Biology subjects

Williams, D. M.

Publications and source records attributed to Williams, D. M..

8 recordsLinked to original sources

bioRxiv2026

Eutherian NLRP3 is distinguished by conserved regulatory features absent in non-eutherian NLRP3-like proteins

NLRP3 is a cytosolic pattern recognition receptor that controls the formation of an inflammasome, a multimolecular complex that cleaves the pro-inflammatory cytokines interleukin-1{beta} and interleukin-18 into their bioactive forms. NLRP3 has been widely assumed to be conserved across vertebrates, suggesting it plays an indispensable role within the vertebrate innate immune system. Here, gene synteny, phylogeny, and structural analysis were used to examine the evolutionary origins of NLRP3 in greater detail. This analysis revealed that modern NLRP3, defined by gene synteny and structural features, is unique to the eutherian lineage. Non-eutherian NLRP genes share limited synteny with the eutherian NLRP3 locus and lack conservation of key features including disc forming residues, cage interfaces, and membrane binding regions. NLRP3s characteristic regulatory architecture therefore appears to have evolved after eutherians split from marsupials 160 million years ago. Whilst further experimental studies are required to validate the conclusions drawn, these findings have potentially important implications for understanding the beneficial roles of NLRP3 signalling and suggest that eutherian specific regulatory control of NLRP3 activity may have arisen in response to distinct aspects of eutherian physiology.

immunology↗

bioRxiv2023

S-acylation of NLRP3 provides a nigericin sensitive gating mechanism that controls access to the Golgi

NLRP3 is an inflammasome seeding pattern recognition receptor activated in response to multiple danger signals which perturb intracellular homeostasis. Electrostatic interactions between the NLRP3 polybasic (PB) region and negatively charged lipids on the trans-Golgi network (TGN) have been proposed to recruit NLRP3 to the TGN. In this study, we demonstrate that membrane association of NLRP3 is critically dependant on S-acylation of a highly conserved cysteine residue (Cys-130), which traps NLRP3 in a dynamic S-acylation cycle at the Golgi, and a series of hydrophobic residues preceding Cys-130 which act in conjunction with the PB region to facilitate Cys-130 dependent Golgi enrichment. Due to segregation from Golgi localised thioesterase enzymes caused by a nigericin induced breakdown in Golgi organisation and function, NLRP3 becomes immobilised on the Golgi through reduced de-acylation of its Cys-130 lipid anchor, suggesting that disruptions in Golgi homeostasis are conveyed to NLRP3 through its acylation state. Thus, our work defines a nigericin sensitive S-acylation cycle that gates access of NLRP3 to the Golgi.

cell biology↗

bioRxiv2021

The indoleamine 2,3 dioxygenase pathway drives intratumoral B cell maintenance.

B cells have been implicated as central regulators of immune responses in settings as diverse as mammalian pregnancy, mucosal tolerance, chronic infection states, autoimmunity, and the tumor microenvironment. Despite the established importance of B cells in these environments, the mechanisms by which B cells are maintained in these contexts remain undefined. Here, we report that IDO1 pathway inhibition with D-1-methyl-tryptophan (D-1MT) and linrodostat significantly decreases tumor infiltrating B (TIL-B) cells in a preclinical model of melanoma. Single cell RNA sequencing (scRNAseq) of murine melanoma demonstrate TIL-B cells are heterogeneous but primarily express markers consistent with an immune stimulatory phenotype. D-1MT decreases splenic B cells and bone marrow derived B cell precursors in tumor-bearing mice, suggesting that IDO1 pathway inhibition impedes B cell maturation. D-1MT decreases intratumoral myeloid derived suppressor cells (MDSCs), which are essential for maintenance of TIL-B cells. Unlike D-1MT, genetic deletion of tumor Ido1 does not impact TIL-B or MDSC numbers. In human solid tumors, intratumoral IDO1 expression consistently associates with high expression of a pan-B cell gene signature, and in patients with melanoma, scRNAseq analysis of tumor samples revealed most TIL-B cells express IDO1. Collectively, our data reveal the impact of pharmacologic IDO1 inhibition on B cells, which may have therapeutic implications for patients with solid tumors by informing the design of future oncology clinical trials.

