Biology subjects

Connolly, E.

Publications and source records attributed to Connolly, E..

9 recordsLinked to original sources

bioRxiv2026

Type 1 immunity linked to CMV exposure improves long-term survival in sepsis without shock

Dysregulated immune responses are at the core of sepsis pathology and can drive both acute organ dysfunction and long-term morbidity and mortality. To better understand the association between specific immune histories, perturbations and sepsis outcomes, we combined immune phenotyping, functional cytokine production assays and antibody repertoire profiling. While sepsis immune profiles were highly heterogeneous, we identified a strong association between the frequency of CXCR3-expressing CD4 memory T cells at time of enrollment and six-month survival in sepsis without shock. Surprisingly, the same population was linked to improved organ function trajectories in septic shock patients but did not influence six-month survival, highlighting the importance of considering physiological states to define immune predictors. Finally, phage display profiling revealed that these Th1 cells were generally expanded in CMV-seropositive individuals, suggesting that previous and latent infections may modulate sepsis outcomes.

immunology↗

bioRxiv2025

A Novel Therapeutic Approach: Notch Inhibition Enhances Radiotherapy and Checkpoint Blockade Therapy via Reprogramming of the Tumor Microenvironment

BackgroundHigh-dose radiotherapy (RT) in cancer is immunogenic but also induces an immunosuppressive tumor microenvironment (TME) that limits the efficacy of immune checkpoint inhibitors (ICIs). Overcoming this immunosuppressive barrier is therefore critical to unlocking the full potential of RT-ICI combinations. As Notch signaling regulates tumor microenvironment, we hypothesized that the {gamma}-secretase inhibitor (GSI), AL101, would suppress radiation-induced immunosuppression and enhance antitumor efficacy when combined with RT and anti-PD-1 (aPD-1) therapy. MethodsSyngeneic neuroblastoma (9464D) and triple-negative breast cancer (EO771) tumors were established in C57BL/6, macrophage-depleted C57BL/6 mice, or athymic mice. Mice received 12 Gy RT (day 3), AL101 (6.5 mg/kg daily, day 0-9), and aPD-1 (days 0, 3, 6). Tumors were analyzed by spectral flow cytometry and single-cell RNA sequencing (scRNA-seq), and lung metastases were evaluated histologically. ResultsThe triple combination of RT, aPD-1, and GSI produced durable tumor growth inhibition and significantly prolonged survival in both models, with median survival more than doubled compared to all other treatment groups. Triple therapy also markedly reduced lung metastases in EO771 mice. These effects were abrogated in athymic nude mice and macrophage-depleted immunocompetent mice, consistent with an immune-dependent mechanism. Based on scRNA-seq and spectral flow cytometry analysis, RT alone increased exhausted T cells and immunosuppressive macrophages, while triple therapy reversed these effects, including expansion of activated CD8 T cells, reduction of Tregs and exhausted T cells, restoration of cross-presenting CD103 dendritic cells, and reprogramming of myeloid cells toward a proinflammatory state. ConclusionsGSI remodels the RT-induced immunosuppressive TME and potentiates the efficacy of RT + ICI. GSI combined with RT+aPD-1 reprograms the TME toward an immunostimulatory state and supports GSI as a promising immuno-radiotherapeutic strategy with strong translational potential.

cancer biology↗

bioRxiv2025

Conserved phenotype and function of human brain border-associated macrophages in iPSC-derived models

Border-associated macrophages (BAMs) are increasingly implicated in protective brain functions including the removal of pathogenic material such as amyloid-beta (A{beta}). However, there is a lack of available and deeply characterized human BAM models. Here, we report that postnatal transplantation of induced pluripotent stem (iPS) cell-derived hematopoietic progenitors to the murine brain sufficiently chimerizes the brain border immune compartment to allow functional interrogations. Human xenotransplanted BAMs (xBAMs) line the leptomeninges and brain vasculature beyond the glia limitans. Via single-cell RNA sequencing, we show that a conserved transcriptional signature distinguishes BAMs from microglia across species origin, age, and genetic background. Both xBAMs and murine BAMs are defined by a hyper-endocytic phenotype and function, surpass other brain macrophages in acute A{beta} scavenging, and exhibit compartment-restricted sampling of parenchymal material. Using a modified differentiation protocol, we find that we can generate iPS-derived BAM-like cells (iBAMs) in vitro, which are also characterized by a hyper-endocytic phenotype and enhanced engulfment capacity relative to iPS-derived microglia-like cells (iMGLs). Together, these data define a conserved hyper-endocytic BAM phenotype and provide a toolbox for studying human BAMs both in vivo and in vitro.

neuroscience↗

bioRxiv2025

Sustainable cattle management by communities supports African wildlife

Community-based conservation (CBC) initiatives aim to reconcile biodiversity protection with local livelihoods, yet their effectiveness in protecting wildlife remains uncertain, often hinging on local management1,2. We evaluated a globally significant CBC model in Kenyas Greater Maasai Mara Ecosystem (GME), where conservancies, run jointly by Maasai landowners and the tourism sector, employ rotational cattle grazing to support both wildlife and pastoralism3,4. Using a [~]1200 km2 grid of 180 camera traps across gradients of livestock pressure in Maasai Mara National Reserve and three conservancies in 2018, we collected and analysed over 2 million images with a customised AI-powered pipeline. We found a positive impact of observed cattle pressure on mammal community occupancy and species richness, except for at the highest levels of cattle grazing. However, sheep and goat grazing and proximity to infrastructure had a negative impact. These results provide evidence that wildlife and pastoralism can coexist under community-led stewardship5, but only with active management and targeted control of emerging threats. AI tools such as our image classifier may contribute to more adaptive community-led management of these areas6. As conservation policy shifts beyond formal protected areas, our findings support CBC as a scalable model for conserving biodiversity within working landscapes, offering a pathway to meet global targets while maintaining local livelihoods7.

