Biology subjects

Young, C.

Publications and source records attributed to Young, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Inflammasome Activation and IL-1β Release in Alveolar Macrophages Infected with Pseudomonas aeruginosa is Reduced in Hypoxia

Pseudomonas aeruginosa is an important agent of acute or chronic airway infections. A complex set of genetic and environmental factors determine the outcome of a P. aeruginosa airway infection. P. aeruginosa can undergo genetic adaptation to fine tune the expression of a type III secretion system (T3SS) and other virulence factors in response to selective pressures encountered during infection. Genetic and environmental factors predispose many patient groups for P. aeruginosa infections, including people with cystic fibrosis (pwCF). CF is a genetic disorder resulting in areas of hypoxia and thick mucus that fosters P. aeruginosa airway infection. Resident alveolar macrophages (AMs) help coordinate immune responses to P. aeruginosa in airways by producing proinflammatory cytokines such as IL-1{beta}, which can be important for infection resistance. AMs infected with laboratory strains of P. aeruginosa detect the T3SS and activate the NLRC4 inflammasome, resulting in IL-1{beta} release. Studies of inflammasome responses in AMs to a clinical CF isolate of P. aeruginosa have not been reported. Here, we characterized the CF clinical isolate DH1137 and found that it has a downregulated but functional T3SS, is adapted to grow in hypoxia, and induces significant production of the inflammasome cytokines IL-1{beta} and IL-1 during lung infection in a CF mouse model. Inflammasome gene expression was primed in AMs by LPS stimulation, and upon DH1137 infection these cells released IL-1[beta]. Intriguingly, we found that infection of AMs with DH1137 in hypoxia resulted in significantly dampened inflammasome activation compared to normoxia. These data describe a new mechanism that P. aeruginosa may exploit to evade immune detection by tissue-resident lung macrophages in the context of CF.

immunology↗

bioRxiv2026

Focal radiotherapy improves CAR T cell therapy targeting prostate cancer

Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as prostate cancer due to the immunosuppressive tumor microenvironment (TME). Combining CAR T cells with existing therapies that remodel the TME and promote endogenous immune responses, such as radiation therapy and chemotherapies, may strengthen antitumor responses. Here, we assessed the potency of combining focal radiotherapy (RT), cyclophosphamide (Cy) preconditioning, and prostate stem cell antigen (PSCA)-CAR T cells against syngeneic prostate cancer models. Focal RT alone increased T cell and dendritic cell infiltration and activation in the irradiated tumor. Furthermore, the combination of all three therapies was critical for enhanced antitumor responses and survival across multiple subcutaneous, bone-metastatic, and multifocal disease models. This combination, in the irradiated TME and tumor-draining lymph nodes (tdLN), led to greater antigen presentation by myeloid cells and endogenous T cell activation and cytotoxicity. Our study demonstrates the potency of combining focal RT with PSCA-CAR T cells, significantly improving therapeutic responses in the irradiated tumor and contributing to a more robust systemic immune response against metastatic burden in prostate cancer.

Cancer Biology↗

bioRxiv2026

The Spatiotemporal Proteome Landscape of Aging: Structural determinants of age-sensitive proteome remodeling

Aging is marked by a decline in cellular functions accompanied by widespread changes in mRNA and protein abundance, yet whether aging broadly remodels subcellular protein localization and concentration--and why some proteins change while others remain stable--remains unclear. This gap matters because cellular function depends not only on expression levels but also on correct spatial organization. Using yeast replicative aging as a model, we built a robotic pipeline to enrich old cells from 5,661 strains, acquired 90 million single-cell 3D images, and applied machine learning to map proteome-wide changes in localization, concentration, and aggregation throughout aging. This age-resolved single-cell atlas uncovers widespread proteome remodeling and rewiring of protein interaction networks. Moreover, structural analysis reveals biophysical determinants of age-sensitive proteome remodeling across ages and species. Together, these results reveal a structure-encoded intrinsic principle underlying spatial proteome breakdown during aging and provide a resource to dissect mechanistic links among aging hallmarks.

systems biology↗

bioRxiv2026

Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging

Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.

systems biology↗

bioRxiv2026

Ascites-Driven Modulation of Cell Phenotypes and Proteomes: Implications for Cancer Progression

