Biology subjects

Bradshaw, W. J.

Publications and source records attributed to Bradshaw, W. J..

8 recordsLinked to original sources

bioRxiv2024

AEGIS: individual-based modeling of life history evolution

Nature presents a staggering diversity of life history strategies, ranging from rapid to slow onset of sexual maturity, short or long life, low or high number of offspring, and much more. Each species-specific life history trait reflects on the one hand specific adaptations to unique environments, e.g., nutrient availability, predation, parasite load, seasonality; and on the other hand, depends on past demographic constraints, such as population bottlenecks, migrations, etc. Studying life history diversity in nature and in the laboratory ultimately aims to identify the ecological, demographic, and intrinsic causes contributing to species-specific growth rate distributions, lifetime reproductive outcomes, as well as lifespans. However, for most species, we cannot rewind the evolutionary and demographic past to identify the causal chain of events leading to the present life history traits. We can infer past events only by sampling extant populations. In silico evolution has the advantage of providing complete time resolution for the events driving life history evolution and enables to directly test the impact of ecological and demographic variables on the evolution of life history traits. We developed AEGIS (Aging of Evolving Genomes In Silico), a software for individual-based modeling of life history trait evolution at the genotype and phenotype level. AEGIS models life history traits evolution in response to a set of factors, including resource availability, extrinsic mortality induced by predators or parasites, different levels of germline mutation rates, population size, sexual vs. asexual reproduction, and more. AEGIS serves as a powerful tool to model life history evolution and allows for parameter inference against ground truths. AEGIS can help generate estimates for the evolution of different life history traits, such as age-dependent mortality and reproduction, in response to different selective pressures and intrinsic genetic constraints.

evolutionary biology↗

bioRxiv2023

Analysis of the Diverse Antigenic Landscape of the Malaria Invasion Protein RH5 Identifies a Potent Vaccine-Induced Human Public Antibody Clonotype

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines that seek to protect against the disease-causing blood-stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here we characterize over 200 human IgG monoclonal antibodies induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule, and establish epitope specificity, antibody association rate and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.

immunology↗

bioRxiv2023

Regulation of inositol 5-phosphatase activity by the C2 domain of SHIP1 and SHIP2

SHIP1, an inositol 5-phosphatase, plays a central role in cellular signalling. As such, it has been implicated in many conditions. Exploiting SHIP1 as a drug target will require structural knowledge and the design of selective small molecules. We have determined apo, and magnesium and phosphate-bound structures of the phosphatase and C2 domains of SHIP1. The C2 domains of SHIP1 and the related SHIP2 modulate the activity of the phosphatase domain. To understand the mechanism, we performed activity assays, hydrogen-deuterium-exchange mass spectrometry and molecular dynamics on SHIP1 and SHIP2. Our findings demonstrate that the influence of the C2 domain is more pronounced for SHIP2 than SHIP1. We determined 91 structures of SHIP1 with fragments bound, with some near the interface between the two domains. We performed a mass spectrometry screen and determined four structures with covalent fragments. These structures could act as starting points for the development of potent, selective probes.

biochemistry↗

bioRxiv2023

Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimers disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM.

neuroscience↗

bioRxiv2023

Development of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic strategy for Alzheimer's disease.

Recent genome-wide association studies have revealed genetic risk factors for Alzheimers disease (AD) that are exclusively expressed in microglia within the brain. A proteomics approach identified moesin (MSN), a FERM (four-point-one ezrin radixin moesin) domain protein, and the receptor CD44 as hub proteins found within a co-expression module strongly linked to AD clinical and pathological traits as well as microglia. The FERM domain of MSN interacts with the phospholipid PIP2 and the cytoplasmic tails of receptors such as CD44. This study explored the feasibility of developing protein-protein interaction inhibitors that target the MSN-CD44 interaction. Structural and mutational analyses revealed that the FERM domain of MSN binds to CD44 by incorporating a beta strand within the F3 lobe. Phage-display studies identified an allosteric site located close to the PIP2 binding site in the FERM domain that affects CD44 binding within the F3 lobe. These findings support a model in which PIP2 binding to the FERM domain stimulates receptor tail binding through an allosteric mechanism that causes the F3 lobe to adopt an open conformation permissive for binding. High-throughput screening of a chemical library identified two compounds that disrupt the MSN-CD44 interaction, and one compound series was further optimized for biochemical activity, specificity, and solubility. The results suggest that the FERM domain holds potential as a drug development target. The small molecule preliminary leads generated from the study could serve as a foundation for additional medicinal chemistry effort with the goal of controlling microglial activity in AD by modifying the MSN-CD44 interaction.

