Biomedical subjects

Caroline Davies

Publications and source records attributed to Caroline Davies.

7 recordsLinked to original sources

PubMed2025

Integrative genomics elucidates the evolutionary, temporal, and developmental origins of a hydrocephalus risk gene.

INTRODUCTION: A prior integrative, multi-omics human genetics and functional genomics study identified maelstrom (MAEL), a gene involved in regulation of DNA transposon activity and genome structure, as a transcriptome-wide predictor of hydrocephalus (HC) in the brain cortex. Here we expand on this discovery and further characterize the evolutionary origin and expression of MAEL across developmental timescales and cell-lineages in the neonatal human brain towards a mechanistic understanding how variation in MAEL expression may cause HC. OBJECTIVE: To characterize the evolutionary, temporal, developmental, and lineages of MAEL expression in HC and the developing human brain. METHODS: Ensembl was used to delineate the evolution and taxonomy of MAEL across species. Analysis of single-cell RNA sequencing (scRNA-seq) of 49 brain regions across pre- and post-natal timescales from the Developing Human Brain Atlas (Allen Institute) identified temporal and spatial MAEL expression patterns. We quantified MAEL expression in primary cortical brain tissue obtained during the surgical treatment of HC. RESULTS: We performed taxonomic gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in vitro and in vivo across species. We find that MAEL is among the top 0.01% human-specific genes and < 50% sequence homology among commonly used model organisms with highly divergent functions, necessitating mechanistic validation in human tissue. scRNA-seq of the non-disease prenatal human brain identified MAEL expression enriched in cortical excitatory neurons, which was recapitulated in primary HC brain tissue obtained during surgery. Finally, using scRNA-seq of primary HC brain tissue, we functionally validated reduced MAEL expression, consistent with a prior human TWAS analysis. CONCLUSIONS: We identify the evolutionary, temporal, and developmental expression pattern of MAEL in the neonatal human brain. We also provide direct evidence for reduced MAEL expression in human HC brain tissue. These data, at least in part, implicate reduced MAEL expression underlying human HC across etiologies.

Journal Article↗

PubMed2006

Distinct subdomain organization and molecular composition of a tight junction with adherens junction features.

Most polarized epithelia constrain solute diffusion between luminal and interstitial compartments using tight junctions and generate mechanical strength using adherens junctions. These intercellular junctions are typically portrayed as incongruent macromolecular complexes with distinct protein components. Herein, we delineate the molecular composition and subdomain architecture of an intercellular junction between sensory and non-sensory cells of the inner ear. In this junction, claudins partition into claudin-14 and claudin-9/6 subdomains that are distinguishable by strand morphology, which contrasts with in vitro data that most claudins co-assemble into heteromeric strands. Surprisingly, canonical adherens junction proteins (p120ctn, alpha- and beta-catenins) colocalize with the claudin-9/6 subdomain and recruit a dense cytoskeletal network. We also find that catenins colocalize with claudin-9 and claudin-6, but not claudin-14, in a heterologous system. Together, our data demonstrate that canonical tight junction and adherens junction proteins can be recruited to a single junction in which claudins partition into subdomains and form a novel hybrid tight junction with adherens junction organization.

Actins↗

PubMed2006

Acting the part.

The implementation of two key policies highlighted the need to support nurses and midwives to challenge colleagues effectively. To overcome the difficulties this presented, an innovative training package using drama provided participants with practical tips and a safe environment to practise newly developed skills. The programme was well evaluated but further work needs to be undertaken to evaluate its impact upon practice.

Drama↗

PubMed2004

Deafness in Claudin 11-null mice reveals the critical contribution of basal cell tight junctions to stria vascularis function.

Generation of a strong electrical potential in the cochlea is uniquely mammalian and may reflect recent evolutionary advances in cellular voltage-dependent amplifiers. This endocochlear potential is hypothesized to dramatically improve hearing sensitivity, a concept that is difficult to explore experimentally, because manipulating cochlear function frequently causes rapid degenerative changes early in development. Here, we examine the deafness phenotype in adult Claudin 11-null mice, which lack the basal cell tight junctions that give rise to the intrastrial compartment and find little evidence of cochlear pathology. Potassium ion recycling is normal in these mutants, but endocochlear potentials were below 30 mV and hearing thresholds were elevated 50 dB sound pressure level across the frequency spectrum. Together, these data demonstrate the central importance of basal cell tight junctions in the stria vascularis and directly verify the two-cell hypothesis for generation of endocochlear potential. Furthermore, these data indicate that endocochlear potential is an essential component of the power source for the mammalian cochlear amplifier.

Animals↗

PubMed2004

An actin molecular treadmill and myosins maintain stereocilia functional architecture and self-renewal.

We have previously shown that the seemingly static paracrystalline actin core of hair cell stereocilia undergoes continuous turnover. Here, we used the same approach of transfecting hair cells with actin-green fluorescent protein (GFP) and espin-GFP to characterize the turnover process. Actin and espin are incorporated at the paracrystal tip and flow rearwards at the same rate. The flux rates (approximately 0.002-0.04 actin subunits s(-1)) were proportional to the stereocilia length so that the entire staircase stereocilia bundle was turned over synchronously. Cytochalasin D caused stereocilia to shorten at rates matching paracrystal turnover. Myosins VI and VIIa were localized alongside the actin paracrystal, whereas myosin XVa was observed at the tips at levels proportional to stereocilia lengths. Electron microscopy analysis of the abnormally short stereocilia in the shaker 2 mice did not show the characteristic tip density. We argue that actin renewal in the paracrystal follows a treadmill mechanism, which, together with the myosins, dynamically shapes the functional architecture of the stereocilia bundle.

Actins↗

PubMedDate not supplied

A national audit of chronic constipation in the community.

This article presents the first available data on current national bowel-care standards. It involves 923 patients based at home or in residential/nursing homes. The baseline findings indicate problems of poorly controlled constipation, a high level of impaction and high use of rectal interventions. All the patients have been receiving laxatives regularly and 42 per cent were on combination laxative therapy. The audit provides evidence of complex, ineffective and/or inappropriate laxative prescribing linked to sub-optimal bowel care.

Aged↗

PubMedDate not supplied

The use of phosphate enemas in the treatment of constipation.

Phosphate enemas are commonly used by community nurses in the treatment of constipation. This article reports on a literature review of evidence relating to their use. No evidence was found to support the use of these enemas conclusively, although a number of articles reported risks, contraindications, and complications. Phosphate enemas should therefore be used with caution and nurses should be aware of the contraindications associated with their use.

Cathartics↗