BackgroundMore than 90% of advanced ovarian cancer patients develop malignant ascites, which describes a buildup of fluid in the peritoneal cavity caused by increased vascular permeability and obstructed lymphatic drainage. Malignant ascites contains spheroidal tumor cell clusters that contain stromal cells, cancer-associated fibroblasts, and blood cells. These spheroids promote peritoneal metastasis and treatment resistance, yet the phenotypic and proteomic changes of cells caused by the ascites environment remain poorly understood, as does its influence on ex vivo responses to chemotherapeutics in personalized medicine approaches. MethodsUsing mass spectrometry, we compared the proteome profiles of cell-free ascites to serum from ovarian cancer patients. We then analyzed the proteomes of immortalized cancer cells grown as monolayers or spheroids in either malignant ascites or standard cell culture medium. The effects of this fluid on the phenotype, molecular composition, and ex vivo chemotherapy responses of cancer cells were also investigated. ResultsProteome analysis revealed that cell-free ascites had higher levels of extracellular, secreted, and membrane proteins compared to serum. Ascites enhanced cell viability and spheroid formation in immortalized ovarian cancer cell lines more effectively than standard cell culture medium. Despite this altered baseline viability, growth of spheroids in ascites versus cell culture medium did not hinder chemotherapy response assessments, indicating the appropriateness of standard cell culture medium in ex vivo applications. The observed phenotypic changes of cells grown in ascites could not be recapitulated by adding chemokines or periostin to the cell culture medium, suggesting that additional factors are required. Notably, elevated levels of transglutaminase 2 were identified in SKOV-3 cells grown in ascites, indicating that ascites directly influences protein expression in cancer cells.

cancer biology↗

bioRxiv2025

Central carbon metabolism switching in lytic versus temperate coral reef viral communities

Coral reefs are declining globally due in part to bacterial overgrowth, a process known as microbialization. However, the role of bacteriophages that may inhibit microbialization by infecting and killing these bacteria remains poorly understood, especially their metabolic impacts on bacterial proliferation. To address this, we analyzed central carbon metabolism gene frequencies in viral communities from healthy (lytic-dominated) and degraded (temperate-dominated) Central Pacific coral reefs. We found that viral metabolism shifted broadly from being dominated by metabolism that builds up pools of central intermediates on degraded reefs dominated by temperate viral infection ("anaplerotic" reactions) to metabolism that consumes these pools to prioritize production of metabolic precursors for virion construction on healthy reefs dominated by lytic infection ("cataplerotic" reactions). This switch was shown by the over-representation of Entner-Doudoroff (ED) glycolysis genes on degraded, temperate-dominated reefs and of pentose phosphate pathway (PPP) and reductive tricarboxylic acid cycle (TCA) genes on healthy, lytic-dominated reefs. As a result of this metabolic dichotomy, our qualitative compartment modeling revealed two distinct ecosystem states: (i) healthy reefs, where lytic viral metabolism enhances viral production and suppresses bacterial overgrowth, and (ii) degraded reefs, where temperate viral metabolism accelerates bacterial proliferation. Because viral switching between lytic and temperate lifestyles is a known function of host physiological state, these findings position viral metabolism as both a driver of reef decline and a conservation lever, with metabolically mediated "re-viralization" offering a novel strategy to restore reef resilience.

ecology↗

bioRxiv2025

Maternal IBD-related antibodies are associated with early life gut inflammatory status and microbiota composition: insights from cord blood

PurposeAntibodies in peripheral blood are used to aid in the diagnosis of inflammatory bowel disease (IBD), but their presence in neonatal cord blood and potential effects on early life development remain unknown. MethodsWe measured anti-CBir1, ANCA, anti-OmpC, ASCA IgA, and ASCA IgG levels in the cord blood of babies born to 78 mothers with or without IBD. Their association with fecal calprotectin (FC), and microbiota composition, characterized by 16S rRNA sequencing, was assessed throughout pregnancy and during the first 3 years of life using linear mixed-effects models. ResultsAntibodies were detected in cord blood, with significantly higher levels of anti-CBir1 and ASCA IgG in babies born to mothers with Crohns disease (p = 0.002) and higher abundance of ANCA and anti-OmpC in babies of mothers with ulcerative colitis (p = 0.002), compared to controls. ASCA IgG levels positively correlated with babies FC (p = 0.006), while babies microbiota Shannon diversity was negatively associated with ANCA, anti-OmpC, and ASCA IgA levels (p = 0.003, 0.04, and 0.008, respectively). Romboutsia spp., Citrobacter spp., Pseudomonas spp., Clostridiaceae, Clostridia, and Varibaculum spp. were positively correlated with either or both ANCA and anti-OmpC levels (all multiple testing adjusted q < 0.1). ConclusionOur findings suggest that maternal IBD-associated antibodies cross the placenta barrier and may be associated with intestinal inflammation and imbalanced microbiota colonization. Whether these serological profiles negatively influence the priming of the babys immune system or IBD risk later in life remains to be determined.

