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Breen, A.

Publications and source records attributed to Breen, A..

5 recordsLinked to original sources

Longitudinal consensus clustering reveals the functional architecture of the developing rat brain

Resting-state fMRI-based mapping of functional networks in developing human populations holds promise for enhancing the diagnosis and treatment of psychiatric disorders, which often emerge during adolescence. Preclinical models offer experimentally tractable lifespans to investigate these trajectories longitudinally, while also enabling direct experimental manipulations that can reveal causal influences on brain and behavioural outcomes. However, unlike in the human neuroimaging field, preclinical neuroimaging often lacks standardisation, making comparison across studies and translation of findings more difficult. In particular, we lack developmentally informed functional brain atlases. Working with a longitudinal sex-balanced resting fMRI dataset collected using a standardised protocol, we aimed to identify robust functional networks in the rat brain and investigate how they change over development (P28, P35, P49, P70 and P91). Employing a consensus clustering approach informed by cluster quality metrics, we mapped functional network development of the rat brain across multiple spatial scales (k=3, k=5 and k=7) from juvenile (pre-puberty) to early adulthood. Force-directed spring embeddings and graph metrics showed global shifts in brain organisation; with increased global system segregation over time, while global network integration (participation coefficient) decreased. At the network-level, the rat brain was characterised by functionally heterogenous network maturation that recapitulated sensorimotor - higher cognitive gradients of development observed in humans. Longitudinal mapping over the adolescent period revealed both linear and non-linear developmental trajectories, and shows that maturation of the rat brain is characterised by network fractionation and delayed cortical specialisation, with the brain transitioning from globally interconnected juvenile networks into functionally segregated adult networks. The functional architecture we describe offers a generalisable structure and nomenclature for the preclinical imaging community, analogous to the Yeo 7-network parcellation in humans. By openly sharing all data, analytic resources, and outputs with the community, this work provides a developmentally informed functional atlas developed under a standardised protocol for anaesthesia and data acquisition and offers resources that will enable preclinical researchers to further advance our understanding of brain development during this critical period.

neuroscience↗

A sex-balanced longitudinal developmental task-free fMRI rat dataset.

Here we present a preclinical longitudinal developmental dataset spanning pre-puberty (juvenile) to early adulthood in Wistar rats. Thirty-six rats (18 female) were scanned during five sessions at approximately postnatal day 28, 35, 49, 70 and 91. A standardised consensus protocol was used for animal sedation and MRI data acquisition (structural MRI and resting-state fMRI). The dataset also includes daily body weight measurements, day of puberty onset, and daily cytological smear images for oestrous tracking. This openly available dataset addresses the need for sex-balanced developmental preclinical datasets spanning puberty and enables researchers to investigate longitudinal brain functional developmental trajectories and Sex As a Biological Variable (SABV).

neuroscience↗

A citywide metagenomic analysis reveals surface-specific microbiome and resistome patterns in outdoor urban environments across Liverpool, UK.

Urbanisation is rapidly increasing worldwide, with increasing attention focused on its consequences for human populations and the environment. Despite the importance of outdoor urban environments for biodiversity and human wellbeing, their microbial ecology remains poorly characterised, particularly in relation to emerging microbial threats including antimicrobial resistance (AMR). Here, we present a citywide metagenomic study of outdoor public surfaces across Liverpool, United Kingdom, examining microbial community composition, diversity, and antimicrobial resistance gene (ARG) distribution across five distinct surface types. We show that patterns of human activity and surface use strongly influence both microbial community structure and AMR signatures in outdoor urban environments. Touchpoints were enriched for human-associated taxa and exhibited the highest overall resistome burdens, whereas Pathway and Waterside niches showed no strong taxonomic enrichment and exhibited low ARG prevalence. Refuse surfaces showed mixed patterns, characterised by sporadic but occasionally high-abundance ARG detections. Soil harboured the most distinct microbial communities but showed minimal ARG prevalence, which may partly reflect the limited representation of environmental taxa in current ARG databases. This study provides a baseline for understanding how urban infrastructure and behaviour shape microbial and resistance landscapes, and highlights the value of outdoor metagenomic surveillance for future environmental and public health research.

microbiology↗

Novel Class B2 and C β-lactamases harboured by Pseudomonas spp. wastewater isolates

IntroductionAntimicrobial resistance has existed in the environment long before its rapid emergence and detection in clinically relevant pathogens. Studying the resistance of environmental bacterial strains may allow novel resistance mechanisms to be identified before they appear in pathogenic strains. Gap StatementSearching for antimicrobial resistance genes in environmental bacteria represents an understudied research area compared to resistance within clinically relevant pathogens. AimTo evaluate resistance genes present within environmental non-aeruginosa Pseudomonas spp. isolates. MethodologyWe screened a set of bacterial isolates from untreated wastewater from Liverpool, UK, for the presence of extended spectrum {beta}-lactamases and carbapenemases. A sub-set of three resistant Pseudomonas spp. isolates were selected for whole-genome sequencing. We performed minimum inhibitory concentration assays against several {beta}-lactams, and ectopic expression of four novel resistance genes within Escherichia coli. ResultsHere, we report the discovery of novel class C {beta}-lactamase genes blaPFL7, blaPFL8 and blaPFL9, as well as a novel subclass B2 metallo-{beta}-lactamase blaPFM5 present within these strains. The class C genes encoded proteins with between 61-71% amino acid identity to the closest known match, blaPFL-1. These novel {beta}-lactamases degraded the cephalosporin nitrocefin and confer piperacillin and ceftazidime resistance to susceptible Escherichia coli when ectopically expressed. The {beta}-lactamase inhibitor tazobactam was effective at inhibiting these enzymes. The sub-class B2 metallo-{beta}-lactamase had 88% amino acid identity to its closet match blaPFM-1 and conferred carbapenem resistance to susceptible E. coli. The {beta}-lactamase inhibitors relebactam, vaborbactam, xeruborbactam and captopril had no impact on the carbapenem resistance phenotype. Analogues of all these novel genes (>95% nucleotide sequence identity) were identified within publicly available whole-genome sequencing data, suggesting they are found sporadically. ConclusionOur analysis adds to the growing number of {beta}-lactamase genes found from environmental Pseudomonas spp. and suggests that continued surveillance of this environmental reservoir for novel, clinically relevant, {beta}-lactamase genes is warranted.

microbiology↗

Remdesivir-Ivermectin combination displays synergistic interaction with improved in vitro antiviral activity against SARS-CoV-2

A key element for the prevention and management of COVID-19 is the development of effective therapeutics. Drug combination strategies of repurposed drugs offer several advantages over monotherapies, including the potential to achieve greater efficacy, the potential to increase the therapeutic index of drugs and the potential to reduce the emergence of drug resistance. Here, we report on the in vitro synergistic interaction between two FDA approved drugs, remdesivir and ivermectin resulting in enhanced antiviral activity against SARS-CoV-2. These findings warrant further investigations into the clinical potential of this combination, together with studies to define the underlying mechanism.

microbiology↗