molecular biology↗

bioRxiv2020

Antibody repertoire sequencing reveals systemic and mucosal immunosenescence in the short-lived turquoise killifish

Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system. Significance StatementImmune function declines dramatically with age, with important consequences for health in the elderly. Changes in the diversity and composition of the bodys antibody repertoire are an important contributor to this age-related dysfunction. However, studying repertoire aging at high spatial and temporal resolution is hampered by the long lifespans of humans and other vertebrate models, and the difficulty of acquiring human samples other than peripheral blood. Here, we characterize the aging of the antibody repertoire in a naturally short-lived vertebrate, the turquoise killifish (Nothobranchius furzeri). We found that aging killifish undergo rapid loss of repertoire diversity in both whole-body and intestinal samples within four months of hatching. Loss of repertoire diversity in the gut was also associated with broader gene-expression changes indicative of reduced B-cell activity. As such, killifish represent a powerful laboratory model to study adaptive immune aging.

immunology↗

bioRxiv2019

Extreme genomic volatility characterises the evolution of the immunoglobulin heavy chain locus in teleost fishes

The evolution of the adaptive immune system has provided vertebrates with a uniquely sophisticated immune toolkit, enabling them to mount precise immune responses against a staggeringly diverse range of antigens. Like other vertebrates, teleost fishes possess a complex and functional adaptive immune system; however, our knowledge of the complex antigen-receptor genes underlying its functionality has been restricted to a small number of experimental and agricultural species, preventing a systematic investigation of how these crucial gene loci evolve. Here, we analyse the genomic structure of the immunoglobulin heavy chain (IGH) gene loci in the cyprinodontiforms, a diverse and important group of teleosts present in many different habitats across the world. We reconstruct the complete IGH loci of the turquoise killifish (Nothobranchius furzeri) and the southern platyfish (Xiphophorus maculatus) and analyse their in vivo gene expression, revealing the presence of species-specific splice isoforms of transmembrane IGHM. We further characterise the IGH constant regions of ten additional cyprinodontiform species, including guppy, amazon molly, mummichog and mangrove killifish. Phylogenetic analysis of these constant regions reveals multiple independent rounds of duplication and deletion of the teleost-specific antibody class IGHZ in the cyprinodontiform lineage, demonstrating the extreme volatility of IGH evolution. Focusing on the cyprinodontiforms as a model taxon for comparative evolutionary immunology, this work provides novel genomic resources for studying adaptive immunity and sheds light on the evolutionary history of the adaptive immune system.

immunology↗

bioRxiv2019

AEGIS: An In Silico Tool to Model Genome Evolution in Age-Structured Populations

AEGIS (Ageing of Evolving Genomes In Silico) is a versatile population-genetics numerical-simulation tool that enables the evolution of life history trajectories under sexual and asexual reproduction and a wide variety of evolutionary constraints. By encoding age-specific survival and reproduction probabilities as discrete genomic elements, AEGIS allows these probabilities to evolve freely and independently over time. Simulation of population evolution with AEGIS demonstrates that ageing-like phenotypes evolve in stable environments under a wide range of conditions, that life history trajectories depend heavily on mutation rates, and that sexual populations are better able to accumulate high levels of beneficial mutations affecting early-life survival and reproduction. AEGIS is free and open-source, and aims to become a standard reference tool in the study of life-history evolution and the evolutionary biology of ageing.

evolutionary biology↗