Biology subjects

Wild, S.

Publications and source records attributed to Wild, S..

6 recordsLinked to original sources

bioRxiv2026

Behavioural type drives discovery and exploitation of anthropogenic resources

Human-influenced environments pose challenges but also provide wildlife with anthropogenic resources. Individuals vary widely in their ability to exploit such resources, often as a function of behavioural type. However, we lack a clear understanding of how variation in behavioural traits influences stages of resource exploitation required to use anthropogenic resources. Using fully automated foraging puzzles, we examined how boldness and sociability influenced three aspects of resource exploitation - discovery, problem-solving, and overall performance - in two wild populations of California ground squirrels (Otospermophilus beecheyi). Bolder individuals discovered the resource earlier, solved the task faster and achieved higher performance, indicating that boldness promotes efficient exploitation of anthropogenic resources across multiple stages in the process. Greater sociability and more opportunities to observe conspecifics solving the task led to faster problem-solving, consistent with evidence for observational learning. Squirrels in the recreational-use population - with regular exposure to humans and anthropogenic food - were faster to discover the resource than those in a trail-use population - where human exposure was transient and no anthropogenic food available. Problem-solving latency and performance were consistent between populations. Our findings highlight how individual variation in behavioural traits drives performance in novel ecological contexts, providing a mechanistic understanding of behavioural plasticity in human-influenced environments.

animal behavior and cognition↗

bioRxiv2025

Sample-level modeling of single-cell data at scale with tinydenseR

Single-cell studies now routinely encompass hundreds of samples and millions of cells, offering unprecedented opportunities to link sample-level phenotypes with cellular and molecular states. However, current workflows often depend on cell-level inference and rigid clustering, which can distort significance and obscure subtle, continuous variation, in particular for complex experimental designs. Here, we present tinydenseR, a clustering-independent framework that enables robust, scalable, and statistically sensitive detection of differential cell state density, outperforming existing workflows in speed and memory usage. Technology-agnostic at its core, tinydenseR works seamlessly on scRNA-seq, flow, mass and spectral cytometry. Across synthetic benchmarks, a preclinical xenograft model, a publicly available COVID-19 study, two immuno-oncology trials and a multi-study atlas, tinydenseR uncovers disease and treatment history-associated effects, including subtle cell state heterogeneity, while embedding samples in a quantitative manner. Designed to accelerate discovery in clinical, preclinical, and translational research, the open-source package is available at GitHub.com/Novartis/tinydenseR.

bioinformatics↗

bioRxiv2025

Identification and proteomic profiling of CD90+ small EVs using a refined immunocapture separation approach targeting stromal-derived EV subpopulations in synovial fluid of arthritis patients

Extracellular vesicles (EVs) have emerged as essential drivers in disease progression and promising biomarkers across various disease conditions, including autoimmune diseases such as rheumatoid arthritis (RA). RA is characterized by chronic inflammation driven by patient-specific cellular sub-phenotypes within the synovium. Since EVs reflect their cellular origin and are detectable in biofluids like synovial fluid, they offer a promising alternative for novel biomarker discovery or diagnostics in arthritis, potentially reducing the need for invasive tissue biopsies. However, the inherent complexity, viscosity and extracellular matrix (ECM) composition of synovial fluid pose significant challenges for efficient EV isolation. Moreover, most previous studies have focused on heterogenous bulk EV populations, neglecting the diverse EV subsets present in patient biofluids. To address these challenges, we established a novel immunocapture-based separation method, that selectively targets and isolates cell type-specific EV subpopulation from the heterogenous EV pool present in synovial fluid of arthritis patients. As a proof-of-concept approach, we targeted a stromal-derived EV population by leveraging the fibroblast-associated surface marker CD90/THY1, representing a subset of synovial fibroblasts implicated as important drivers in synovitis and chronic inflammation in RA. Western Blot and data independent acquisition (DIA) liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) proteomic analysis of immunocaptured CD90+ EVs isolated from cultured primary synovial fibroblasts and synovial fluid of arthritis patients, confirmed the successful separation of stromal vs a myeloid/lymphoid EV populations. The in-depth proteomic profiling of synovial fluid EVs offers unprecedented insights into EV heterogeneity in arthritis. This analysis enables the classification of cell-type associated EV subsets and the identification of novel EV markers for future immunocapture-based EV separation strategies. Our refined fit-for-purpose EV separation approach, coupled to in depth proteomic profiling, provides a powerful tool to identify disease-relevant EV subpopulations and novel biomarker candidates in synovial fluid, facilitating advances in arthritis diagnostics and personalized medicine

immunology↗

bioRxiv2024

The PIN1-p38-CtIP signaling axis protects stalled replication forks from deleterious degradation

Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signaling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive. Here, we show that phosphorylation of CtIP by the p38 stress kinase and subsequent PIN1-mediated CtIP cis-to-trans isomerization is required for fork stabilization but dispensable for HR. We found that stalled forks are degraded in cells expressing non-phosphorylatable CtIP or lacking PIN1-p38 activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1-p38 in fork protection. We further reveal that Brca1-deficient mammary tumor cells that have acquired PARPi resistance regain chemosensitivity after PIN1 or p38 inhibition. Collectively, our findings identify the PIN1-p38-CtIP signaling pathway as a critical regulator of replication fork integrity.

molecular biology↗

bioRxiv2024

The transcription factor ZNF469 regulates collagen production in liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the worlds population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

molecular biology↗

bioRxiv2017

Hyperactivation of extracellular signal-regulated kinase (ERK) by RAS-mediated signaling or inhibition of dual specificity phosphatase 6 (DUSP6) is associated with toxicity in lung adenocarcinoma cells with mutations in KRAS or EGFR

We recently described the synthetic lethality that results when mutant KRAS and mutant EGFR are coexpressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for the mutual exclusivity of KRAS and EGFR mutations in lung cancers. We have now further defined the biochemical events responsible for the toxic effects of signaling through the RAS pathway. By combining pharmacological and genetic approaches, we have developed multiple lines of evidence that signaling through extracellular signal-regulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes that drive signaling through the RAS pathway must restrain the activity of ERK1/2 to avoid cell toxicities and enable tumor growth. In particular, a dual specificity phosphatase, DUSP6, regulates phosphorylated (P)-ERK levels in lung adenocarcinoma cells, providing negative feedback to the RAS signaling pathway. Accordingly, inhibition of DUSP6 is cytotoxic in LUAD cells driven by either mutant KRAS or mutant EGFR, phenocopying the effects of co-expression of mutant KRAS and EGFR. Together, these data suggest that targeting DUSP6 or other feedback regulators of the EGFR-KRAS-ERK pathway may offer a strategy for treating certain cancers by exceeding an upper threshold of RAS-mediated signaling.

cancer biology↗