immunology↗

bioRxiv2025

The relationships among alkaloid production, fungal biomass, and host genetics in the Tall Fescue-Epichloe symbiosis

Tall fescue (Lolium arundinaceum) is an important forage and turf grass that covers 35 million acres (140,000 square kilometers) in the transition zone of the southeastern United States. Most tall fescue in the US is infected with a symbiotic fungus, Epichloe coenophiala, which confers biotic and abiotic stress tolerance for the plant but also produces toxic alkaloids that harm livestock. Although there has been prior evidence that the grass host can influence alkaloid production levels, these have never been precisely quantified. Here, we report on testing alkaloid production and relative fungal biomass on >1000 genetically distinct tall fescue plants. We find that these two traits are weakly correlated, and that both show evidence of moderate to high influence by the host genome. Genome-wide association find only a single marginally significant hit, however, implying that any genetic control by the host is spread among a large number of genes. These results indicate that the host plant exerts moderate influence on these endophytic traits, that the two are largely independent of each other, and that the hosts influence is likely due to a large number of genes of small effect. These results have relevance for breeding tall fescue for forage and turf production, and especially for optimizing the endophyte relationship for tall fescue management.

plant biology↗

bioRxiv2025

Region-specific Brain Targets Drive Circuit Formation and Maturation of Human Retinal Ganglion Cells

Human vision relies on retinal ganglion cells (RGCs), and their connectivity with distinct brain regions enables higher order visual processing. RGCs vary considerably between species, and many model organisms display distinct RGC types and innervation patterns from those in humans. There is thus a need for robust models of human RGC circuit formation that preserves innervation specificity. Here, we developed an in vitro microfluidics eye-to-brain connectivity model using human pluripotent stem cell (hPSC)-derived RGCs to assess brain region-specific connectivity features. We found that cultured human RGCs segregate their dendrites and axons and display axonal features that align with those of their in vivo human RGC counterparts. To identify brain target surrogates, we conducted bioinformatic similarity assessments, which revealed high conservation and lower variability between human LGN and mouse counterparts relative to available thalamocortical organoids. We thus provided region-specific mouse visual targets to assess specificity and activity. We found that human RGC axons terminals differentially connected with distinct mouse retinorecipient brain regions and promoted region-specific neural activity. Increased synapse formation occurred between RGCs and lateral geniculate neurons relative to that with suprachiasmatic nucleus neurons, modeling retina brain connectivity differences. Both retinorecipient partners induced the formation of more synapses relative to non-retinorecipient brain target controls. These results suggest that human RGC innervation properties are preserved in culture systems and that human RGCs can differentially sense and respond to retinorecipient targets to control wiring outcomes. These systems may aid in the discovery of wiring factors for potential therapeutic applications. Significance StatementThis study presents a novel in vitro model to investigate human retinal ganglion cell (RGC) connectivity, using human pluripotent stem cell-derived RGCs and specific mouse brain targets. By modeling eye-to-brain connections in a microfluidics device, we reveal that cultured human RGCs can form selective, region-specific synapses with mouse-derived brain areas like the lateral geniculate nucleus and the suprachiasmatic nucleus. The findings demonstrate that human RGCs retain their innervation specificity presences in culture, mimicking in vivo human connectivity patterns. This model thus provides a powerful tool for understanding the factors controlling human-specific brain wiring, with potential applications in therapies for visual and neurological disorders.

