Biology subjects

Butler, S.

Publications and source records attributed to Butler, S..

11 recordsLinked to original sources

bioRxiv2026

MHC-I downregulation is associated with immune-evasion in breast cancers with heterogeneous activation of epithelial-mesenchymal plasticity

Cancer cell-intrinsic epithelial-mesenchymal plasticity (EMP) drives carcinoma progression through increased intratumoral heterogeneity and an immunosuppressive tumor microenvironment (TME). Specifically, EMP activation in murine mammary carcinomas results in exclusion of CD8+ T-cells and recruitment of immunosuppressive M2-like macrophages, resulting in resistance to anti-CTLA-4 immune checkpoint blockade (ICB) therapy. Notably, mixed E-qM tumors in which only 10% of cancer cells have activated EMP are resistant anti-CTLA-4 immune checkpoint blockade (ICB) therapy. This suggests that minority fractions of qM cancer cells could, in theory, exert immunosuppressive effects on surrounding E cancer and immune cells to shield the entire heterogeneous tumor against immune attack. However, this has not yet been demonstrated. Here, we use spatial transcriptomic profiling to demonstrate that mixed E-qM tumors assemble immunosuppressive cellular niches. Furthermore, E cancer cells within mixed E-qM tumors experience long-term MHC-I downregulation leading to resistance to elimination by CD8+ T-cells. This is associated with the exclusion of T-cells from the tumor core and a dysfunctional phenotype in the remaining CD8+ T-cells. qM cancer cells recruit immunosuppressive M2-like macrophages to mixed tumors, which further downregulates E cancer cell-intrinsic MHC-I levels. Finally, we demonstrate that human triple-negative breast cancers with increased EMP activation exclude T-cells from the tumor core. Together, these findings reveal that qM cancer cells modulate the immune infiltrate of mixed tumors, promoting MHC-I downregulation and evasion of immunological control by CD8+ T-cells.

cancer biology↗

bioRxiv2026

Coxiella burnetii type IVB secretion system modulates TLR3/TRIF-dependent NF-κB and IRF responses during infection

Coxiella burnetii ( Cb ), the causative agent of Q fever, replicates within host macrophages by modulating innate immune responses through its type IVB secretion system (T4SS). Host cells sense pathogens via Pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), to recognize pathogen-associated molecular patterns (PAMPs) and initiate signaling pathways that drive pro-inflammatory cytokine and interferon responses. Toll-like receptor 3 (TLR3) triggers the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) and Interferon regulatory factors (IRFs) resulting in pro-inflammatory cytokine production and type I interferon (IFN-I) induction. Here we demonstrate that Cb requires T4SS to suppress TLR3-induced NF-{kappa}B and IRF transcriptional responses. Furthermore, RNA purified from both virulent and avirulent Cb is sufficient to activate TLR3, identifying pathogen RNA as a relevant PAMP in this context. Using a pulmonary infection model with virulent Cb, we found that TLR3/ Toll-Interleukin-1 Receptor Domain-Containing Adapter Protein Inducing Interferon Beta (TRIF)-dependent innate immune pathway inhibits cachexia. In contrast, signaling through the interferon-/{beta} receptor (IFNAR) restricts bacterial dissemination, indicating that these pathways play distinct but complementary roles in host defense. Mechanistically, Cb suppresses TLR3/TRIF signaling in a T4SS-dependent manner by preventing host TLR3 recruitment to the Coxiella-containing vacuole (CCV) and disrupting TRIF-TNF Receptor-Associated Factor 6 (TRAF6) interactions, thereby selectively inhibiting impairing NF-{kappa}B activation. Consistent with this, we identify five T4SS effector proteins that attenuate TLR3-induced NF-{kappa}B signaling, including CBU1292, which suppresses both NF-{kappa}B and IRF-dependent responses downstream of TLR3.

microbiology↗

bioRxiv2025

Divergent selection on dispersal targets chemosensory and neuronal genes in Tribolium castaneum