immunology↗

bioRxiv2021

The effects of maternal social connectivity and integration on offspring survival in a marmot

In social species, maternal social relationships, in addition to direct care, impact offspring survival but much of what we know about these effects comes from studies of obligately social and cooperatively breeding species. Yellow-bellied marmots (Marmota flaviventer) are a facultatively social species whose social groups vary in composition, size, and cohesiveness. This natural variation in sociality and cooperative breeding behavior makes yellow-bellied marmots an ideal species within which to study the effects of maternal affiliative and agonistic social behavior on offspring. We used social network analysis to investigate the relationship between maternal social connectivity and integration on offspring summer and yearly survival, with the hypothesis that offspring with more affiliative mothers are more likely to survive than the offspring of more agonistic mothers. However, we found the inverse to be true: pups born to mothers who received more affiliative interactions were less likely to survive while the offspring of mothers who were more highly integrated into agonistic networks had enhanced survival. Overall, maternal social network measures were positively and negatively correlated with offspring survival, indicating that pups are influenced by their mothers social world, often in contradictory ways. Relative predation risk and colony location also mediated the effects of social relationships on pup survival. This study contributes to a small but growing body of work that demonstrates that specific attributes of sociality have specific consequences and that by adopting an attribute-focused view of sociality we are better able to understand how environmental conditions mediate the costs and benefits of sociality. Lay SummaryMaternal social relationships can impact offspring survival but much of what we know about these effects comes from studies of obligately social species. In faculatively social yellow-bellied marmots we found that pups born to mothers who received more affiliative interactions were less likely to survive while the offspring of mothers who were more highly integrated into agonistic networks had enhanced survival. Overall, pups are influenced by their mothers social world, often in contradictory ways.

animal behavior and cognition↗

bioRxiv2020

On Classification and Taxonomy of Coronaviruses (Riboviria, Nidovirales, Coronaviridae) with the special focus on severe acute respiratory syndrome-related coronavirus 2 (SARS-Cov-2)

Coronaviruses are highly pathogenic and therefore important human and veterinary pathogens viruses worldwide (1). Members of family Coronaviridae have previously been analysed phylogenetically, resulting in proposals of virus interrelationships (2-5). However, available Coronavirus phylogenies remain unrooted, based on limited sampling, and normally depend on a single method (2-11). The main subjects of this study are the taxonomy and systematics of coronaviruses and our goal is to build the first natural classification of Coronaviridae using several methods of cladistic analyses (12), Maximum Likelihood method, as well as rigorous taxonomic sampling, making the most accurate representation of Coronaviridaes relationships to date. Nomenclature recommendations to help effectively incorporate principles of binary nomenclature into Coronaviridae taxonomy are provided. We have stressed that no member of Sarbecovirus clade is an ancestor of SARS-Cov-2, and humans are the only known host. One Sentence SummaryMultiple comprehensive phylogenetic analyses of all coronavirus species enabled testing of critical proposals on virus interrelationships.

evolutionary biology↗

bioRxiv2018

A neuron-optimized CRISPR/dCas9 activation system for robust and specific gene regulation

Recent developments in CRISPR-based gene editing have provided new avenues to interrogate gene function. However, application of these tools in the central nervous system has been delayed due to difficulties in transgene expression in post-mitotic neurons. Here, we present a highly efficient, neuron-optimized dual lentiviral CRISPR-based transcriptional activation (CRISPRa) system to drive gene expression in primary neuronal cultures and the adult brain of rodent model systems. We demonstrate robust, modular, and tunable induction of endogenous target genes as well as multiplexed gene regulation necessary for investigation of complex transcriptional programs. CRISPRa targeting unique promoters in the complex multi-transcript gene Brain-derived neurotrophic factor (Bdnf) revealed both transcript- and genome-level selectivity of this approach, in addition to highlighting downstream transcriptional and physiological consequences of Bdnf regulation. Finally, we illustrate that CRISPRa is highly efficient in vivo, resulting in increased protein levels of a target gene in diverse brain structures. Taken together, these results demonstrate that CRISPRa is an efficient and selective method to study gene expression programs in brain health and disease.

