Biology subjects

Williams, V.

Publications and source records attributed to Williams, V..

6 recordsLinked to original sources

bioRxiv2026

Artificial endoplasmic reticulum-lipid droplet tethers facilitate lipid incorporation into lipid droplets

Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids to meet cellular energetic and signaling needs. As a unique monolayer structure, LDs arise from the endoplasmic reticulum (ER) and acquire proteins and lipids through their membrane contact sites (MCSs) with the ER. In this study, we exogenously induce ER-LD MCSs using a dimerization-dependent fluorescent protein (ddFP) system. Strikingly, inducing these MCSs increases LD size without influencing LD total amount per cell, in a manner that is distinct from LD biogenesis induced by the dietary fatty acid oleic acid. By examining the trafficking of the triacylglycerol synthesis enzyme DGAT2 under ddFP induction, we found that artificial tethering recruits LD proteins to the ER-LD interface but not to the LD surface, unlike oleic acid supplementation. However, by supplementing ddFP-transfected cells with fluorescent fatty acids, we found that ddFP-positive LDs preferentially incorporate exogenous lipid, suggesting that inducing MCSs can facilitate ER-to-LD lipid transfer. These results demonstrate ddFPs as a tool for manipulating LD MCSs and elucidate the role of ER-LD MCSs following LD biogenesis to continue to promote LD growth.

Cell Biology↗

bioRxiv2025

Is cultural context the crucial touch? Neurophysiological and self-reported responses to affective touch in women in South Africa and the United Kingdom.

Affective touch, involving touch-sensitive C-tactile (CT-) afferent nerve fibres, is integral to human development and wellbeing. Despite presumed cultural differences, affective touch research typically includes Western, minority-world contexts, with findings extrapolated cross-culturally. We report the first cross-cultural study to experimentally investigate subjective and neurophysiological correlates of affective touch in women in South Africa (SA) and the United Kingdom (UK) using (1) subjective touch ratings, and (2) cortical oscillations for slow CT-optimal (vs. faster non-CT-optimal) touch on two body regions (arm, palm). Cultural context modulated affective touch experiences: SA (vs. UK) participants rated touch as more positive and less intense, with enhanced differentiation in sensorimotor beta band oscillations, especially during palm touch. UK participants differentiated between stroking speeds, with opposite directions of effects at arm and palm for frontal theta oscillations. Results highlight the importance of cultural context in subjective experience and neural processing of affective touch.

neuroscience↗

bioRxiv2024

Genome-wide screen overexpressing mycobacteriophage Amelie genes identifies multiple inhibitors of mycobacterial growth

The genome sequences of thousands of bacteriophages have been determined and functions for many of the encoded genes have been assigned based on homology to characterized sequences. However, functions have not been assigned to more than two-thirds of the identified phage genes as they have no recognizable sequence features. Recent genome-wide overexpression screens have begun to identify bacteriophage genes that encode proteins that reduce or inhibit bacterial growth. This study describes the construction of a plasmid-based overexpression library of 76 genes encoded by Cluster K1 mycobacteriophage Amelie, which is genetically similar to Cluster K phages Waterfoul and Hammy recently described in similar screens and closely related to phages that infect clinically important mycobacteria. 26 out of the 76 genes evaluated in our screen, encompassing 34% of the genome, reduced growth of the host bacterium Mycobacterium smegmatis to various degrees. More than one-third of these 26 toxic genes have no known function, and 10 of the 26 genes almost completely abolished host growth upon overexpression. Notably, while several of the toxic genes identified in Amelie shared homologs with other Cluster K phages recently screened, this study uncovered eight previously unknown gene families that exhibit cytotoxic properties, thereby broadening the repertoire of known phage-encoded growth inhibitors. This work, carried out under the HHMI-supported SEA-GENES project (Science Education Alliance Gene-function Exploration by a Network of Emerging Scientists), underscores the importance of comprehensive overexpression screens in elucidating genome-wide patterns of phage gene function and novel interactions between phages and their hosts.