Dispersal is key to the life history, ecology and evolution of many organisms, and important in pest invasiveness. However, the genetic architecture underlying variation in dispersal behaviour remains poorly understood outside of a few model species. We investigated the genomic basis of dispersal using artificial selection on replicated lines of Tribolium castaneum, a flour beetle, an emergent model system, and an economically important agricultural pest. Combining whole-genome resequencing with population-level genotype-phenotype association analysis, we identify genomic regions associated with selection on dispersal. Identified candidate genes were significantly enriched for functions related to neuronal structure and function, as well as chemosensory behaviour and mating, suggesting that variation in dispersal is mediated by neural and chemosensory pathways. Our results demonstrate that dispersal propensity has a polygenic basis and support an interaction between dispersal and mating ecology in this system. These findings contribute to a deeper understanding of the genetic mechanisms driving dispersal evolution of dispersal and its role in shaping eco-evolutionary dynamics.

evolutionary biology↗

bioRxiv2025

Comparing analytical protocols for identifying causes of population changes

Conservation decision-making requires accurate identification of causes of population changes. Ecologists often rely on analytical protocols that aggregate high-dimensional monitoring data. We hypothesise that compressing data - either spatially, as in conventional time series (TS) analysis, or temporally, as in static species distribution models (SDMs) - destroys covariance structures and obscures the identification of causal drivers. To quantify this aggregation cost, we conducted a rigorous simulation experiment using virtual species to establish a known ground truth of population drivers. We then employed a virtual ecologist approach to mimic a 20-year large-scale bird monitoring scheme, and generate realistic spatiotemporal datasets to evaluate the analytical pipelines. We benchmarked the causal attribution accuracy of aggregated TS and SDM protocols against a full-resolution spatiotemporal (FRST) framework, which retains native data dimensions and integrates mechanistic spatiotemporal covariance structures. Our simulations revealed that spatial compression severely compromises causal inference: unpenalised TS models failed to detect any true underlying drivers (accuracy = 0.50, sensitivity = 0.00). Temporal compression (SDMs) performed moderately better (accuracy = 0.68), while the FRST model achieved superior accuracy (0.88), sensitivity (0.84), and specificity (0.93). Furthermore, we identified a variable selection paradox: double penalty shrinkage marginally improved underpowered TS models, although it degraded the specificity of SDM and FRST frameworks by forcing spurious, correlated variables to absorb residual variance. Our findings demonstrate that protocols that involve data aggregation reduce the informational value of large-scale monitoring datasets. Full-resolution, mechanistically informed frameworks are essential for reliable causal attribution and robust biodiversity monitoring. HighlightsO_LISpatiotemporal data aggregation obscures causal drivers in biodiversity monitoring. C_LIO_LISpatial compression in time series models fails to detect true population drivers. C_LIO_LIFull-resolution spatiotemporal models accurately identify true drivers. C_LIO_LIAutomated variable selection introduces false positives in high-resolution models. C_LI

ecology↗

bioRxiv2024

Wound state monitoring by multiplexed, electrochemical, real-time, localized, inflammation-tracking nitric oxide sensor (MERLIN)

Nitric oxide (NO) released endogenously by induced nitric oxide synthase (iNOS) in macrophages is a key regulatory biomarker for wound inflammation. Detecting NO directly on the wound bed is challenging due to its short half-life time (6 - 50 s), low physiological concentration (nM - {micro}M) and interferences in the complex wound environment. Existing NO sensors suffer from limitations such as rigid substrates, single point of detection and complex measurement setup. Here we present a compliant, multiplexed, electrochemical, real-time, localized, inflammation-tracking nitric oxide sensor (MERLIN) array for in vivo spatiotemporal measurement of NO, with high sensitivity (15.6 {+/-} 5.0 nA/M for 1.5 mm diameter electrodes), selectivity against nitrites (ca. 27900-fold), ascorbic acid (ca. 3800-fold), and uric acid (ca. 6900-fold), and low limit of detection (8.00 nM). We developed a robust device fabrication protocol, comprehensive and highly reproducible in vitro characterization yielding a consistent device performance deployed for wound healing diagnostics. MERLIN spatiotemporally tracked NO on rat skin wounds for 7 days and results indicated that NO peaks on day 3, in line with previously reported iNOS activity. MERLIN allows spatial mapping of the NO gradient across the wound bed, which can be used to provide diagnostic information to assist wound care.