ecology↗

bioRxiv2025

Stability and Processing Impacts on Faecal Microbiota Transplant Products: An Integrated Metagenomic-Culturomic Analysis

BackgroundFaecal microbiota transplantation (FMT) is an increasingly used microbiome-based therapy, whose clinical success depends on the stability and viability of the donor microbiota. Few studies have systematically evaluated these parameters for FMT preparations. Here, we integrate metagenomic sequencing with culturing-based recovery of viable microbes to comprehensively characterise FMT preparations from healthy Australian donors. ResultsMetagenomic profiling of bacterial communities from repeat FMT faecal donations revealed high temporal stability within individual donors, supporting donor suitability for consistent and standardised FMT production. The community structure and diversity of final FMT products remained largely consistent with their source material, reflecting limited disruption during processing. Culturing and sweep metagenomics showed bacterial species representing 98% of faecal microbiota abundance was recoverable, underscoring the potential of FMTs to deliver a viable and functionally active bacterial community to a recipient. When FMT donor microbiomes were compared to >7,000 healthy gut microbiomes from 27 countries, donor samples were distinct but clustered most closely with other Westernised populations, while also exhibiting significantly higher diversity than most global cohorts. These results highlight the geographic specificity of gut microbiomes and the need to consider population context in donor selection. ConclusionsThis study strengthens the evidence base for FMT product standardisation and viability, with implications for FMT clinical use, donor screening protocols, and associated regulatory frameworks.

microbiology↗

bioRxiv2023

Acceleration of Large-Scale Single Cell Differential Gene Expression Analysis with FastDE

The major bottleneck in single cell transcriptomic processing is identification of marker genes for individual cell clusters. We introduce FastDE, an implementation of the standard Wilcoxon Rank Sum test in C++ that results in 50X speed-up of the standard Seurat pipeline on a dataset of 1.2 million cells. Proof of methodology is demonstrated by replicating age and gender effects on immune cell differentiation in two large PBMC atlases.

bioinformatics↗

bioRxiv2019

Regenerative neurogenesis is induced from glia by Ia-2 driven neuron glia communication

Some animals can regenerate their central nervous system (CNS) after injury by inducing de novo neurogenesis: discovering the underlying mechanisms would help promote regeneration in the damaged human CNS. Glial cells could be the source of regenerative neurogenesis, but this is debated. The glia transmembrane protein Neuron-Glia antigen-2 (NG2) may have a key role in sensing injury-induced neuronal signals, however these have not been identified. Here, we used Drosophila genetics to search for functional neuronal partners of the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Alterations in Ia-2 function induced neural stem cell fate, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic epistasis analysis and lineage tracing, we demonstrate that Ia-2 functions with Kon to regulate Drosophila insulin-like peptide 6 (Dilp-6) which in turn generates both more glial cells and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia, and reprograms glia into neural stem cells for CNS regeneration.

neuroscience↗

bioRxiv2017

On the genetic and environmental reasons why intelligence correlates with criminal victimization

Researchers have expended considerable effort to understand the causes and correlates of criminal victimization. More recently, scholars have focused on identifying individual-level traits that increase the odds of victimization. Generally absent from this line of research, however, is examining the extent to which previously unmeasured genetic and environmental influences contribute to the covariation between victimization and individual-level risk factors. The current study aims to replicate and extend prior research by examining the contribution of genetic and environmental influences on the association between intelligence and victimization by analyzing twin and sibling data from two nationally representative samples of American youth. Quantitative genetic analyses indicate that common additive genetic factors, as well as non-shared environmental factors, explained the phenotypic association between intelligence and victimization. Finally, our results revealed that after correcting for possible familial confounding, the effect of intelligence on victimization experiences remained statistically significant. The findings of the current study replicate and extend prior research on the phenotypic association between indicators of general intelligence and the experience of victimization.

epidemiology↗

bioRxiv2017

On the heritability of criminal justice processing

An impressive number of researchers have devoted a great amount of effort toward examining various predictors of criminal justice processing outcomes. Indeed, a vast amount of research has examined various individual- and aggregate-level predictors of arrests, incarceration, and sentencing decisions. To this point, less attention has been devoted toward uncovering the relative contribution of genetic and environmental effects on variation in risk for criminal justice processing. As a result, the current study employs a behavioral genetic design in order to help fill this void in the existing literature. Using twin data from a national sample of youth, the current study produced evidence suggesting that genetic factors accounted for at least a portion of variance in risk for incarceration among female twins and probation among male twins. Shared and nonshared environmental influences accounted for the variance in risk for arrest among both female and male twins, probation among female twins, and incarceration among male twins. Ultimately, it appears that risk for contact with the criminal justice system and criminal justice processing is structured by a combination of factors beyond shared cultural and neighborhood environments, and appear to also include genetic factors as well. Moving forward, continuing to not use genetically sensitive research designs capable of estimating the role of genetic and nonshared environmental influences on criminal justice outcomes may result in misleading results.

epidemiology↗