microbiology↗

bioRxiv2023

Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/537874v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1bb1277org.highwire.dtl.DTLVardef@b978dborg.highwire.dtl.DTLVardef@adafc8org.highwire.dtl.DTLVardef@efa0f3_HPS_FORMAT_FIGEXP M_FIG Early life trauma and obesogenic diet effects of feeding control.Consumption of a Western-like high-saturated fat diet (WD, 42% kcal from fat) during adolescence in combination with (2) Exposure to early-life psychosocial stress leads to (3) changes in brain neurocircuitry and metabolic dysregulation. These alterations lead to (4) stress susceptibility, (5) emotional and feeding dysregulation, and (6) obesity. Dysregulation of feeding control and obesity leads to increased hedonic feeding and engages individuals in a cycle of aberrant feeding behaviors. C_FIG BackgroundChildhood overweight/obesity is associated with the development of stress-related psychopathology. However, the pathways connecting childhood obesity to stress susceptibility remain poorly understood. Here, we used a systems biology approach to determine linkages underlying obesity-induced stress susceptibility. MethodsSixty-two (62) adolescent Lewis rats (PND21) were fed for four weeks with a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). Subsequently, a group of rats (n = 32) was exposed to a well-established 31-day model of predator exposures and social instability (PSS). The effects of the WD and PSS were assessed with a comprehensive battery of behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), high throughput 16S ribosomal RNA gene sequencing for gut microbiome profiling, hippocampal microglia morphological and gene analysis, and gene methylation status of the stress marker, FKBP5. Parallel experiments were performed on human microglial cells (HMC3) to examine molecular mechanisms by which palmitic acid primes these cells to aberrant responses to cortisol. ResultsRats exposed to the WD and PSS exhibited deficits in sociability indices and increased fear and anxiety-like behaviors, food consumption, and body weight. WD and PSS interacted to alter indices of microstructural integrity within the hippocampal formation (subiculum) and subfields (CA1). Microbiome diversity and taxa distribution revealed that WD/PSS exposure caused significant shifts in the diversity of gut dominant bacteria and decreased the abundance of various members of the Firmicutes phylum, including Lachnospiracae NK4A136. Interestingly, the WD and PSS synergized to promote hippocampal microglia morphological and gene signatures implicated in neuroinflammation. These alterations were associated with changes in the microbiome, and in the expression and methylation status of the corticosterone receptor chaperone rat gene Fkbp5. HMC3 responses to cortisol were markedly disrupted after incubating cells in palmitate, shown by morphological changes and pro-inflammatory cytokine expression and release. Notably, these effects were partly mediated by the human FKBP5 gene. ConclusionsThe combination of psychosocial stress and poor diet during adolescence has a deleterious synergistic impact on brain health. This study enhances our understanding of mechanisms and adaptations by which obesogenic environments shape the maturational trajectories of common neurobiological correlates of resilience. HighlightsO_LIObesogenic diet consumption during adolescence leads to stress-induced anxiety-like behaviors in rats. C_LIO_LIExposure to an obesogenic environment during adolescence alters indices of hippocampal microstructural integrity. C_LIO_LIObesogenic diet and chronic stress promote selective gut microbiota dysbiosis. C_LIO_LIObesogenic diet and chronic stress synergize to expand putative pro-inflammatory microglia populations in the CA1 subfield of the hippocampus. C_LIO_LIObesogenic diet and chronic stress influence hippocampal Fkbp5 gene methylation status at specific sites. C_LIO_LIFKBP5 integrates microglial pro-inflammatory signals under obesogenic conditions. C_LI

neuroscience↗

bioRxiv2022

CD8 T Cell Memory Inflation is Driven by Latent CMV Infection of Lymphatic Endothelial Cells

CMV, a ubiquitous herpesvirus, elicits an extraordinarily large T cell response that is sustained or increases over time, a phenomenon termed memory inflation. Remarkably, even latent, non-productive infection can drive memory inflation. Despite intense research on this phenomenon, the infected cell type(s) involved are unknown. To identify the responsible cell type(s), we designed a Cre-lox murine CMV (MCMV) system, where a spread-deficient ({Delta}gL) virus expresses recombinant SIINFEKL only in Cre+ host cells. We found that latent infection of endothelial cells (ECs), but not dendritic cells (DCs) or hepatocytes, was sufficient to drive CD8 T cell memory inflation. Infection of Lyve-1-Cre and Prox1-CreERT2 mice revealed that amongst EC subsets, infection of lymphatic ECs was sufficient. Genetic ablation of {beta}2m on lymphatic ECs did not prevent inflation, suggesting another unidentified cell type can also present antigen to CD8 T cells during latency. This novel system definitively shows that antigen presentation by lymphatic ECs drives robust CD8 T cell memory inflation. SUMMARYActive T cell immunosurveillance during latent CMV infection results in T cell memory inflation. A novel Cre-lox genetic system for cell-specific antigen expression reveals that lymphatic ECs, but not DCs or hepatocytes, can drive CD8 T cell memory inflation.

immunology↗

bioRxiv2019

Estimating the impact of pneumococcal conjugate vaccines on childhood pneumonia in sub-Saharan Africa: A systematic review.

BackgroundThe impact of pneumococcal conjugate vaccine introduction in reducing the incidence of childhood pneumonia has not been well documented in sub-Saharan Africa. Many studies evaluating vaccine impact have used invasive pneumococcal disease or pneumococcal pneumonia as an outcome. ObjectiveTo estimate the impact of routine administration of 10-valent and 13-valent PCV on the incidence of pneumonia in children under five years of age in sub-Saharan Africa. Data sourcesA systematic review was conducted between 16 and 31 July 2019. The review was registered on PROSPERO with registration number CRD42019142369. The literature search was conducted in indexed databases including Medline and Embase, grey literature databases and online libraries of two universities. Manual search of the references of included studies was performed to identify additional relevant studies. The search strategy combined pneumococcal conjugate vaccine, pneumonia and child as search concepts. Study selectionStudies investigating the impact of 10- or13-valent PCV on childhood pneumonia in a sub-Saharan African country were eligible for inclusion. Case-control, cohort, pre-post and time-series study designs were eligible for inclusion. Exclusion criteria were use of 7- or 9-valent PCV, systematic review studies, clinical trials and record publication prior to 2009. Data extractionIndependent data extraction was conducted. Key variables include year study conducted, type of study design, type of PCV used and year of introduction, reported PCV coverage, outcome measure evaluated and the effect measure. Data synthesisEight records were included in the final analysis, 6 records were pre-post or time-series studies, 1 was a case-control study and 1 report combined pre-post and case-control studies. Vaccine impact measured as percentage reduction in risk (%RR) of clinical pneumonia was mostly small and non-significant. The risk reduction was more significant and consistent on radiological and pneumococcal pneumonia. Vaccine effectiveness reported in case-control studies was mostly non-significant. ConclusionEvidence of the positive impact of routine infant pneumococcal vaccination on pneumonia in sub-Saharan Africa is weak. There is a need for more research in this area to evaluate the influence of pathogen or serotype replacement in pneumonia after PCV introduction. Ongoing surveillance is also required to establish the long term trend in pneumonia epidemiology after PCV introduction.

pathology↗