity with RVFV, a genetically distinct phenuivirus. Selected mAbs provided prophylactic protection in a murine model of TOSV infection. Together, our findings establish Gc as an important target of protective neutralizing antibodies and provide insights that may guide the rational design of widely effective interventions, strengthening readiness against future phenuivirus outbreaks.

immunology↗

bioRxiv2025

Feasibility of a parent-delivered attention and working memory intervention for early school-aged children born preterm

Preterm birth is a common neurodevelopmental condition that can have lasting impacts on cognition, including attention and working memory. Interventions that strengthen these skills in early childhood could support school readiness. Dino Island is a tablet-based intervention that combines process-specific practice of attention and working memory skills with a compensatory component that teaches metacognitive skills to scaffold learning. In this pilot study, we evaluated the feasibility of parent-delivered Dino Island in young children born preterm (N=10), alongside a control group who played educational games (N=12). Both groups were instructed to play 2-3 times per week for approximately 20 minutes over a 12-week period. Attention and working memory on untrained tasks were assessed before and after completing the intervention. Parents provided fidelity data through tracking sheets and participated in exit interviews to offer feedback and identify barriers and facilitators. We found that the Dino Island program was successfully delivered by parents with high fidelity. Attrition was higher in the Dino Island group, likely reflecting the challenges of delivering cognitive remediation in home settings. Comparison of attention and working memory scores on untrained tasks pre- and post-showed practice effects but no specific benefit of Dino Island. However, parent reports suggested behavioral improvements specific to the Dino Island group, noting far-transfer effects where children applied metacognitive strategies in other contexts. Overall, this work shows feasibility and tolerability of Dino Island in young children born preterm. Future research should examine its potential impact on school readiness and longer-term academic outcomes in this population.

neuroscience↗

bioRxiv2024

Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

Memory lymphocytes are durable cells that persist in the absence of antigen, but few human B cell subsets have been characterized in terms of durability. The relative durability of eight non-overlapping human B cell sub-populations covering 100% of all human class-switched B cells was interrogated. Only two long-lived B cell populations persisted in the relative absence of antigen. In addition to canonical germinal center-derived switched-memory B cells with an IgD-CD27+ CXCR5+ phenotype, a second, non-canonical, but distinct memory population of IgD-CD27- CXCR5+ DN1 B cells was also durable, exhibited a unique TP63-linked transcriptional and anti-apoptotic signature, had low levels of somatic hypermutation, but was more clonally expanded than canonical switched-memory B cells. DN1 B cells likely evolved to preserve immunological breadth and may represent the human counterparts of rodent extrafollicular memory B cells that, unlike canonical memory B cells, can enter germinal centers and facilitate B cell and antibody evolution. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/624972v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@169c77forg.highwire.dtl.DTLVardef@1a872f5org.highwire.dtl.DTLVardef@1360cforg.highwire.dtl.DTLVardef@38d7ed_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Iron deficiency in people with obesity drives defective natural killer cell mitochondrial fitness and function

Natural killer (NK) cells are a population of innate effector lymphocytes, involved in host-defences against viral infections and cancer. Upon activation, NK cells can produce a milieu of cytotoxic molecules and cytokines, which can directly target infected and transformed cells, but also amplify an immune response. Metabolic rewiring underpins NK cell effector functionality, providing the required signals, energy and biointermediates to support their immune responses. Obesity is associated with significant defects in the functionality of human NK cells, especially in the periphery. Dysregulated cellular metabolism has been demonstrated to be a major mechanistic driver of the reported defects. However, how obesity links to defective NK cell metabolism and functionality remains unclear. Iron deficiency is a common co-morbidity in people living with obesity (PWO). Recent studies have highlighted the importance for iron in host immunity, with murine models of iron deficiency resulting in defective cellular metabolism and function. We hypothesized that obesity-driven iron deficiency might underpin the reported defects in NK cells. Our data demonstrates that in response to cytokine stimulation, healthy human NK cells utilize iron to support their metabolic activity and cytokine responses. In a cohort of PWO, we demonstrate alterations in NK cell metabolism, mitochondrial fitness and cytokine production. Furthermore, upon stratification into PWO with normal iron status versus low iron status, we show the observed obesity-related defects in NK cell metabolism, mitochondrial fitness and cytokine production are concentrated in the PWO with low-iron status. Collectively, our data highlights the importance of iron for human NK cell responses and provides evidence that obesity-driven defects in NK cell metabolism and function are linked in part to altered iron availability.

immunology↗

bioRxiv2022

Lipidomic analysis reveals differences in Bacteroides species driven largely by plasmalogens, glycerophosphoinositols and certain sphingolipids

