Biology subjects

Gill, R.

Publications and source records attributed to Gill, R..

12 recordsLinked to original sources

bioRxiv2026

HIV remodels germinal centers through T follicular helper cell loss

T follicular helper cells (Tfh) within germinal centers are among the most permissive cells for HIV infection and serve as a critical part of the viral reservoir. Given the key role of Tfh in affinity maturation and the production of plasma cells and memory B cells, an understanding of this critical viral reservoir is fundamental not only for cure strategies but also for understanding immunodeficiency in people living with HIV (PLWH). Using rare clinical specimens from PLWH, we demonstrate that HIV causes both a change in the cellular composition of germinal centers and changes in their overall architecture in ways that are consistent with the immunodeficiency seen in PLWH, independent of their CD4 count. We note a significant decrease in the number of GC Tfh cells and an increase in the number of follicular CD8 T cells in lymphoid tissues obtained from PLWH. Our data further show that GC size is decreased both by HIV and with increased age. Single-cell RNA sequencing data demonstrate that HIV acutely decreases the expression of Tfh B-cell support pathways and disrupts Tfh expression of cell trafficking receptors. Additionally, in a lymphoid organoid model of acute infection that forms GC-like structures, these findings are recapitulated, suggesting that New Approach Methodologies could be germane to understanding the impact of HIV on the reservoir and immunodeficiency. This study describes previously undocumented remodeling of the germinal center niche in PLWH, providing insight into the immune microenvironment of a key HIV reservoir that may help inform future cure strategies.

microbiology↗

bioRxiv2026

Humanized patient-derived xenografts preserve tumour-specific immune microenvironments

Defining the genetic and cellular programs that allow solid tumours to evade immune control requires preclinical models that preserve the complexity of the human tumour immune microenvironment. Most available systems capture only part of this biology. Organoid cultures and ex vivo tumour fragments can retain patient-derived tumour architecture and associated immune cells, but immune populations are typically maintained only for short periods. These models also cannot capture antitumour immune responses in the physiological setting of a living organism. Patient-derived xenografts propagated in humanized mice offer a potential path to overcome these limitations by combining patient-derived tumour tissue with a reconstituted human immune system. However, few studies have systematically tested whether these models reproduce the diverse immune cell phenotypes present in the parental tumours from which they are derived. This has limited their use for studying tumour-intrinsic mechanisms that shape immune composition and promote immune evasion. To address this gap, we profiled tumour-infiltrating, splenic, and bone marrow immune cells from ovarian, head and neck, and renal PDX models propagated in CD34+ hematopoietic stem cell (HSC)-derived huNOG-EXL mice expressing human IL-3 and GM-CSF. By comparing tumours grown across distinct HSC donor backgrounds with their matched primary tumour samples, we found that tumour-intrinsic factors are a dominant determinant of immune composition in humanized PDX tumours. Across models, these immune infiltrates generally resembled those of the corresponding parental tumours. These findings support humanized PDX models as a platform for functionally interrogating tumour-intrinsic drivers of immune composition and immune evasion in solid tumours.

cancer biology↗

bioRxiv2025

A single-cell spatial transcriptomic census of human skin anatomy

The skin is the largest human organ and a site of significant disease burden, yet its cellular and molecular organization across the body are largely undefined. Here, we construct a spatially-resolved single-cell atlas of 1.2 million cells from normal adult human skin to localize 45 cell types across 15 anatomic sites. We define principles of organ-wide cell composition, including axes of cell diversity and specialization, and distinguish site-enriched cell types. Each body site is comprised of 10 multicellular neighborhoods that define cell-cell communication. Notably, we identify a perivascular neighborhood enriched for immune-stromal crosstalk with features resembling a homeostatic immune niche similar to skin-associated lymphoid tissue. Finally, mapping these neighborhoods onto skin disease reveals pathogenic neighborhood disruptions, including pan-disease immune alterations in the perivascular neighborhood. We present a framework charting the skins multiscale spatial organization across a molecular to macroanatomic scale. This work advances our understanding of organ-wide skin cellular organization and communication, and its architectural disruption in disease. HIGHLIGHTSO_LIHuman skin MERFISH spatial atlas of 1.2 million cells from 114 samples and 22 donors C_LIO_LICellular diversity varies along a central to peripheral body site spatial axis C_LIO_LI10 multicellular neighborhoods define skin microanatomy and homeostatic interactions C_LIO_LIHuman skin diseases feature spatial and transcriptional neighborhood remodeling C_LI

genomics↗

bioRxiv2025

The Sphingosine-1-phosphate pathway is differentially activated in human gestational tissues.

