Biology subjects

Gilchrist, M.

Publications and source records attributed to Gilchrist, M..

7 recordsLinked to original sources

bioRxiv2025

Conserved roles of GATA4 and its target gene TBX2 in regulation of human cardiogenesis

The transcription factor (TF) GATA4 is a key mediator of cardiogenesis. GATA4 regulates cardiogenesis through the expression of its target genes, only some of which have been identified. We have used a gain of function model based on pluripotent embryonic ectoderm explants from Xenopus embryos expressing GATA4, to identify a set of downstream targets of GATA4 which are also regulated by Nodal, a known cardiogenic signal. GATA4 was shown to be required for the expression of target genes tbx2 and prdm1 in vivo, likely acting in a direct fashion by interacting with their regulatory regions. In addition, tbx2 and prdm1 are shown to have roles of their own in vivo, as downregulation of tbx2, a positive target, and overexpression of prdm1, a negative target, interferes with cardiac development in Xenopus embryos. The conservation of the GATA4-TBX2-PRDM1 regulatory relationship was shown in human iPSC-derived cardiomyocytes. Loss of function of GATA4 lead to downregulation of TBX2, upregulation of PRDM1 expression and failure of cardiogenesis. GATA4-deficient cells failed to form normal cardiomyocytes, with most cells adopting alternative fates and only a small minority expressing an aberrant cardiomyocyte phenotype. Genome-wide transcriptomic analysis documented severe reduction of cardiomyocyte and endothelial cell transcriptomes and upregulation of transcriptional profiles of smooth muscle cells and fibroblasts. Disruption of TBX2 function did not alter cardiomyocyte differentiation efficiency but led to the formation of hypertrophic cardiomyocytes characterised by defective sarcomeres and deficient calcium signalling. In addition, we show that whilst PRDM1 is not essential for formation of cardiomyocytes it is implicated in suppression of alternative cell fates. The results presented establish a conserved regulatory relationship between GATA4 and its target genes TBX2 and PRDM1 and roles for these genes in the modulation of cardiomyocyte development, expanding the cardiac gene regulatory network and providing further insight into how cardiogenesis proceeds.

developmental biology↗

bioRxiv2025

Effects of aging on upper body express visuomotor responses while reaching under varying postural demands

Humans can react remarkably quickly to novel or displaced visual stimuli when time is of the essence. Such movements are thought to be initiated by a subcortical fast visuomotor network, but it is unclear how this network declines with age. Past work in the upper limb has detailed delayed reaching corrections to jumped visual stimuli in the elderly, but the underlying mechanisms contributing to these changes of the fast visuomotor network are poorly understood. Conversely, work in the lower limb has reported delayed muscle recruitment during obstacle avoidance, but such findings may be confounded by age-related challenges in postural control. The output of the fast visuomotor network can be quantified by measuring express visuomotor responses (EVRs), which are the earliest and very short-latency bursts of muscle activity that follow visual target presentation. Here, we compare the prevalence, latency, and magnitude of EVRs in elderly (58-80 years old) and younger (18-25 years old) participants performing visually-guided reaches. We also investigated the impact of postural stability by having participants reach either while seated on a stable chair, or on a wobble stool. Both the elderly and younger cohorts expressed EVRs, but EVRs in the elderly were comparatively less frequent, and had longer latencies and smaller magnitude. Postural instability had no effects on these outcomes. Our results suggest age-related declines in the fast visuomotor network, potentially resulting from deterioration of underlying circuits and a prioritization of stability over speed. This study serves as an important standard for future research investigating clinical populations. HighlightsO_LIDo aging and postural stability affect express visuomotor responses (EVRs)? C_LIO_LIEVRs were recorded from the pectoralis muscle during rapid goal-directed reaches C_LIO_LIEVRs were smaller and delayed, and movement was slower, in elderly participants C_LIO_LIAge-related differences were independent of our postural stability manipulation C_LIO_LIOur results suggest age-related declines of the fast visuomotor network C_LI

neuroscience↗

bioRxiv2024

Parkinson's Disease affects the contextual control, but not the expression, of a rapid visuomotor response that initiates visually-guided reaching: Evidence for multiple, interacting motor pathways and implications for motor symptoms in Parkinson's Disease