There has been increasing interest in bacterial lipids in recent years due, in part, to their emerging role as molecular signalling molecules. Bacteroides thetaiotaomicron is an important member of the mammalian gut microbiota that has been shown to produce sphingolipids (SP) that pass through the gut epithelial barrier to impact host SP metabolism and signal into host inflammation pathways. B. thetaiotaomicron also produces a novel family of N-acyl amines (called glycine lipids) that are potent ligands of host Toll-like receptor 2 (TLR2). Here, we specifically examine the lipid signatures of 4 species of gut associated Bacteroides. In total we identify 170 different lipids and we report that the range and diversity of Bacteroides lipids is species-specific. Multi-variate analysis reveals that the differences in the lipid signatures are largely driven by the presence/absence of plasmalogens, glycerophosphoinositols and certain SP. Moreover, we show that, in B. thetaiotaomicron, mutations altering either SP or glycine lipid biosynthesis results in significant changes in the levels of other lipids suggesting the existence of compensatory mechanisms required to maintain the functionality of the bacterial membrane. ImportanceBacteroides are important beneficial members of the gut microbiome that produce lipids that can function as cross-kingdom signalling molecules. We describe, for the first time, a comprehensive and qualitative comparison of the lipid signatures of 4 important Bacteroides species. We identify a group of Bacteroides core lipids and uncover species-specific differences in plasmalogen, glycerophospholipid and SP metabolism with more subtle differences observed in glycine lipid production. This data will provide a useful platform for the further characterisation of the lipid-based host-microbe dialogue and the influence of microbial lipids on host health and disease states.

microbiology↗

bioRxiv2021

The language network supports both lexical access and sentence generation during language production

A fronto-temporal brain network has long been implicated in language comprehension. However, this networks role in language production remains debated. In particular, it remains unclear whether all or only some language regions contribute to production, and which aspects of production these regions support. Across three fMRI experiments that rely on robust individual-subject analyses, we characterize the language networks response to high-level production demands. We report three novel results. First, sentence production, spoken or typed, elicits a strong response throughout the language network. Second, the language network responds to both phrase-structure building and lexical access demands, although the response to phrase-structure building is stronger and more spatially extensive, present in every language region. Finally, contra some proposals, we find no evidence of brain regions--within or outside the language network--that selectively support phrase-structure building in production relative to comprehension. Instead, all language regions respond more strongly during production than comprehension, suggesting that production incurs a greater cost for the language network. Together, these results align with the idea that language comprehension and production draw on the same knowledge representations, which are stored in a distributed manner within the language-selective network and are used to both interpret and generate linguistic utterances.

neuroscience↗

bioRxiv2019

Longitudinal impact of oral probiotic Lactobacillus acidophilus vaccine strains on the immune response and gut microbiome of mice

The potential role of probiotic bacteria as adjuvants in vaccine trials led to their use as nonparenteral live mucosal vaccine vectors. Yet, interactions between these vectors, the host and the microbiome are poorly understood. This study evaluates impact of three probiotic, Lactobacillus acidophilus, vector strains, and their interactions with the hosts immune response, on the gut microbiome. One strain expressed the membrane proximal external region from HIV-1 (MPER). The other two expressed MPER and either secreted interleukin-1{beta} (IL-1{beta}) or expressed the surface flagellin subunit C (FliC) as adjuvants. We also used MPER with rice bran as prebiotic supplement. We observed a strain dependent, differential effect suggesting that MPER and IL-1{beta} induced a shift of the microbiome while FliC had minimal impact. Joint probiotic and prebiotic use resulted in a compound effect, highlighting a potential synbiotic approach to impact efficacy of vaccination. Careful consideration of constitutive adjuvants and use of prebiotics is needed depending on whether or not to target microbiome modulation to improve vaccine efficacy. No clear associations were observed between total or MPER-specific IgA and the microbiome suggesting a role for other immune mechanisms or a need to focus on IgA-bound, resident microbiota, most affected by an immune response.

immunology↗

bioRxiv2018

KH-type splicing regulatory protein controls colorectal cancer cell growth and modulates the tumor microenvironment

KH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large datasets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Elevated expression was found in tumor versus matched normal tissue, and we validated these findings in larger independent cohorts in silico. KHSRP expression was a prognostic indicator of worse overall survival (HR=3.74, 95% CI = 1.43-22.97, p=0.0138). Mechanistic data in CRC cell line models supported a role of KHSRP in driving epithelial cell proliferation in both a primary and metastatic setting, through control of the G1/S transition. Additionally, KHSRP promoted a pro-angiogenic extracellular environment by regulating the secretion of oncogenic proteins involved in diverse cellular processes such as migration and response to cellular stress. Our study provides novel mechanistic insight into the tumor-promoting effects of KHSRP in CRC.

cancer biology↗