neuroscience↗

bioRxiv2025

Dystrophin Dp71 is essential for the development and function of macrophages

Mutations in the DMD gene, encoding dystrophins, cause progressive muscle degeneration with severe sterile inflammation. While macrophages predominate amongst muscle-infiltrating cells, being central to both damage and regeneration, they were not known to express dystrophin. Yet, we recently demonstrated Dp71 dystrophin expression correlating with tumour infiltrating macrophages. Here we report physiological, developmentally regulated expression of Dp71 in human and mouse hematopoietic stem cells, which decreases with cell maturation into bone marrow macrophages (BMM). Proteomics with molecular and functional analyses in mouse dystrophin-null BMM and peritoneal macrophages reveal that absence of dystrophin disturbs their development. Alterations in over 300 proteins mapped to pathways and networks relating to reduced migration and phagocytosis and increased NLRP3 inflammasome functions. These defects are Dp71-dependent and not caused by the dystrophic environment, since Dmdmdx mouse macrophages, which express Dp71, are not affected. Thus, we identify an important new role for the DMD gene. Altered Dp71 expression in tumour microenvironment cells and in dystrophin-null patients should be investigated to understand the commonalities between DMD and tumours, and potentially identify new treatments.

cell biology↗

bioRxiv2025

Warming disrupts plant-fungal endophyte symbiosis more strongly in leaves than roots

Disruptions to species interactions from global change will negatively impact plant primary production, with broader consequences for species abundances, distribution, and community composition. Fungal endophytes that live inside plant leaves and roots could potentially mitigate plant heat stress from global warming. Conversely, disruptions of these symbioses could exacerbate the negative impacts of warming. To better understand the consistency and strength of warming-induced changes to fungal endophytes, we examined fungal leaf and root endophytes in three grassland warming experiments in the US ranging from 2 to 25 years and spanning 2000 km, 12 {degrees}C of mean annual temperature, and 600 mm of precipitation. We found that experimental warming disrupted symbiosis between plants and fungal endophytes. Colonization of plant tissues by septate fungi decreased in response to warming by 90% in plant leaves and 35% in roots. Warming also reduced fungal diversity and changed community composition in plant leaves but not roots. The strength, but not direction, of warming effects on fungal endophytes varied by up to 75% among warming experiments. Finally, warming decoupled fungal endophytes from host metabolism. Overall, warming-driven disruption of fungal endophyte community structure and function suggests that this symbiosis may not be a reliable mechanism to promote plant resilience and ameliorate stress responses under global change.

ecology↗

bioRxiv2025

Debiasing Sinkhorn divergence in optimal transport of cellular dynamics

Single-cell RNA-seq analysis characterizes developmental mechanisms of cellular differentiation, lineage determination, and reprogramming with differential conditioning of the microenvironment. In this article, the underlying dynamics are formulated via optimal transport with algorithms that calculate the transition probability of the state of cell dynamics over time. The algorithmic biases of optimal transport (OT) due to entropic regularization are balanced by Sinkhorn divergence, which normally de-biases the regularized transport by centering them. In the case of reprogramming mouse embryonic fibroblasts [1] with dense time points, Sinkhorn divergence is shown to improve the trajectories of targeted cell fates depending on the specific cell types. When the time points are filtered out with sparser 9 and 5 time points, some cell phenotypes show better outcomes from strong entropic regularization. For 9 time points with 2 days interval, Sinkhorn divergence shows a clear advantage with broad bandwith of optimal entropic regularization. For these derived time points, when the cell population is scaled down from n = 8000 to n = 2000, there comes no benefit from Sinkhorn divergence for some specific cell types. In the case of stratifying morphogenesis of the epidermis [2], the sparsity of time points makes it not significant to prescribe Sinkhorn divergence in the accuracy of transporting to the expected cell fates. Overall, whether to prescribe Sinkhorn divergence for the accurate prediction of lineages of single cells depends on temporal sparsity.

bioinformatics↗

bioRxiv2024

Building a Collaborative DNA Barcode Library for the Diptera of Churchill, Canada: A Resource for Northern Research

