Biology subjects

Ford, A.

Publications and source records attributed to Ford, A..

10 recordsLinked to original sources

bioRxiv2026

Maternal Obesity Decreases Offspring Lifespan

Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age. This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of MO may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.

physiology↗

bioRxiv2024

Behavioural rhythms of two gammarid species Echinogammarus marinus and Gammarus pulex under increasing levels of light at night

Artificial light at night (ALAN) is proliferating at an alarming rate across the globe, particularly around aquatic habitats. Natural and predictable light cycles dictate much of an individual organisms life by acting as a major signal for their circadian clock, driving rhythmic behaviours and physiological changes throughout the body. Light cycles also help populations coordinate group behaviour and greatly impact the interspecies dynamics of a community. Research into the ecological impacts of ALAN has highlighted numerous effects on these biological processes, including higher predation rates, impaired growth and development, and diminished reproductive success. Invertebrates play an undeniable role in ecosystem functioning and show robust daily rhythms. As such, it is vital to understand how ALAN may disrupt their behavioural patterns. The aim of this study was to monitor the impacts of increasing levels of light at night (0 lux - 80 lux), as well as constant light and constant darkness, on the behavioural rhythms of the intertidal amphipod, Echinogammarus marinus, and the freshwater species, Gammarus pulex. G. pulex activity was not strongly synchronised to any of the light at night treatments. E. marinus, however, exhibited strong behavioural rhythmicity in diurnal cycles with dark night periods. All the ALAN treatments resulted in a significant decrease in E. marinus rhythmicity and overall activity. Moreover, ALAN between 1-50 lux disrupted nocturnality in this species. These results indicate that while some gammarids show some adaptive plasticity when it comes to light pollution, others may experience strong direct impacts on their activity. This may be relevant to individual and population level fitness of vulnerable species in more heavily urbanised areas.

animal behavior and cognition↗

bioRxiv2024

Copy number variations of Plasmodium vivax DBP1, EBP/DBP2, and RBP2b in Duffy-positive and Duffy-negative Ethiopians

Recent evidence challenges the belief that Duffy-negative individuals are resistant to Plasmodium vivax due to lacking Duffy Antigen Receptor for Chemokines (DARC). Erythrocyte Binding Protein (EBP/DBP2) has shown moderate binding to Duffy-negative erythrocytes in vitro. Reticulocyte Binding Protein 2b (RBP2b) interactions with Transferrin Receptor 1 (TfR1) suggest involvement in Duffy-negative infections. Gene copy number variations in PvDBP1, PvEBP/DBP2, and PvRBP2b were investigated in Duffy-positive and Duffy-negative P. vivax-infected individuals from Ethiopia. Among Duffy-positive samples, 34% displayed PvDBP1 duplications (Cambodian-type). In Duffy-negative infections, 30% showed duplications, mostly Cambodian-type. For PvEBP/DBP2 and PvRBP2b, Duffy-positive samples exhibited higher duplication rates (1-8 copies for PvEBP/DBP2, 1-5 copies for PvRBP2b 46% and 43% respectively) compared to Duffy-negatives (20.8% and 26% respectively). The range of copy number variations was lower in Duffy-negative infections. Demographic and clinical factors associated with gene multiplications in both Duffy types were explored, enhancing understanding of P. vivax evolution in Duffy-negative Africans.

microbiology↗

bioRxiv2023

Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. In this study, we designed and synthesized 85 noncovalent PLpro inhibitors that bind to the newly discovered Val70Ub site and the known BL2 groove pocket. Potent compounds inhibited PLpro with inhibitory constant Ki values from 13.2 to 88.2 nM. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 {micro}M. Oral treatment with Jun12682 significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates. One-Sentence SummaryStructure-guided design of SARS-CoV-2 PLpro inhibitors with in vivo antiviral efficacy in a mouse model.

