Biology subjects

Pickering, C.

Publications and source records attributed to Pickering, C..

6 recordsLinked to original sources

bioRxiv2026

Astroglial Dysfunction in Models of CDKL5 Deficiency Disorder

CDKL5 Deficiency Disorder (CDD) is a rare developmental epileptic encephalopathy typically caused by loss of function variants in the gene encoding the X-linked serine-threonine kinase CDKL5. CDKL5 is highly expressed in the brain during development, and key neuronal functions of the kinase include cytoskeletal organisation and synaptic stability. However, at present, little is known about the function of astroglia in CDD. Given the importance of these cells in synaptic development and homeostasis, as well as dysfunction in other epileptic diseases, it was hypothesised that astrocytes may contribute to CDD pathology. Induced pluripotent stem cells harbouring a CDKL5 loss-of-function mutation (and isogenic controls) were derived from CDD patient fibroblasts and differentiated into astrocytes (iAstros). Analysis of iAstros revealed transcriptomic, proteomic and functional dysregulation in CDKL5-mutant iAstros relating to water transport and immunological function, including a diminished response to TNF stimulation. Moreover, iAstros showed increased branching and reduced phosphorylation of the known CDKL5 target end-binding protein 2 (EB2) - indicative of disrupted cytoskeletal regulation in a manner similar to CDKL5-null neurons. Finally, we report the generation of novel in vitro models of CDD. CDKL5 was knocked down in adult and foetal human organotypic brain slices through transduction with an AAV encoding a novel CDKL5 shRNA. Slices transduced with the CDKL5 shRNA displayed increased spontaneous network activity, demonstrating the functionality of this model. Importantly, interrogation of these models revealed dysregulation of key astrocytic proteins congruous with the human glial stem cell model. Consequently, this study describes the generation of novel human models of CDD and their associated astrocytic dysfunction - paving the way for novel discovery and therapeutic intervention.

genetics↗

bioRxiv2022

A systematic review of the effects of recreation on mammals and birds in mountains: Insights and future research directions

Mountainous areas are popular destinations for outdoor recreation, which can have environmental impacts on wildlife. We assessed research studies about the impacts of recreation on mammals and birds in montane, subalpine and alpine zones using a systematic literature review methodology to identify trends and gaps. We found that research on this topic so far has concentrated on specific regions, seasons, infrastructure, activities and taxa. Most of the 67 articles revived were from Europe (52%) or Northern America (37%) and mainly from subalpine habitats (49%), focused on recreation infrastructure (51%) and mainly done either in summer (47%) or winter (25%). Research was not taxonomically representative but focused on cervids (Cervidae, 21%), bovids (Bovidae, 17%) and grouse (Phasianidae, 8%). It included few species of high conservation value. Almost all research (91%) found significant effects, which were predominantly negative (82%). Infrastructure, such as trails, had the most evidence for negative effects, followed by activities such as hiking and backcountry skiing. Much of the research looked at impacts at individual (42%) or population level (40%) responses, such as changes in behaviour or reductions in habitat, with limited research on communities (7%) or for popular activities such as mountain biking. We invite researchers to make use of emerging technologies, such as remote sensing, and to address research gaps including more regions, taxa and activities. Utilizing current research, land managers can implement more evidence-based strategies to minimise impacts of recreation and mitigate human-wildlife conflicts.

ecology↗

bioRxiv2022

Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants

The UK Biobank Pharma Proteomics Project (UKB-PPP) is a collaboration between the UK Biobank (UKB) and thirteen biopharmaceutical companies characterising the plasma proteomic profiles of 54,306 UKB participants. Here, we describe results from the first phase of UKB-PPP, including protein quantitative trait loci (pQTL) mapping of 1,463 proteins that identifies 10,248 primary genetic associations, of which 85% are newly discovered. We also identify independent secondary associations in 92% of cis and 29% of trans loci, expanding the catalogue of genetic instruments for downstream analyses. The study provides an updated characterisation of the genetic architecture of the plasma proteome, leveraging population-scale proteomics to provide novel, extensive insights into trans pQTLs across multiple biological domains. We highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement proteins, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug target discovery by extending the genetic proxied effect of PCSK9 levels on lipid concentrations, cardio- and cerebro-vascular diseases, and additionally disentangle specific genes and proteins perturbed at COVID-19 susceptibility loci. This public-private partnership provides the scientific community with an open-access proteomics resource of unprecedented breadth and depth to help elucidate biological mechanisms underlying genetic discoveries and accelerate the development of novel biomarkers and therapeutics.

genetics↗

bioRxiv2021

High Enhancer Activity is an Epigenetic Feature of HPV Negative Atypical Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.

cancer biology↗

bioRxiv2018

Dissociating time and number in reinforcement rate learning

Animals are highly sensitive to the temporal properties of predictive cues 1, a feature of learning unexplained by traditional trial-based associative theories of learning 2-4. It has been proposed that animals symbolically encode temporal durations in order to extract statistical information about events, such as the reinforcement rate during a cues presentation 5,6. Thus, long-duration cues elicit weaker responding than short-duration cues ( cue duration effect), because they signal a lower rate of reinforcement 7,8. An alternative, simple account is that time-dependent changes in stimulus processing, such as short-term habituation, lead to the effect of cue duration on learning 9,10, with attention decreasing throughout the duration of a cue, limitin ...

animal behavior and cognition↗

bioRxiv2017

A genetic-based algorithm for recovery: A pilot study

Exercise training creates a number of physical challenges to the body, the overcoming of which drives exercise adaptation. The balance between sufficient stress and recovery is a crucial, but often under-explored, area within exercise training. Genetic variation can also predispose some individuals to a greater need for recovery after exercise. In this pilot study, 18 male soccer players underwent a repeated sprint training session. Countermovement jump (CMJ) heights were recorded immediately pre-and post-training, and at 24-and 48-hours post-training. The reduction in CMJ height was greatest at all post-training time points in subjects with a larger number of gene variants associated with a reduced exercise recovery. This suggests that knowledge of genetic information can be important in individualizing recovery timings and modalities in athletes following training.

genetics↗