Biology subjects

Bishop, J.

Publications and source records attributed to Bishop, J..

8 recordsLinked to original sources

bioRxiv2026

Temporal stasis in three facets of biodiversity reveals mechanisms of community assembly across elevation gradients

Understanding spatial and temporal variation in community composition is central to protecting and monitoring biodiversity. Similarity in the composition of two communities decreases along spatial and temporal gradients, a relationship known as distance decay. Comparing distance-decay relationships across taxonomic, functional, and bioclimatic facets of diversity provides a means of interrogating niche-based versus neutral influences on community assembly. Furthermore, the context in which these facets yield overlapping or complementary information about global change impacts remains poorly understood. In this study, we examined spatiotemporal distance-decay relationships for taxonomic, functional, and bioclimatic facets of alpine plant diversity leveraging elevation gradients on five peaks in the White Mountains, California, USA, sampled at 3-4 time points between 2007 and 2024. Using multivariate Bayesian beta regression models, we estimated the slopes of elevation distance decay over multiple surveys and across taxonomic, functional and bioclimatic diversity to understand how spatial distance-decay relationships are changing through time and across different facets of diversity. We found strong spatial distance decay of taxonomic similarity across all peaks, with the highest elevation peak showing the strongest decay. Functional and bioclimatic similarities decayed more weakly than taxonomic similarity, suggesting environmental filtering shapes trait and niche distributions. Critically, spatial decay patterns showed no temporal signal across facets of diversity, indicating community stasis rather than biotic homogenization or differentiation. This study adds further evidence that xeric alpine plant communities are resisting climate change impacts through time.

ecology↗

bioRxiv2026

Subclonal IDH1/2 Mutations as a Targetable Vulnerability in Vascular Tumors

Despite extensive sequencing, the genetic etiology of sporadic angiosarcoma remains poorly defined (1-3). Maffucci syndrome, characterized by vascular tumors and elevated cancer risk, is driven by mosaic gain-of-function mutations in IDH1/2 (4,5), though these have not been reported in sporadic angiosarcoma. We identify recurrent, low-variant allele frequency hotspot mutations in IDH1/2 in over half of sporadic angiosarcomas. Mutations were validated by Sanger sequencing and immunohistochemistry. Mutant IDH1 endothelial cells promote tumorigenesis through non-cell-autonomous mechanisms, secreting 2-hydroxyglutarate (2-HG) to increase growth factor and endothelial-to-mesenchymal transition gene expression, activate pAkt/pERK signaling, induce DNA methylation changes, and promote anchorage-independent growth, which are reversed by the mutant IDH1 inhibitor ivosidenib. Patients with mosaic IDH1 mutations show reduced serum 2-HG and marked tumor regression following ivosidenib treatment. The clinical efficacy of ivosidenib in vascular tumors with subclonal IDH1 mutations suggests that low VAF IDH1/2 mutations may be a targetable vulnerability in sporadic angiosarcoma. (6,7) Statement of SignificanceWe identify recurrent, low-VAF IDH1/2 mutations in angiosarcoma and provide evidence that these subclonal mutations promote tumorigenesis through non-cell-autonomous mechanisms. Vascular tumors driven by subclonal IDH1 mutations responded dramatically to ivosidenib, thus revealing a novel treatment for a subset of vascular tumors.

cancer biology↗

bioRxiv2025

YfgH is a transmembrane glycine-zipper containing lipoprotein that stabilizes excess cardiolipin and outer membrane proteins during envelope stress

The outer membrane (OM) of Escherichia coli is an essential, asymmetric bilayer composed of lipopolysaccharide and phospholipids that protects cells from environmental stress. While several systems maintain OM integrity during stress, the roles of many outer membrane lipoproteins are less well characterized. Here, we identify YfgH, a glycine-zipper domain containing lipoprotein, as a novel OM-stabilizing factor that functions distinctly from the previously studied SlyB. Deletion of yfgH increases sensitivity to detergents and metal chelators, enhances OM permeability, and leads to global loss of OM proteins under stress. YfgH is essential for survival during CRISPR interference-mediated depletion of OM biogenesis genes, and its overexpression rescues these phenotypes. AlphaFold modeling predicts YfgH forms oligomeric ring-like structures similar to SlyB, but genetic suppressor screens indicate distinct mechanisms: clsA (cardiolipin synthase) mutations suppress yfgH deletion, while slyB suppressors map to the Mla lipid transport pathway. Biochemical analyses reveal YfgH interacts with multiple OM proteins, especially under stress. Together these findings suggest YfgH functions by stabilizing cardiolipin-rich nanodomains, representing a novel response to OM stress. This work expands our understanding of glycine-zipper lipoproteins as stress-specific membrane stabilizers and highlights the critical role of YfgH in preserving OM integrity during envelope perturbation. ImportanceThe bacterial outer membrane is essential for survival in harsh environments, yet how Gram-negative cells maintain its stability under stress remains less understood. We identify YfgH, a previously uncharacterized outer membrane lipoprotein, as a key factor that preserves membrane integrity during envelope stress. Our findings show that YfgH stabilizes cardiolipin-rich nanodomains and protects outer membrane proteins when biogenesis pathways are compromised. This work reveals a new mechanism of outer membrane maintenance and expands the functional repertoire of glycine zipper- containing lipoproteins, highlighting a broader family of stress-specific membrane stabilizers that may be conserved across Gram-negative bacteria.