BACKGROUNDDysregulated myometrial contractility contributes to obstetric complications. Sphingosine-1-phosphate (S1P) is an important inflammatory regulator in the myometrium and decidua, yet its metabolic dynamics during pregnancy are poorly characterized. This study aimed to profile the expression of S1P metabolic enzymes and receptors, and quantify sphingolipid metabolism in human gestational tissues across pregnancy. METHODSMyometrium, decidua parietalis, and chorioamnion were collected from women undergoing cesarean sections at term ([≥]37 weeks gestation) without labor (TNL), at term with labor (TL), and preterm (<37 weeks gestation) without labor (PTNL). Messenger RNA (mRNA) expression of S1P metabolic enzymes and receptors was assessed using quantitative polymerase chain reaction, while sphingolipids were quantified using targeted liquid chromatography-tandem mass spectrometry. RESULTSS1P metabolic enzymes and receptors were differentially expressed across gestational tissues. At TNL, SPHK1 expression was significantly higher in the decidua parietalis than in the chorioamnion and myometrium. The myometrium exhibited the highest mRNA expression of S1P receptors (S1PR1-4) compared to the decidua and chorioamnion. At term, S1P was more abundant in the myometrium than in the decidua parietalis and chorioamnion. Both SPHK1 and S1P were significantly increased in TL compared to TNL myometrium. S1P levels were higher in the myometrium at TNL compared to PTNL, while no significant differences were observed in the decidua and chorioamnion. Overall, sphingolipid metabolism was highest in the decidua and myometrium and lowest in the chorioamnion at term. CONCLUSIONThese findings reveal tissue-specific regulation of S1P metabolism and signaling in human gestational tissues, suggesting a therapeutic role of S1P in modulating myometrial contractility.

developmental biology↗

bioRxiv2024

Exploring Organ-Specific Extracellular Vesicles in Metabolic Improvements Following Bariatric Surgery in Adolescents with Obesity

Aims/hypothesisVertical sleeve gastrectomy (VSG) leads to significant metabolic improvements, though the underlying molecular mechanisms are not yet fully understood. Emerging evidence suggests that small extracellular vesicles (sEVs) contribute to metabolic improvements post-VSG; however, it is still unclear which organ-specific sEV correlate with various metabolic parameters and how they exert these effects. The study aimed to establish the role of organ-specific sEVs in the metabolic improvements associated with VSG. MethodsDemographic, anthropometric, and blood samples were collected pre-VSG and 3- and 6-month post-VSG in adolescents with obesity. Blood samples were utilized to measure metabolic parameters and to isolate sEVs. sEV RNAs were analyzed via small RNA sequencing then bioinformatics analyses. ResultsA significant reduction in mRNA cargo from liver-specific genes was observed post- VSG, whereas adipose tissue- or skeletal muscle-specific genes showed no such reduction. Liver-derived RNA correlated with BMI, leptin, and resistin, while adipose-derived RNA correlated with leptin. Analysis of delta values (post-minus pre-surgery) revealed that adipose-derived RNA cargo correlated with markers of liver damage and HOMA-IR, whereas liver-derived RNA cargo correlated with BCAAs. ConclusionsVSG modulates the EV system in the liver and adipose tissue. Liver-derived sEVs appear to regulate adipose metabolism, while adipose-derived sEVs are associated with liver function, suggesting a dynamic crosstalk between these tissues through sEVs that shapes systemic metabolic outcomes. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABS- Vertical sleeve gastrectomy (VSG) is the most performed bariatric surgery, leading to significant metabolic improvements. - Small extracellular vesicles (sEVs) and their RNA cargo play a crucial role in metabolic regulation. - Levels of branched-chain amino acids (BCAAs), which are known metabolic regulators, decrease following bariatric surgery. What is the key question?- How do sEVs, BCAA and other metabolic molecules interact to drive the significant metabolic improvements observed after VSG? What are the new findings?- The levels of liver-specific RNA cargo in sEVs decrease after VSG and are correlated with BMI and leptin levels at 6 months post-surgery, suggesting a potential role for liver-specific RNA cargo in the metabolic benefits associated with VSG. - Changes in BCAA levels from baseline to 6 months post-surgery correlate with changes in liver-specific RNA cargo in sEVs, indicating liver-specific RNA cargo in sEVs may influence metabolic parameters through BCAA modulation. - Changes in the level of adipose-specific RNA cargo in sEVs from baseline to 6 month post-surgery correlate with changes HOMA-IR and ALT levels. How might this impact on clinical practice in the foreseeable future?The study identifies liver- and adipose-derived sEV RNA cargo as potential targets for non-invasive therapies that could replicate the metabolic benefits of VSG. While further investigation is needed, these findings suggest a tentative alternative for adolescents facing obesity who may be ineligible or reluctant to undergo bariatric surgery.