bioengineering↗

bioRxiv2023

Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in C. elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

physiology↗

bioRxiv2022

An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection

Zika virus (ZIKV), an arbovirus transmitted by mosquitoes, was identified as a cause of congenital disease during a major outbreak in the Americas in 2016. Vaccine design strategies relied on limited available isolate sequence information due to the rapid response necessary. The first-generation ZIKV mRNA vaccine, mRNA-1325, was initially generated and, as additional strain sequences became available, a second mRNA vaccine, mRNA-1893, was developed. Herein, we compared the immune responses following mRNA-1325 and mRNA-1893 vaccination and reported that mRNA-1893 generated comparable neutralizing antibody titers to mRNA-1325 at 1/20th of the dose and provided complete protection from ZIKV challenge in non-human primates. In depth characterization of these vaccines indicated that the observed immunologic differences could be attributed to a single amino acid residue difference that compromised mRNA-1325 virus-like particle formation.

immunology↗

bioRxiv2019

Enhancers predominantly regulate gene expression in vivo via transcription initiation.

Gene transcription occurs via a cycle of linked events including initiation, promoter proximal pausing and elongation of RNA polymerase II (Pol II). A key question is how do transcriptional enhancers influence these events to control gene expression? Here we have used a new approach to quantify transcriptional initiation and pausing in vivo, while simultaneously identifying transcription start sites (TSSs) and pause-sites (TPSs) from single RNA molecules. When analyzed in parallel with nascent RNA-seq, these data show that differential gene expression is achieved predominantly via changes in transcription initiation rather than Pol II pausing. Using genetically engineered mouse models deleted for specific enhancers we show that these elements control gene expression via Pol II recruitment and/or initiation rather than via promoter proximal pause release. Together, our data show that enhancers, in general, control gene expression predominantly by Pol II recruitment and initiation rather than via pausing.

genomics↗

bioRxiv2019

Apcdd1 is a dual BMP/Wnt inhibitor in the developing nervous system and skin

Animal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling, here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish, and humans. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways central to animal development and human disease. Significance StatementApcdd1 is a taxon-restricted gene that inhibits both BMP and Wnt intercellular signaling pathways in multiple organisms including mice, frog, zebrafish, and chicken. It encodes a bi-functional protein with a novel protein domain that can bind to Wnt and BMP receptors and block downstream signaling.

systems biology↗

bioRxiv2019

Cooperation and Stability for Complex Systems in Resource Limited Environments

Resource-limited complex systems are ubiquitous in the natural world, as is the potential for instability in such systems. Classic models of interacting species have provided a basis for our understanding of stability in these systems, and suggest that stable coexistence requires weak, rare, and asymmetric interactions. But missing from these models is an explicit understanding of how resource exchange and resource limitation can drive or prevent instability. Here we show that systems based on general rules for the consumption and exchange of resources are guaranteed to be stable when exchange of resources is reciprocated by each pair of partners. These cooperative, mutualistic interactions can be arbitrarily strong and yet not disrupt stability. More general modes of exchange will lead to instability when supply rates are low, but when resource supply from outside the system is sufficiently high, arbitrary exchange is consistent with a stable equilibrium.

ecology↗

bioRxiv2018

Stability Criteria for Complex Microbial Communities

Competition and mutualism are inevitable processes in microbial ecology, and a central question is which and how many taxa will persist in the face of these interactions. Ecological theory has demonstrated that when direct, pairwise interactions among a group of species are too numerous, or too strong, then the coexistence of these species will be unstable to any slight perturbation. This instability worsens when mutualistic interactions complement competition. Here, we refine and to some extent overturn that understanding, by considering explicitly the resources that microbes consume and produce. In contrast to more complex organisms, microbial cells consume primarily abiotic resources, and mutualistic interactions are often mediated by these same abiotic resources through the mechanism of cross-feeding. Our model therefore considers the consumption and production of a set of abiotic resources by a group of microbial species. We show that if microbes consume, but do not produce resources, then any positive equilibrium will always be stable to small perturbations. We go on to show that in the presence of crossfeeding, stability is no longer guaranteed. However, stability still holds when mutualistic interations are either symmetric, or sufficiently weak.

ecology↗