molecular biology↗

bioRxiv2025

Mass photometry reveals stoichiometry and binding dynamics of bispecific tetravalent anti-VEGF-PD-1 antibody ivonescimab

BackgroundThe bispecific antibody ivonescimab targets programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF). Recent clinical trials have shown it has greater efficacy against PD-L1 positive non-small cell lung cancer than pembrolizumab (Keytruda), a frequently prescribed anti-PD-1 monoclonal antibody. Ivonescimab binds to two VEGF and two PD-1 molecules, with complex formation through higher-order structure formation (or daisy chain binding). However, the binding stoichiometries and interaction dynamics of ivonescimab with VEGF and PD-1 have not been characterized in depth. MethodsWe used mass photometry (MP) and kinetic modelling to analyze these interactions, quantifying the complexes formed and their affinities. Dissociation constants (KD) for ivonescimabs binding to VEGF and PD-1 were calculated from equilibrium counts and real-time measurements, respectively. ResultsVEGF drove oligomerization of ivonescimab, which bound VEGF predominantly in a 2:2 stoichiometry, with KD=0.08 nM. Higher-order oligomeric complexes, present only at low abundance, displayed markedly weaker affinities (3.17 nM; 1.29 nM). Ternary complexes of ivonescimab with its two targets consistently presented two PD-1 antigens for each ivonescimab molecule, with a 1.66 nM KD for the binding of the first PD-1 and the slightly stronger 0.89 nM for the second PD-1 molecule. ConclusionsMP confirmed VEGF-induced ivonescimab oligomerization and revealed that dimers, not higher-order structures, were the most stable stoichiometry. MP enables detailed analysis of antibody-antigen interactions, even for bispecific antibodies that interact with antigens with complex stoichiometries. Statement of significanceWe report the first application of mass photometry to characterize the binding of the clinically promising bispecific antibody ivonescimab to its targets, VEGF and PD-1. The most stable assembly is a dimeric complex, not higher-order, as expected - advancing understanding of ivonescimab and demonstrating mass photometrys value for complex biologics analysis.

biophysics↗

bioRxiv2020

Identification and Mechanistic Characterization of a Novel Peptide Inhibitor of Glycogen Synthase Kinase (GSK3) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein

Glycogen Synthase Kinase 3-beta (GSK3{beta}) is a critical regulator of several cellular pathways involved in neuroplasticity and is a potential target for neurotherapeutic development in the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3{beta} have been focused on developing small molecule inhibitors that compete with ATP through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The Disrupted in Schizophrenia (DISC1) protein, has previously been shown to bind and inhibit GSK3{beta} activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3{beta} in a non-competitive mode that is distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3{beta}: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3{beta} binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3{beta}.

neuroscience↗

bioRxiv2019

Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. We demonstrate that the Hh signaling pathway is activated in lung stroma in a paracrine manner. Genetic deletion of Shh in autochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, not SHH, activates the pathway in stroma to drive its tumor suppressive effects - a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased reactive oxygen species (ROS). Treatment of KP mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor ROS levels, inhibited tumor growth and prolonged mouse survival suggesting that increased ROS levels from stromal Hh pathway inhibition spurred lung tumor growth. Thus, IHH induces stromal Hh pathway activation to suppress tumor growth and metastases, in part, by limiting ROS production.

cancer biology↗

bioRxiv2019

Community turnover by composition and climate affinity across scales in an alpine system

Premise of the studyExamining community turnover across climate gradients at multiple scales is vital to understanding biogeographic response to climate change. This approach is especially important for alpine plants in which the relative roles of topographic complexity and non-climatic or stochastic factors vary across spatial scales.\n\nMethodsWe examined the structure of alpine plant communities across elevation gradients in the White Mountains, California. Using community climatic niche means (CCNMs) and measures of community dissimilarity, we explored the relationship between community composition and elevation gradients at three scales: the mountain range, individual peaks, and within elevation contours.\n\nKey ResultsAt the mountain range scale, community turnover and CCNMs showed strongly significant relationships with elevation, with an increase in the abundance of cooler and wetter-adapted species at higher elevations. At the scale of a single peaks, we found weak and inconsistent relationships between CCNMs and elevation, but variation in community composition explained by elevation increased. Within the elevation contours, the range of CCNMs was weakly positively correlated with turnover in species identity, likely driven by microclimate and other site-specific factors.\n\nConclusionsOur results suggest that there is strong environmental sorting of alpine plant communities at broad scales, but microclimatic and site-specific, non-climatic factors together shape community turnover at finer scales. In the context of climate change, our results imply that community-climate relationships are scale-dependent, and predictions of local alpine plant range shifts are limited by a lack of topoclimatic and habitat information.

ecology↗

bioRxiv2019

The Endocrine and Metabolic Response in Male Survivors of Major Trauma

ContextSurvival rates after severe injury are improving, but complication rates and outcomes are variable. ObjectiveThis cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DesignWe undertook a prospective, observational cohort study from time of injury to six months post-injury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) >15). Main outcome measuresWe measured adrenal and gonadal steroids in serum and 24-h urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction and sepsis); results were analysed by generalized mixed-effect linear models. FindingsWe screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analysed all male survivors <50 years not treated with steroids (N=60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after one and six weeks, respectively. Serum testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased immediately after trauma and took two, four and more than six months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. ConclusionThe catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation. PrecisA cohort study in male survivors of major trauma revealed acute and sustained androgen suppression and protein catabolism including muscle loss. Serum androgens correlated with probability of sepsis.

physiology↗