Biology subjects

Wilkins, A.

Publications and source records attributed to Wilkins, A..

7 recordsLinked to original sources

bioRxiv2025

Prediction of mosquito vector abundance for threespecies in the Anopheles gambiae complex

BackgroundThe dynamics of vector borne disease transmission depend on the abundances of vectors. The dominant malaria vector species complex of Anopheles gambiae sensu lato is a target of vector control strategies designed to reduce and eliminate malaria transmission. The three most widely distributed dominant malaria vectors within the species complex are An. arabiensis, An. coluzzii and An. gambiae sensu stricto. MethodsPrevious studies across the extent of the species complex range have been restricted to annual predictions of species occurrence or relative abundance. This study incorporated relative abundance data at the species level and abundance data at the species complex level to estimate and predict daily equilibrium vector abundances of each species. Statistical models with interpretable parameters were used to gain insight into how factors such as meteorological conditions, insecticide treated net use, and human density affect the spatial and temporal predictions. The statistical models were used to predict daily equilibrium vector abundance that is an important factor in indices of malaria transmission such as the basic reproduction number and vectorial capacity. ResultsMeteorological factors, such as precipitation and relative humidity, and human factors, such as population density and insecticide treated nets, were important predictors of these three malaria vector species in Africa. Insecticide treated net use was negatively associated with per capita vector abundance of the An. gambiae species complex and interacted with year to suggest an a negative effect on the ratio of An. gambiae s.s. to An. arabiensis at the end of the prediction period that extended from 2002 to 2020. A predicted increasing interannual trend for An. coluzzii was potentially caused by changing species identification methods. ConclusionThe predicted equilibrium abundances of the three species showed potentially high levels of geographical overlap, niche overlap, and evidence for stable coexistence despite substantial interspecific competition. Improving collection of longitudinal species abundance data across the spatial range of the An. gambiae species complex will facilitate future explorations of causal hypotheses that relate vector abundance to control measures, malaria interventions and meteorological conditions.

ecology↗

bioRxiv2024

A nutritional immunity blockade controls extracellular bacterial replication in Legionella pneumophila infections.

The accidental human pathogen Legionella pneumophila (Lp) is the etiological agent for a severe atypical pneumonia known as Legionnaires disease. In human infections and animal models of disease alveolar macrophages are the primary cellular niche that supports bacterial replication within a unique intracellular membrane-bound organelle. The Dot/Icm apparatus - a type IV secretion system that translocates [~]300 bacterial proteins within the cytosol of the infected cell - is a central virulence factor required for intracellular growth. Mutant strains lacking functional Dot/Icm apparatus are transported to and degraded within the lysosomes of infected macrophages. The early foundational work from Dr. Horwitzs group unequivocally established that Legionella does not replicate extracellularly during infection - a phenomenon well supported by experimental evidence for four decades. Our data challenges the dogma in the field by demonstrating that macrophages and monocytes provide the necessary nutrients and support robust Legionella extracellular replication. We show that the previously reported lack of Lp extracellular replication is not a bacteria intrinsic feature but rather a result of robust restriction by serum-derived nutritional immunity factors. Specifically, the host iron-sequestering protein Transferrin was identified as a critical suppressor of Lp extracellular replication in an iron-dependent manner. In iron-overload conditions or in the absence of Transferrin, Lp bypasses growth restriction by IFN{psi}-primed macrophages though extracellular replication. It is well established that certain risk factors associated with development of Legionnaires disease, such as smoking, produce a chronic pulmonary environment of iron-overload. Our work indicates that iron-overload could be an important determinant of severe infection by allowing Lp to overcome nutritional immunity and replicate extracellularly, which in turn would circumvent intracellular cell intrinsic host defenses. Thus, we provide evidence for nutritional immunity as a key underappreciated host defense mechanism in Legionella pathogenesis.

microbiology↗

bioRxiv2023

The intracellular growth of the vacuolar pathogen Legionella pneumophila is dependent on the acyl chain composition of host membranes

Legionella pneumophila is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires disease. As a prototypical vacuolar pathogen L. pneumophila establishes a unique endoplasmic reticulum (ER)-derived organelle within which bacterial replication takes place. Bacteria-derived proteins are deposited in the host cytosol and in the lumen of the pathogen-occupied vacuole via a type IVb (T4bSS) and a type II (T2SS) secretion system respectively. These secretion system effector proteins manipulate multiple host functions to facilitate intracellular survival of the bacteria. Subversion of host membrane glycerophospholipids (GPLs) by the internalized bacteria via distinct mechanisms feature prominently in trafficking and biogenesis of the Legionella-containing vacuole (LCV). Conventional GPLs composed of a glycerol backbone linked to a polar headgroup and esterified with two fatty acids constitute the bulk of membrane lipids in eukaryotic cells. The acyl chain composition of GPLs dictates phase separation of the lipid bilayer and therefore determines the physiochemical properties of biological membranes - such as membrane disorder, fluidity and permeability. In mammalian cells, fatty acids esterified in membrane GPLs are sourced endogenously from de novo synthesis or via internalization from the exogenous pool of lipids present in serum and other interstitial fluids. Here, we exploited the preferential utilization of exogenous fatty acids for GPL synthesis by macrophages to reprogram the acyl chain composition of host membranes and investigated its impact on LCV homeostasis and L. pneumophila intracellular replication. Using saturated fatty acids as well as cis- and trans- isomers of monounsaturated fatty acids we discovered that under conditions promoting lipid packing and membrane rigidification L. pneumophila intracellular replication was significantly reduced. Palmitoleic acid - a C16:1 monounsaturated fatty acid - that promotes membrane disorder when enriched in GPLs significantly increased bacterial replication within human and murine macrophages but not in axenic growth assays. Lipidome analysis of infected macrophages showed that treatment with exogenous palmitoleic acid resulted in membrane acyl chain reprogramming in a manner that promotes membrane disorder and live-cell imaging revealed that the consequences of increasing membrane disorder impinge on several LCV homeostasis parameters. Collectively, we provide experimental evidence that L. pneumophila replication within its intracellular niche is a function of the lipid bilayer disorder and hydrophobic thickness.