Churchill, Manitoba, Canada is a diverse subarctic region that has been the focus of DNA barcoding efforts and research for decades. Despite this effort, there are still taxa in this region that are underrepresented in public databases, particularly hyper diverse insect groups. We present a collaborative large-scale DNA barcode reference library for Diptera based on molecular data and expert taxonomic identification, and we explore habitat occupancy, biogeographic patterns, and molecular evolution. The reference library contains 16786 specimens sampled around Churchill from 2005 to 2011. Selected specimens were identified by morphological means, sequenced for the animal barcode marker, and sorted into 2225 Molecular Operational Taxonomic Units (using Barcode Index Numbers: BINs) representing 68 families and 1216 named species. Eighty-five species shared a BIN with another species, 143 species were split across several BINs, and 990 species were assigned to a unique BIN, including 129 BINs new to the Barcode of Life Data System. The intraspecific and nearest neighbour distances varied across families, but most species can be easily distinguished from their nearest neighbours. By combining molecular data with taxonomic expertise, the barcode library provides species-level information for 12608 specimens, supplying future researchers with detailed taxonomic information and the opportunity to perform barcode-based specimen identifications for large-scale studies through sequence matching. Comparison of the Diptera composition of Churchill to other subarctic regions reflected likely postglacial colonization northwards as well as a Beringian and circumpolar component. This study also provides an initial investigation of molecular evolution in the best-represented species and finds variability in the rate of molecular evolution, opening intriguing avenues for further investigation. This study provides a publicly available, detailed reference library for use in future research, as well as new insights into the current diversity and taxonomic composition of Diptera present among the diverse habitats of Churchill.

molecular biology↗

bioRxiv2024

Spatial proteomics and transcriptomics of placenta accreta spectrum

In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4+, CD3+ and CD8+ T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITG{beta}1, including with fibronectin and ADAMS, emerging as central in increta. These ITG{beta}1 ligand interactions are involved in activation of epithelial-mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring. Overall, this study suggests the biological processes leading to deep trophoblast invasion in the myometrium in placenta increta are as a result of upregulation of transcription factors and subsequent genes and proteins which promote trophoblast invasion. This occurs in a locally immune suppressed environment, with increased ECM degradation suggesting these findings are secondary to iatrogenic uterine injury. Significance statementPlacenta Accreta Spectrum (PAS) is a rare pregnancy complication, where the placenta fails to separate from the womb resulting in severe bleeding, which is associated with significant maternal morbidity and mortality. As Caesarean section rates increase, the incidence of PAS is increasing. The underlying pathophysiology of PAS is poorly understood. Here, we apply a spatial multi-omic approach to explore the biologic changes at the maternal-fetal interface in severe PAS (placenta increta). Using spatial transcriptomics and proteomics, we identified genes and proteins that are dysregulated in severe PAS involving processes such as extracellular matrix degradation, local immune suppression and promotion of epithelial-mesenchymal transition. This study provides new insights into the biological changes and underlying pathophysiology leading to placenta increta.

bioinformatics↗

bioRxiv2024

Involvement of ArlI, ArlJ, and CirA in Archaeal Type-IV Pilin-Mediated Motility Regulation

Many prokaryotes use swimming motility to move toward favorable conditions and escape adverse surroundings. Regulatory mechanisms governing bacterial flagella-driven motility are well-established, however, little is yet known about the regulation underlying swimming motility propelled by the archaeal cell surface structure, the archaella. Previous research showed that deletion of the adhesion pilins (PilA1-6), subunits of the type IV pili cell surface structure, renders the model archaeon Haloferax volcanii non-motile. In this study, we used EMS mutagenesis and a motility assay to identify motile suppressors of the {Delta}pilA[1-6] strain. Of the eight suppressors identified, six contain missense mutations in archaella biosynthesis genes, arlI and arlJ. Overexpression of these arlI and arlJ mutant constructs in the respective multi-deletion strains {Delta}pilA[1-6]{Delta}arlI and {Delta}pilA[1-6]{Delta}arlJ confirmed their role in suppressing the {Delta}pilA[1-6] motility defect. Additionally, three suppressors harbor co-occurring disruptive missense and nonsense mutations in cirA, a gene encoding a proposed regulatory protein. A deletion of cirA resulted in hypermotility, while cirA overexpression in wild-type cells led to decreased motility. Moreover, qRT-PCR analysis revealed that in wild-type cells, higher expression levels of arlI, arlJ, and the archaellin gene arlA1 were observed in motile early-log phase rod-shaped cells compared to non-motile mid-log phase disk-shaped cells. Conversely, {Delta}cirA cells, which form rods during both early and mid-log phases, exhibited similar expression levels of arl genes in both growth phases. Our findings contribute to a deeper understanding of the mechanisms governing archaeal motility, highlighting the involvement of ArlI, ArlJ, and CirA in pilin- mediated motility regulation. ImportanceArchaea are close relatives of eukaryotes and play crucial ecological roles. Certain behaviors, such as swimming motility, are thought to be important for archaeal environmental adaptation. Archaella, the archaeal motility appendages, are evolutionarily distinct from bacterial flagella, and the regulatory mechanisms driving archaeal motility are largely unknown. Previous research has linked the loss of type IV pili subunits to archaeal motility suppression. This study reveals three Haloferax volcanii proteins involved in pilin-mediated motility regulation, offering a deeper understanding of motility regulation in this understudied domain while also paving the way for uncovering novel mechanisms that govern archaeal motility. Understanding archaeal cellular processes will help elucidate the ecological roles of archaea as well as the evolution of these processes across domains.