microbiology↗

bioRxiv2023

Ancient and ongoing hybridization in the Oreochromis cichlid fishes

Hybridization may enable adaptive diversification by generating unique genetic combinations when hybrid lineages are faced with ecological opportunity. Conversely, hybridization with exotic species may be detrimental to native biodiversity, by leading to homogenisation and the loss of important genetic material associated with local adaptation. Here we studied both ancient and contemporary hybridization in cichlid fishes of the genus Oreochromis (tilapia), which are among the most important fish for global aquaculture. We use whole genome resequencing of 575 individuals from 23 species, focussing on Tanzania, a natural hotspot of tilapia diversity, and a country where hybridization between exotic and native species in the natural environment has been previously reported. We reconstruct the first genome-scale phylogeny of the genus and reveal prevalent ancient gene flow across the Oreochromis phylogeny. This introgression has not led to large-scale adaptive radiation as seen in other cichlid lineages. We identify multiple cases of contemporary hybridization between native and introduced species in the wild, linked to the use of non-native species in aquaculture improvement and stocking for capture fisheries. Our study shows how ancient hybridization contributed to modern tilapia diversity, but is now a threat to both the genetic integrity of wild populations and the long-term prospects of the global tilapia aquaculture industry.

evolutionary biology↗

bioRxiv2021

Synaptic Mechanisms of Top-Down Control by The Auditory Cortico-Collicular Pathway

Corticofugal projections to evolutionarily ancient, sub-cortical structures are ubiquitous across mammalian sensory systems. These "descending" pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor dependent, supra-linear EPSP summation, indicating that descending signals can non-linearly amplify IC neurons moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control, and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathways role in plasticity and perceptual learning.

neuroscience↗

bioRxiv2021

Whole genome resequencing data enables a targeted SNP panel for conservation and aquaculture of Oreochromis cichlid fishes

Cichlid fish of the genus Oreochromis form the basis of the global tilapia aquaculture and fisheries industry. Non-native farmed tilapia populations are known to be widely distributed across Africa and to hybridize with native Oreochromis species. However, many species are difficult to distinguish morphologically, hampering attempts to maintain good quality farmed strains or to identify pure populations of native species. Here, we describe the development of a single nucleotide polymorphism (SNP) genotyping panel from whole-genome resequencing data that enables targeted species identification in Tanzania. We demonstrate that an optimized panel of 96 genome-wide SNPs based on FST outliers performs comparably to whole genome resequencing in distinguishing species and identifying hybrids. We also show this panel outperforms microsatellite-based and phenotype-based classification methods. Case studies indicate several locations where introduced aquaculture species have become established in the wild, threatening native Oreochromis species. The novel SNP markers identified here represent an important resource for assessing broodstock purity and helping to conserve unique endemic biodiversity, and in addition potentially for assessing broodstock purity in hatcheries.

evolutionary biology↗

bioRxiv2021

Large-scale design and refinement of stable proteins using sequence-only models

Engineered proteins generally must possess a stable structure in order to achieve their designed function. Stable designs, however, are astronomically rare within the space of all possible amino acid sequences. As a consequence, many designs must be tested computationally and experimentally in order to find stable ones, which is expensive in terms of time and resources. Here we report a neural network model that predicts protein stability based only on sequences of amino acids, and demonstrate its performance by evaluating the stability of almost 200,000 novel proteins. These include a wide range of sequence perturbations, providing a baseline for future work in the field. We also report a second neural network model that is able to generate novel stable proteins. Finally, we show that the predictive model can be used to substantially increase the stability of both expert-designed and model-generated proteins.

biophysics↗

bioRxiv2020

Whole Genome Sequencing of Plasmodium vivax Isolates Reveals Frequent Sequence and Structural Polymorphisms in Erythrocyte Binding Genes