cell biology↗

bioRxiv2024

RTF1 mediates epigenetic control of Th17 cell differentiation via H2B monoubiquitination

A gene encoding the transcription factor RTF1 has been associated with an increased risk of ulcerative colitis (UC). In this study, we investigated its function in modulating T cells expressing interleukin-17A (Th17 cells), a cardinal cell type promoting intestinal inflammation. Our results indicate that Rtf1 deficiency disrupts the differentiation of Th17 cells, while leaving regulatory T cells (Treg) unaffected. Mechanistically, RTF1 facilitates histone H2B monoubiquitination (H2Bub1), which requires its histone modification domain (HMD), for supporting Th17 cell function. Impaired Th17 differentiation was also observed in cells lacking the H2Bub1 E3 ligase subunit RNF40, an enzyme known to physically interact with RTF1. Thus, our study underscores the essential role of RTF1 in H2Bub1-mediated epigenetic regulation of Th17 cell differentiation. Understanding this process will likely provide valuable insights into addressing Th17-associated inflammatory disorders. Key PointsO_LIRTF1 is crucial for Th17 cell differentiation via histone H2B monoubiquitination C_LIO_LIRTF1 deficiency impairs Th17 differentiation, similar to H2Bub1 ligase RNF40 deficiency C_LIO_LIRTF1 and H2Bub1 colocalize on genes regulating Th17 cells, indicating an epigenetic role C_LI

immunology↗

bioRxiv2024

Dissecting Regulatory Non-Coding Heart Disease GWAS Loci with High-Resolution 3D Chromatin Interactions Reveals Causal Genes with Pathophysiological Relevance to Heart Failure

Heart failure is caused in part by cardiac remodeling processes that include the death of cardiac myocytes and their replacement by cardiac fibroblasts. We hypothesized that these two cell types may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease. Accordingly, we generated high-resolution Hi-C data layered with chromatin accessibility and transcriptomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters. Our analysis identified several target genes with established roles in cardiac fibrosis and/or heart disease (GJA1, TBC1D32, CXCL12, IL6R, and FURIN). Perturb-seq in cardiac fibroblasts to knock out putative regulatory elements confirmed regulatory relationships involving GJA1, CXCL12, and FURIN, as gene editing led to changes in transcriptomic signatures associated with fibroblasts in heart failure. Our results demonstrate how integrative multi-omic approaches can delineate pathophysiologically relevant regulatory circuits that connect protein-coding genes to non-coding genetic variants associated with disease.

genomics↗

bioRxiv2024

Aquatic metabolism throughout impoundment of a low productivity boreal reservoir using free water oxygen

Inland water bodies play a significant role in the global cycling of greenhouse gases (GHGs). Impoundment of rivers changes their GHG dynamics and leads to a pulse of emissions, primarily due to the respiration of introduced organic matter (OM). Aquatic metabolism estimates using free water oxygen curves were calculated at five sites on the lower Nelson River, Manitoba, Canada to assess the impact of impounding a new hydroelectric reservoir at the Keeyask Generating Station. After impoundment, the greatest ecosystem respiration (R) rates were seen in a former tributary inflow (-1.94 {+/-} 1.03 g C m-2 d-1) and then in the forebay (-1.06 {+/-} 0.74 g C m-2 d-1), an order of magnitude greater than the upstream extent of the reservoir area that appeared unimpacted (-0.13 {+/-} 0.29 g C m-2 d-1). Benthic and pelagic R were of greater relative importance in the former tributary inflow and the forebay, respectively. Loading of allochthonous OM was a key factor regulating R. Further, evidence of "priming," wherein labile OM facilitates the breakdown of more recalcitrant OM, was observed. Light limitation appeared to be prevalent throughout the study area, consistent with previous studies in the region. Despite the unique water chemistry present (i.e., high total phosphorus, high turbidity), aquatic metabolism in the study area appeared similar to other boreal impoundments. The results presented here updated the understanding of aquatic metabolism in a region characterized by hydroelectric development. Further, challenges in the methodology (e.g., gas transfer velocity estimation) were identified and discussed.

