Biology subjects

Mead, E.

Publications and source records attributed to Mead, E..

5 recordsLinked to original sources

bioRxiv2026

Assessing Enclosure Modifications to Enhance Accessibility for Zoo-Housed Meerkats (Suricata suricatta)

Scientific advancements have contributed to increased longevity of animals in zoos and aquariums, creating a growing need for environments that remain accessible to geriatric animals and animals with disabilities. However, few empirical studies have evaluated whether accessibility-focused enclosure modifications impact species-appropriate behavior. We evaluated the effects of accessibility modifications on a group of four adult zoo-housed meerkats (Suricata suricatta), including one individual with a forelimb amputation and one geriatric individual. Low-level logs and steps were added to the enclosure to provide intermediate heights and facilitate access to elevated areas. Following the introduction of these enclosure modifications, sentry behavior increased, with all individuals engaging in this behavior compared with only one individual during baseline. The meerkats also increased their overall use of low-elevated areas following modification, although individual responses varied. Posture differed between study phases, with meerkats more frequently adopting tri/quadrupedal postures following modification. Together, these findings suggest that relatively simple accessibility-focused modifications can expand opportunities for geriatric animals and animals with disabilities to engage in species-appropriate behavior. More broadly, this case study highlights the importance of empirically evaluating accessibility interventions and incorporating universal design principles into animal spaces to accommodate individuals with diverse physical abilities and promote positive animal welfare.

animal behavior and cognition↗

bioRxiv2025

SHIP1 regulates TREM2 signalling and macrophage functions in a hiPSC-derived model

Genetic and functional studies strongly implicate microglia in the pathology of Alzheimers disease (AD). The Triggering Receptor Expressed on Myeloid cells 2 (TREM2) pathway is an important functional regulator of microglia in AD, promoting phagocytosis of apoptotic cells, debris and pathogenic proteins including amyloid beta (A{beta}). Additionally, genome-wide association studies have identified risk bearing polymorphisms in several members of the pathway including INPP5D, encoding the inositol phosphatase SHIP1. Recent studies utilising in vitro macrophage and microglia models and preclinical mouse models have identified a role for SHIP1 in both modulating TREM2 signalling and modulating neurotoxic microglial activation. In this study, we characterised the role of SHIP1 in regulating TREM2 signalling and global microglial functions using human induced pluripotent stem cell (hiPSC)-derived macrophages as a physiologically-relevant in vitro model of microglia. Isogenic parent and SHIP1 knockout (SHIP1 KO) lines were generated and macrophage phenotype and functions investigated. Knocking out SHIP1 was associated with a decreased expression of the lipopolysaccharide (LPS) co-receptor CD14, which translated to lower secretion of pro-inflammatory cytokines on stimulation with LPS. Additionally, SHIP1 KO hiPSC-derived macrophages showed decreased signalling upon TREM2 stimulation, which was further reflected in a reduced level of phagocytosis of apoptotic neurons compared to the parental line. The observed attenuated TREM2 signalling did not correspond to decreased TREM2 protein levels nor increased shedding of the receptor. Examination of macrophage scavenger receptor expression revealed reduced cell surface levels of CD163 and CD206 involved in resolution of inflammation but increased levels of the phagocytic receptor MerTK, while morphological analysis revealed a less amoeboid activated phenotype and increased adhesion. Taken together, our data indicates that SHIP1 plays a key role in regulating global macrophage functions in addition to modulating TREM2 signalling and inflammation.

immunology↗

bioRxiv2025

Epigenetic phase variation in the gut microbiome enhances bacterial adaptation

The human gut microbiome within the gastrointestinal tract continuously adapts to variations in diet, medications, and host physiology. A strategy for bacterial genetic adaptation is epigenetic phase variation (ePV) mediated by bacterial DNA methylation, which can regulate gene expression, enhance clonal heterogeneity, and enable a single bacterial strain to exhibit variable phenotypic states. Genome-wide and site-specific ePVs have been characterized in human pathogens antigenic variation and virulence factor production. However, the role of ePV in facilitating adaptation within the human microbiome remains poorly understood. Here, we comprehensively cataloged genome-wide and site-specific ePV in human infant and adult gut microbiomes. First, using long-read metagenomic sequencing, we detected genome-wide ePV mediated by complex structural variations of DNA methyltransferases, highlighting those associated with antibiotics or fecal microbiota transplantation. Second, we analyzed a collection of public short-read metagenomic sequencing datasets, uncovering a great prevalence of genome-wide ePV in the human gut microbiome. Third, we quantitatively detected site-specific ePVs using single-molecule methylation analysis to identify dynamic variation associated with antibiotic treatment or probiotic engraftment. Finally, we performed an in-depth assessment of an Akkermansia muciniphila isolate from an infant, highlighting that ePVs can regulate gene expression and enhance the bacterial adaptive capacity by employing a bet-hedging strategy to increase tolerance to differing antibiotics. Our findings indicate that epigenetic modifications are a common strategy used by gut bacteria to adapt to the fluctuating environment.

microbiology↗

bioRxiv2024

Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor

Inhibition of the mitochondrial deubiquitinating enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinsons Disease and mitophagy-related disorders. We have integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small molecule containing a cyanopyrrolidine reactive group, USP30-I-1. The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells. Enzyme kinetics and Hydrogen Deuterium eXchange mass spectrometry (HDX-MS) infers that the inhibitor binds tightly to regions surrounding the USP30 catalytic cysteine and positions itself to form a binding pocket along the thumb and palm domains of the protein, thereby interfering its interaction with ubiquitin substrates. A comparison to a non-covalent USP30 inhibitor containing a benzosulfonamide scaffold revealed a slightly different binding mode closer to the active site Cys77, which may provide the molecular basis for improved selectivity towards USP30 against other members of the DUB enzyme family. Our results highlight advantages in developing covalent inhibitors, such as USP30-I-1, for targeting USP30 as treatment of disorders with impaired mitophagy.

biochemistry↗

bioRxiv2021

Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain

Single point mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration including Alzheimers disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signalling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterised. Here, we present phage display generated scFv antibody binders to human TREM2 ectodomain. Cocrystal structures revealed the binding of two scFvs to an epitope on the globular TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterisation of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.

molecular biology↗