microbiology↗

bioRxiv2023

Development of peptides for targeting cell ablation agents concurrently to the Sertoli and Leydig cell populations of the testes: an approach to non-surgical sterilization

The surgical sterilization of cats and dogs has been used to prevent their unwanted breeding for decades, but this is an expensive and invasive procedure, and often impractical in wider contexts, for example the control of feral populations. A sterilization agent that could be administered in a single injection would not only eliminate the risks imposed by surgery but also be a much more cost-effective solution to this worldwide problem. In this study, we sought to develop a targeting peptide that would selectively bind to Leydig cells of the testes. Subsequently, after covalently attaching a cell ablation agent, Auristatin, to this peptide we aimed to apply this conjugated product (LH2Auristatin) to adult male mice in vivo, both alone and together with a previously developed Sertoli cell targeting peptide (FSH2Menadione). The application of LH2Auristatin alone resulted in an increase in DNA damage, reduced mean testes weights and mean seminiferous tubule size, along with extensive germ cell apoptosis and a reduction in litter sizes. Together with FSH2Menadione there was also an increase in embryo resorptions. These promising results were observed in around a third of all treated animals. Given this variability we discuss how these reagents might be adjusted in order to increase target cell ablation and improve their efficacy as sterilization agents.

biochemistry↗

bioRxiv2021

Spatial modelling for population replacement of mosquito vectors at continental scale

Malaria is one of the deadliest vector-borne diseases in the world. Researchers are developing new genetic and conventional vector control strategies to attempt to limit its burden. Novel control strategies require detailed safety assessment to ensure responsible and successful deployments. Anopheles gambiae sensu stricto (s.s.) and Anopheles coluzzii, two closely related subspecies within the species complex Anopheles gambiae sensu lato (s.l.), are among the dominant malaria vectors in sub-Saharan Africa. These two subspecies readily hybridise and compete in the wild and are also known to have distinct niches, each with spatially and temporally varying carrying capacities driven by precipitation and land use factors. We model the spread and persistence of a population-modifying gene drive system in these subspecies across sub-Saharan Africa by simulating introductions of genetically modified mosquitoes across the African mainland and its offshore islands. We explore transmission of the gene drive between the two subspecies that arise from different hybridisation mechanisms, the effects of both local dispersal and potential wind-aided migration to the spread, and the development of resistance to the gene drive. Given the best current available knowledge on the subspecies life histories, we find that an introduced gene drive system with typical characteristics can plausibly spread from even distant offshore islands to the African mainland with the aid of wind-driven migration, with resistance taking over within a decade. Our model accounts for regional to continental scale mechanisms, and demonstrates a range of realistic dynamics including the effect of prevailing wind on spread and spatio-temporally varying carrying capacities for subspecies. As a result, it is well-placed to answer future questions relating to mosquito gene drives as important life history parameters become better understood.

synthetic biology↗

bioRxiv2019

A FIJI Macro for quantifying pattern in extracellular matrix

Diverse extracellular matrix patterns are observed in both normal and pathological tissue. However, most current tools for quantitative analysis focus on a single aspect of matrix patterning. Thus, an automated pipeline that simultaneously quantifies a broad range of metrics and enables a comprehensive description of varied matrix patterns is needed. To this end we have developed an ImageJ plugin called TWOMBLI, which stands for The Workflow Of Matrix BioLogy Informatics. TWOMBLI is designed to be quick, versatile and easy-to-use particularly for non-computational scientists. TWOMBLI can be downloaded from https://github.com/wershofe/TWOMBLI together with detailed documentation. Here we present an overview of the pipeline together with examples from a wide range of contexts where matrix patterns are generated.

cancer biology↗

bioRxiv2017

Using phylogenomic data to explore the effects of relaxed clocks and calibration strategies on divergence time estimation: Primates as a test case

Primates have long been a test case for the development of phylogenetic methods for divergence time estimation. Despite a large number of studies, however, the timing of origination of crown Primates relative to the K-Pg boundary and the timing of diversification of the main crown groups remain controversial. Here we analysed a dataset of 372 taxa (367 Primates and 5 outgroups, 61 thousand base pairs) that includes nine complete primate genomes (3.4 million base pairs). We systematically explore the effect of different interpretations of fossil calibrations and molecular clock models on primate divergence time estimates. We find that even small differences in the construction of fossil calibrations can have a noticeable impact on estimated divergence times, especially for the oldest nodes in the tree. Notably, choice of molecular rate model (auto-correlated or independently distributed rates) has an especially strong effect on estimated times, with the independent rates model producing considerably more ancient estimates for the deeper nodes in the phylogeny. We implement thermodynamic integration, combined with Gaussian quadrature, in the program MCMCTree, and use it to calculate Bayes factors for clock models. Bayesian model selection indicates that the auto-correlated rates model fits the primate data substantially better, and we conclude that time estimates under this model should be preferred. We show that for eight core nodes in the phylogeny, uncertainty in time estimates is close to the theoretical limit imposed by fossil uncertainties. Thus, these estimates are unlikely to be improved by collecting additional molecular sequence data. All analyses place the origin of Primates close to the K-Pg boundary, either in the Cretaceous or straddling the boundary into the Palaeogene.

evolutionary biology↗