ecology↗

bioRxiv2023

The search behavior of terrestrial mammals

Animals moving through landscapes need to strike a balance between finding sufficient resources to grow and reproduce while minimizing encounters with predators 1,2. Because encounter rates are determined by the average distance over which directed motion persists 1,3-5, this trade-off should be apparent in individuals movement. Using GPS data from 1,396 individuals across 62 species of terrestrial mammals, we show how predators maintained directed motion ~7 times longer than for similarly-sized prey, revealing how prey species must trade off search efficiency against predator encounter rates. Individual search strategies were also modulated by resource abundance, with prey species forced to risk higher predator encounter rates when resources were scarce. These findings highlight the interplay between encounter rates and resource availability in shaping broad patterns mammalian movement strategies.

ecology↗

bioRxiv2021

Kinesin-II motors differentially impact biogenesis of distinct extracellular vesicle subpopulations shed from C. elegans sensory cilia

Extracellular vesicles (EVs) are bioactive lipid-bilayer enclosed particles released from nearly all cells. One specialized site for EV shedding is the primary cilium, a conserved signaling organelle. The mechanisms underlying cargo enrichment and biogenesis of heterogeneous EVs shed from cilia are unclear. Here we discover the conserved ion channel CLHM-1 as a new ciliary EV cargo. Using super-resolution microscopy, we imaged EVs released into the environment from sensory neuron cilia of C. elegans expressing fluorescently-tagged CLHM-1 and TRP polycystin-2 channel PKD-2 EV cargoes at endogenous levels. We find that these proteins are enriched in distinct EV subpopulations that are differentially shed in response to availability of hermaphrodite mating partners. Both CLHM-1 and PKD-2 localize to the ciliary base and middle segment of the cilium proper, but PKD-2 alone is present in the cilium distal tip and EVs shed from this site. CLHM-1 EVs released into the environment bud from a secondary site, the periciliary membrane compartment at the ciliary base. We show that individual heterotrimeric and homomeric kinesin-II motors have discrete impacts on the colocalization of PKD-2 and CLHM-1 in both cilia and EVs. Total loss of kinesin-II activity significantly decreases shedding of PKD-2 but not CLHM-1 EVs. Our data demonstrate that anterograde kinesin-II-dependent intraflagellar transport is required for selective enrichment of specific protein cargoes into heterogeneous EVs with different signaling potentials.

cell biology↗

bioRxiv2020

Blocking gephyrin phosphorylation or microglia BDNF signaling prevents synapse loss and reduces infarct volume after ischemia

Microglia interact with neurons to facilitate synapse plasticity; however, signal transducers between microglia and neuron remain unknown. Here, using in vitro organotypic hippocampal slice cultures and transient MCAO in genetically-engineered mice in vivo, we report that at 24 h post-ischemia microglia release BDNF to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the CA1 hippocampal formation in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75NTR and TrkB receptors respectively. Post-MCAO, we report that in the peri- infarct area and in the corresponding contralateral hemisphere similar neuroplasticity occur through microglia activation and gephyrin phosphorylation at Ser268, Ser270 in vivo. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point-mutations protect against ischemic brain damage, neuroinflamation and synapse downregulation normally seen post-MCAO. Collectively, we report that gephyrin phosphorylation and microglia derived BDNF faciliate synapse plasticity after transient ischemia.

neuroscience↗

bioRxiv2018

Pesticide exposure affects flight dynamics and reduces flight endurance in bumblebees

The emergence of agricultural land use change creates a number of challenges that insect pollinators, such as eusocial bees, must overcome. Resultant fragmentation and loss of suitable foraging habitats, combined with pesticide exposure, may increase demands on foraging, specifically the ability to reach resources under such stress. Understanding the effect that pesticides have on flight performance is therefore vital if we are to assess colony success in these changing landscapes. Neonicotinoids are one of the most widely used classes of pesticide across the globe, and exposure to bees has been associated with reduced foraging efficiency and homing ability. One explanation for these effects could be that elements of flight are being affected, but apart from a couple of studies on the honeybee, this has scarcely been tested. Here we used flight mills to investigate how exposure to a field realistic (10ppb) acute dose of imidacloprid affected flight performance of a wild insect pollinator - the bumblebee, Bombus terrestris audax. Intriguingly, intial observations showed exposed workers flew at a significantly higher velocity over the first [3/4] km of flight. This apparent hyperactivity, however, may have a cost as exposed workers showed reduced flight distance and duration to around a third of what control workers were capable of achieving. Given that bumblebees are central place foragers, impairment to flight endurance could translate to a decline in potential forage area, decreasing the abundance, diversity and nutritional quality of available food, whilst potentially diminishing pollination service capabilities.\n\nSummary StatementAcute neonicotinoid exposure impaired flight endurance and affected velocity of Bombus terrestris workers, which may dramatically reduce colony foraging potential and pollination provision in pesticide applied landscapes.

ecology↗