Plasmodium vivax malaria is much less common in Africa than the rest of the world because the parasite relies primarily on the Duffy antigen/chemokine receptor (DARC) to invade human erythrocytes, and the majority of Africans are Duffy negative. Recently, there has been a dramatic increase in the reporting of P. vivax cases in Africa, with a high number of them being in Duffy negative individuals, potentially indicating P. vivax has evolved an alternative invasion mechanism that can overcome Duffy negativity. Here, we analyzed single nucleotide polymorphism (SNP) and copy number variation (CNV) in Whole Genome Sequence (WGS) data from 44 P. vivax samples isolated from symptomatic malaria patients in southwestern Ethiopia, where both Duffy positive and Duffy negative individuals are found. A total of 236,351 SNPs were detected, of which 21.9% was nonsynonymous and 78.1% was synonymous mutations. The largest number of SNPs were detected on chromosomes 9 (33,478 SNPs; 14% of total) and 10 (28,133 SNPs; 11.9%). There were particularly high levels of polymorphism in erythrocyte binding gene candidates including reticulocyte binding protein 2c (RBP2c), merozoite surface protein 1 (MSP1), and merozoite surface protein 3 (MSP3.5, MSP3.85 and MSP3.9). Thirteen genes related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. Variation in gene copy number was also concentrated in genes involved in host-parasite interactions, including the expansion of the Duffy binding protein gene (PvDBP) on chromosome 6 and several PIR genes. Based on the phylogeny constructed from the whole genome sequences, the expansion of these genes was an independent process among the P. vivax lineages in Ethiopia. We further inferred transmission patterns of P. vivax infections among study sites and showed various levels of gene flow at a small geographical scale. The genomic features of P. vivax provided baseline data for future comparison with those in Duffy-negative individuals, and allowed us to develop a panel of informative Single Nucleotide Polymorphic markers diagnostic at a micro-geographical scale.

genomics↗

bioRxiv2019

Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance

Plasmodium vivax invasion of human erythrocytes depends on the Duffy Binding Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number varies between P. vivax isolates, but the prevalence of PvDBP multiplications in Sub-Saharan Africa and its impact are unknown. We determined the prevalence and type of PvDBP duplications, as well as PvDBP copy number variation among 178 Ethiopian P. vivax isolates using a PCR-based diagnostic method, a novel quantitative real-time PCR assay and whole genome sequencing. For the 145 symptomatic samples, PvDBP duplications were detected in 95 isolates, of which 81 had the Cambodian and 14 Malagasy-type PvDBP duplications. PvDBP varied from 1 to >4 copies. Isolates with multiple PvDBP copies were found to be higher in symptomatic than asymptomatic infections. For the 33 asymptomatic samples, PvDBP was detected with two copies in two of the isolates, and both were the Cambodian-type PvDBP duplication. PvDBP copy number in Duffy-negative heterozygotes was not significantly different from that in Duffy-positives, providing no support for the hypothesis that increased copy number is a specific association with Duffy-negativity, although the number of Duffy-negatives was small and further sampling is required to test this association thoroughly. Author summaryPlasmodium vivax invasion of human erythrocytes relies on interaction between the Duffy antigen and P. vivax Duffy Binding Protein (PvDBP). Whole genome sequences from P. vivax field isolates in Madagascar identified a duplication of the PvDBP gene and PvDBP duplication has also been detected in non-African P. vivax-endemic countries. Two types of PvDBP duplications have been reported, termed Cambodian and Malagasy-type duplications. Our study used a combination of PCR-based diagnostic method, a novel quantitative real-time PCR assay, and whole genome sequencing to determine the prevalence and type of PvDBP duplications, as well as PvDBP copy number on a broad number of P. vivax samples in Ethiopia. We found that over 65% of P. vivax isolated from the symptomatic infections were detected with PvDBP duplications and PvDBP varied from 1 to >4 copies. The majority of PvDBP duplications belongs to the Cambodian-type while the Malagasy-type duplications was also detected. For the asymptomatic infections, despite a small sample size, the majority of P. vivax were detected with a single-copy based on both PCR and qPCR assays. There was no significant difference in PvDBP copy number between Duffy-null heterozygote and Duffy-positive homozygote/heterozygote. Further investigation is needed with expanded Duffy-null homozygotes to examine the functional significance of PvDBP expansion.

epidemiology↗