microbiology↗

bioRxiv2024

Self-reactive B cells traverse a perfect storm of somatic mutagenesis to cause a virus-induced autoimmune disease

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-CV). We traced the evolution of the pathogenic rheumatoid factor (RhF) autoantibodies in four HCV-CV patients by deep single cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive accumulation of a large disease causing clone. A sensitive method for quantifying low affinity binding revealed three recurring heavy/light chain combinations created by V(D)J recombination bound self IgG but not viral E2 antigen. Whole genome sequencing revealed accumulation of thousands of somatic mutations, at levels comparable to CLL and normal memory B cells, but with 1-2 corresponding to driver mutations found recurrently in B cell leukemia/lymphoma. V(D)J hypermutation created autoantibodies with compromised solubility. In this virus-induced autoimmune disease, infection promotes a perfect storm of somatic mutagenesis in the descendants of a single B cell.

immunology↗

bioRxiv2023

An Excitatory Projection from the Basal Forebrain to the Ventral Tegmental Area Underlying Anorexia-like Phenotypes

Adaptation to potential threat cues in feeding regulation is key for animal survival. Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptation remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA). Glutamatergic neurons in both the BF and the VTA displayed correlated responses to various external stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BFVTA circuit reduces appetite, increases locomotion, and elicits avoidance. In consistence, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of anxiety, all hallmarks of typical anorexia phenotypes. Importantly, activation of BF glutamatergic terminals in the VTA reduced dopamine release in the nucleus accumbens (NAc). Collectively, our results point to overactivation of the glutamatergic BFVTA circuit as a potential cause of anorexia-like phenotypes involving reduced dopamine release.

neuroscience↗

bioRxiv2022

Analysis of an Indian colorectal cancer faecal microbiome collection demonstrates universal colorectal cancer-associated patterns, but closest correlation with other Indian cohorts.

It is increasingly being recognised that changes in the gut microbiome have either a causative or associative relationship with colorectal cancer (CRC). However, most of this research has been carried out in a small number of developed countries with high CRC incidence. It is unknown if lower incidence countries such as India have similar microbial associations. Having previously established protocols to facilitate microbiome research in regions with developing research infrastructure, we have now collected and sequenced microbial samples from a larger cohort study of 46 Indian CRC patients and 43 healthy volunteers. When comparing to previous global collections, these samples resemble other Asian samples, with relatively high levels of Prevotella. Predicting cancer status between cohorts shows good concordance. When compared to a previous collection of Indian CRC patients, there was similar concordance, despite different sequencing technologies between cohorts. These results show that there does seem to be a global CRC microbiome, and that some inference between studies is reasonable. However, we also demonstrate that there is definite regional variation, with more similarities between location-matched comparisons. This emphasises the importance of developing protocols and advancing infrastructure to allow as many countries as possible to contribute to microbiome studies of their own populations. ImportanceColorectal cancer is increasing in many countries, thought to be partly due to the interaction between gut bacteria and changing diets. While it is known that populations in different parts of the world have very different gut microbiomes, the study of their role in colorectal cancer is almost exclusively based in the USA and Europe. We have previously shown that there is overlap between the colorectal cancer microbiome in multiple different countries, establishing robust protocols in the process. Here we expand that into a new Indian cohort. We show that while there are similarities between countries, by concentrating on one country, we can uncover important local patterns. This shows the value of sharing expertise and ensuring that work of this nature is possible wherever this disease occurs.

cancer biology↗