neuroscience↗

bioRxiv2017

A frailty index for UK Biobank participants

BackgroundFrailty indices (FIs) measure variation in health between aging individuals. Researching FIs in resources with large-scale genetic and phenotypic data will provide insights into the causes and consequences of frailty. Thus, we aimed to develop an FI using UK Biobank data, a cohort study of 500,000 middle-aged and older adults.\n\nMethodsAn FI was calculated using 49 self-reported questionnaire items on traits covering health, presence of diseases and disabilities, and mental wellbeing, according to standard protocol. We used multiple imputation to derive FI values for the entire eligible sample in the presence of missing item data (N =500,336). To validate the measure, we assessed associations of the FI with age, sex, and risk of all-cause mortality (follow-up [≤] 9.7 years) using linear and Cox proportional hazards regression models.\n\nResultsMean FI in the cohort was 0.125 (standard deviation = 0.075), and there was a curvilinear trend towards higher values in older participants. FI values were also marginally higher on average in women than men. In survival models, 10% higher baseline frailty (i.e. a 0.1 FI increment) was associated with higher risk of death (hazard ratio (HR) = 1.65; 95% confidence interval: 1.62, 1.68). Associations were stronger in younger participants than in old, and in men compared to women (HRs: 1.72 vs. 1.56, respectively).\n\nConclusionsThe FI is a valid measure of frailty in UK Biobank. The cohorts data are open-access for researchers to use, and we provide script for deriving this tool to facilitate future studies on frailty.

epidemiology↗

bioRxiv2017

Association of pre-pregnancy body mass index with future offspring metabolic profile: findings from three independent European birth cohorts

BackgroundA high proportion of women start pregnancy overweight/obese. According to the developmental overnutrition hypothesis, this could lead offspring to have metabolic disruption throughout their lives, and, thus perpetuate the obesity epidemic across generations. Concerns about this hypothesis are influencing antenatal care. However, it is unknown whether maternal pregnancy adiposity is associated with long-term risk of adverse metabolic profiles in offspring, and if so, whether this association is causal, via intrauterine mechanisms, or explained by shared familial (genetic, lifestyle, socioeconomic) characteristics. We aimed to determine if associations between maternal body mass index (BMI) with offspring systemic metabolite profile are causal via intrauterine mechanisms or familial factors.\n\nMethods and FindingsWe used one and two-stage individual participant data (IPD) metaanalysis, and a negative-control (paternal BMI) to examine the association between maternal prepregnancy BMI and offspring serum metabolome from three European birth cohorts (offspring age at metabolite assessment 16, 17 and 31 years). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics. Results from one-stage IPD meta-analysis (N=5327 to 5377 mother-father-offspring trios) showed that increasing maternal and paternal BMI was associated with an adverse cardio-metabolic profile in offspring. We observed strong positive associations with VLDL-lipoproteins, VLDL-C, VLDL-triglycerides, VLDL-diameter, branched/aromatic amino acids, glycoprotein acetyls, and triglycerides, and strong negative associations with HDL-lipoprotein, HDL-diameter, HDL-C, HDL2-C and HDL3-C (all P<0.003). Stronger magnitudes of associations were present for maternal compared with paternal BMI across these associations, however there was no strong statistical evidence for heterogeneity between them (all bootstrap P >0.003, equivalent to 0.05 after accounting for multiple testing). Results were similar in each individual cohort, and in the two-stage analysis. Offspring BMI showed similar patterns of crosssectional association with metabolic profiles as for parental pre-pregnancy BMI associations, but with greater magnitudes. Adjustment of the parent BMI-offspring metabolite associations for offspring BMI suggested the parental associations were largely due to the association of parental BMI measures with offspring BMI.\n\nConclusionOur findings suggest that maternal BMI-offspring metabolome associations are likely to be largely due to shared genetic or familial lifestyle confounding, rather than intrauterine programming mechanisms. They do not support the introduction of measures to reduce maternal BMI in order to prevent adverse offspring cardio-metabolic health.

epidemiology↗