Despite significant deficits in voluntary motor control, patients with Parkinsons disease (PD) can generate reflexive or stimulus-driven movements. How are such spared capabilities realized? Here, we recorded upper limb muscle activity in patients with PD and age-matched healthy controls (HCs) as they reached either toward or away from a visual stimulus. The task promoted express visuomotor responses (EVRs), which are brief bursts of muscle recruitment time-locked (<100 ms) to stimulus presentation that are thought to originate from the midbrain superior colliculus. Across two experiments, we observed a remarkable sparing of the latency and magnitude of EVRs in patients with PD, but a decreased ability for patients with PD to contextually modulate the EVR depending on trial instruction. EVR Magnitudes were strikingly strongly correlated with PD Reaction times and Error rates, despite compromised levels of electromyographic (EMG) recruitment in subsequent phases of muscle activity, which predicted lower Peak velocities. Our results are consistent with a differential influence of PD on parallel-but-interacting subcortical and cortical pathways that converge onto brainstem and spinal circuits during reaching. This differential influence is discriminable even within a single trial in the selective sparing of stimulus-aligned but not movement-aligned muscle recruitment, and has implications for our understanding of the motor and cognitive deficits seen in PD.

neuroscience↗

bioRxiv2020

A spatially-explicit model of stabilizing selection for improving phylogeneticinference

Ultraconserved elements (UCEs) are stretches of hundreds of nucleotides with highly conserved cores flanked by variable regions. Although the selective forces responsible for the preservation of UCEs are unknown, they are nonetheless believed to contain phylogenetically meaningful information from deep to shallow divergence events. Phylogenetic applications of UCEs assume the same degree of rate heterogeneity applies across the entire locus, including variable flanking regions. We present a Wright-Fisher model of selection on nucleotides (SelON) which includes the effects of mutation, drift, and spatially varying, stabilizing selection for an optimal nucleotide sequence. The SelON model assumes the strength of stabilizing selection follows a position dependent Gaussian function whose exact shape can vary between UCEs. We evaluate SelON by comparing its performance to a simpler and spatially invariant GTR+{Gamma} model using an empirical dataset of 400 vertebrate UCEs used to determine the phylogenetic position of turtles. We observe much improvement in model fit of SelON over the GTR+{Gamma} model, and support for turtles as sister to lepidosaurs. Overall, the UCE specific parameters SelON estimates provide a compact way of quantifying the strength and variation in selection within and across UCEs. SelON can also be extended to include more realistic mapping functions between sequence and stabilizing selection as well as allow for greater levels of rate heterogeneity. By more explicitly modeling the nature of selection on UCEs, SelON and similar approaches can be used to better understand the biological mechanisms responsible for their preservation across highly divergent taxa and long evolutionary time scales.

evolutionary biology↗

bioRxiv2019

Evaluating a digital sepsis alert in a London multi-site hospital network: a natural experiment using electronic health record data

