Biology subjects

Butcher, R.

Publications and source records attributed to Butcher, R..

4 recordsLinked to original sources

bioRxiv2026

Maternal age modulates progeny social behavior via a small RNA-neuropeptide axis

Parental age influences offspring traits across species, yet the molecular pathways by which maternal state modulates progeny neural function remain poorly defined. Here we demonstrate that maternal age in C. elegans regulates progeny avoidance of the social pheromone by modulating the activity of a defined sensory circuit. Progeny of young mothers exhibit stronger activity of the pheromone-sensing ADL neurons and enhanced pheromone avoidance, whereas progeny of old mothers display reduced neuronal responses and weaker repulsion. We identify an ERI-1-microRNA-neuropeptide signaling axis operating in peptidergic AVH interneurons that modulates ADL circuit responsiveness. ERI-1 promotes expression of the neuropeptide gene flp-26 by repressing mir-8207, and signaling from AVH to ADL establishes pheromone sensitivity. Maternal aging is associated with reduced ERI-1 expression in progeny AVH neurons and dampening this signaling pathway. Consequently, progeny of young mothers, though developmentally less robust, disperse more readily from crowded, pheromone-rich environments, offsetting their early-life disadvantages. Our findings reveal a molecular and circuit-level mechanism by which maternal physiology adaptively configures offspring neural computation and behavioral strategy across generations.

neuroscience↗

bioRxiv2024

Systematic empirical evaluation of individual base editing targets: validating therapeutic targets in USH2A and comparison of methods

Base editing shows promise for the correction of human mutations at a higher efficiency than other repair methods and is especially attractive for mutations in large genes that are not amenable to gene augmentation therapy. Here, we demonstrate a comprehensive workflow for in vitro screening of potential therapeutic base editing targets for the USH2A gene and empirically validate the efficiency of adenine and cytosine base editor/guide combinations for correcting 35 USH2A mutations. Editing efficiency and bystander edits are compared between different target templates (plasmids versus transgenes) and assays (Next generation sequencing versus Sanger), as well as comparisons between unbiased empirical results and computational predictions. Based on these observations, practical assay recommendations are discussed. Finally, a humanized knock-in mouse model was created with the best-performing target, the nonsense mutation c.11864G>A p.(Trp3955*). Split-intein AAV9 delivery of editing reagents resulted in the restoration of USH2A protein and a correction rate of 65 {+/-} 3% at the mutant base pair and of 52 {+/-} 3% excluding bystander amino acid changes. This efficiency compares favorably to a prior genome editing strategy tested in the retina that completed a clinical trial and demonstrates the effectiveness of this overall strategy to identify and test base editing reagents with the potential for human therapeutic applications.

genetics↗

bioRxiv2017

Age-specific prevalence of anti-Pgp3 antibodies and severe conjunctival scarring in the Solomon Islands

BackgroundTrachomatous trichiasis (TT) and ocular Chlamydia trachomatis (Ct) infection in the Solomon Islands are scarce, whereas trachomatous inflammation-follicular (TF) is prevalent.\n\nMethodsWe enrolled 1511 people aged [≥]1 year from randomly selected households in 13 villages in which >10% of the population had TF prior to a single round of azithromycin MDA undertaken six months previously. Blood was collected from people of all ages to be screened for anti-Pgp3 antibodies. Photographs were collected from people of all ages for analysis of scarring severity.\n\nResultsConjunctival scars were visible in 13.1% of photographs. Mild (p<0.0001) but not severe (p=0.149) scars increased in prevalence with age. Anti-Pgp3 antibody seroprevalence was 18% in 1-9 year olds, increased sharply around the age of sexual debut, and reached 69% in those over 25 years. Anti-Pgp3 seropositivity did not increase significantly between the ages of 1-9 years, and was not associated with scarring in children (p=0.472) or TF in children (p=0.581).\n\nConclusionsSigns of trachoma are common in the Solomon Islands but occur frequently in individuals who have no serological evidence of prior ocular infection with Ct. WHO recommendations for directing MDA provision based on signs alone may not be suitable in this context.

epidemiology↗

bioRxiv2017

Active Trachoma Cases In The Solomon Islands Have Varied Polymicrobial Community Structures But Do Not Associate With Individual Non-Chlamydial Pathogens Of The Eye

BackgroundSeveral non-chlamydial microbial pathogens are associated with clinical signs of active trachoma in trachoma-endemic communities with a low prevalence of ocular Chlamydia trachomatis (Ct) infection. In the Solomon Islands, the prevalence of Ct among children is low despite the prevalence of active trachoma being moderate. We therefore set out to investigate whether active trachoma was associated with a common non-chlamydial infection or with a dominant polymicrobial community dysbiosis in the Solomon Islands.\n\nMethodsWe studied DNA from conjunctival swabs collected from 257 Solomon Islanders with active trachoma and matched controls. Droplet digital PCR was used to test for pathogens suspected to be able to induce follicular conjunctivitis. Polymicrobial community diversity and composition were studied by sequencing of hypervariable regions of the 16S ribosomal ribonucleic acid gene in a subset of 54 cases and 53 controls.\n\nResultsAlthough Ct was associated with active trachoma, the number of infections was low (cases: 3.9%, controls: 0.4%). Estimated prevalence (cases, controls) of each non-chlamydial infection was as follows: S. aureus (1.9%, 1.9%), Adenoviridae (1.2%, 1.2%), coagulase-negative Staphylococcus (5.8%, 4.3%), H. influenzae (7.4%, 11.7%), M. catarrhalis (2.3%, 4.7%) and S. pneumoniae (7.0%, 6.2%). There was no statistically significant association between clinical signs of trachoma and presence or load of any of the non-Ct infections that were assayed. Inter-individual variations in the conjunctival microbiome were characterised by differences in the levels of Corynebacterium, Proprionibacterium, Helicobacter and Paracoccus, but diversity and relative abundance of these specific genera did not differ significantly between cases and controls.\n\nDiscussionIt is unlikely that the prevalent trachoma-like follicular conjunctivitis in the Solomon Islands has a dominant bacterial aetiology. Before implementing community-wide azithromycin distribution for trachoma, policy makers should consider that clinical signs of trachoma can be observed in the absence of any detectable azithromycin-susceptible organism.

microbiology↗