ObjectiveTo determine the impact of a digital sepsis alert on patient outcomes in a UK multi-site hospital network.\n\nMethodsA natural experiment utlising the phased introduction of a digital sepsis alert into a multi-site hospital network. Sepsis alerts were either visible to clinicans (the intervention group) or running silently and not visible (the control group). Inverse probability of treatment weighted multivariable logistic regression was used to estimate the effect of the intervention on patient outcomes.\n\nOutcomes: In-hospital 30-day mortality (all inpatients), prolonged hospital stay ([≥]7 days) and timely antibiotics ([≤]60 minutes of the alert) for patients who alerted in the Emergency Department.\n\nResultsThe introduction of the alert was associated with lower odds of death (OR:0.76; 95%CI:(0.70, 0.84) n=21,183); lower odds of prolonged hospital stay [≥]7 days (OR:0.93; 95%CI:(0.88, 0.99) n=9988); and in patients who required antibiotics, an increased odds of receiving timely antibiotics (OR:1.71; 95%CI:(1.57,1.87) n=4622).\n\nDiscussionCurrent evidence that digital sepsis alerts are effective is mixed. In this large UK study a digital sepsis alert has been shown to be associated with improved outcomes, including timely antibiotics, which may suggest a causal pathway. It is not known whether the presence of alerting is responsible for improved outcomes, or whether the alert acted as a useful driver for quality improvement initiatives.\n\nConclusionsThese findings strongly suggest that the the introduction of a network-wide digital sepsis alert is associated with improvements in patient outcomes, demonstrating that digital based interventions can be successfully introduced and readily evaluated.\n\nFundingImperial NIHR Biomedical Research Centre: NIHR-BRC-P68711.

epidemiology↗

bioRxiv2017

Measuring Selection Across HIV Gag: Combining Physico-Chemistry and Population Genetics

We present physico-chemical based model grounded in population genetics. Our model predicts the stationary probability of observing an amino acid residue at a given site. Its predictions are based on the physico-chemical properties of the inferred optimal residue at that site and the sensitivity of the proteins functionality to deviation from the physico-chemical optimum at that site. We contextualize our physico-chemical model by comparing our model fit and parameters it to the more general, but less biologically meaningful entropy based metric: site sensitivity or 1/E. We show mathematically that our physico-chemical model is a more restricted form of the entropy model and how 1/E is proportional to the log-likelihood of a parameter-wise saturated model. Next, we fit both our physico-chemical and entropy models to sequences for subtype Cs Gag poly-protein in the LANL HIV database. Comparing our models site sensitivity parameters G' to 1/E we find they are highly correlated. We also compare the ability of G', 1/E, and other indirect measures of HIV fitness to empirical in vitro and in vivo measures. We find G' does a slightly better job predicting empirical fitness measures of in vivo viral escape time and in vitro spreading rates. While our predictive gain is modest, our model can be modified to test more complex or alternative biological hypotheses. More generally, because of its explicit biological formulation, our model can be easily extended to test for stabilizing vs. diversifying selection. We conjecture that our model could also be extended include epistasis in a more realistic manner than Ising models, while requiring many fewer parameters than Potts models.

evolutionary biology↗

bioRxiv2017

Population Genetics Based Phylogenetics Under Stabilizing Selection for an Optimal Amino Acid Sequence: A Nested Modeling Approach

We present a new phylogenetic approach SelAC (Selection on Amino acids and Codons), whose substitution rates are based on a nested model linking protein expression to population genetics. Unlike simpler codon models which assume a single substitution matrix for all sites, our model more realistically represents the evolution of protein coding DNA under the assumption of consistent, stabilizing selection using cost-benefit approach. This cost-benefit approach allows us generate a set of 20 optimal amino acid specific matrix families using just a handful of parameters and naturally links the strength of stabilizing selection to protein synthesis levels, which we can estimate. Using a yeast dataset of 100 orthologs for 6 taxa, we find SelAC fits the data much better than popular models by 104-105 AICc units. Our results indicate there is great potential for more accurate inference of phylogenetic trees and branch lengths from already existing data through the use of nested, mechanistic models. Additional parameters estimated by SelAC indicate that a large amount of non-phylogenetic, but biologically meaningful, information can be inferred from exisiting data. For example, SelAC prediction of gene specific protein synthesis rates correlates well with both empirical (r=0.33-0.48) and other theoretical predictions (r=0.45-0.64) for multiple yeast species. SelAC also provides estimates of the optimal amino acid at each site. Finally, because SelAC is a nested approach based on clearly stated biological assumptions, future modifications, such as including shifts in the optimal amino acid sequence within or across lineages, are possible.

evolutionary biology↗