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M Pearson

Publications and source records attributed to M Pearson.

10 recordsLinked to original sources
PubMed2025

Reproducibility of genetic risk factors identified for long COVID using combinatorial analysis across US and UK patient cohorts with diverse ancestries.

BACKGROUND: Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence, staggering cost, severe impact on patients' lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (>&#x2009;91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population. METHODS: We assessed the reproducibility of the 5343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure. RESULTS: For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77-83%, p&#x2009;<&#x2009;0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study. CONCLUSION: These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual's susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease. This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

Humans↗
PubMed1992

Structural diversity in the extracellular faces of peptidergic G-protein-coupled receptors. Molecular cloning of the mouse C5a anaphylatoxin receptor.

The mouse C5a receptor gene was isolated using the human C5a receptor cDNA probe recently described (Gerard, N. P., and C. Gerard. 1991. Nature 349:614). By analogy with the human gene, the mouse homolog contains two exons with the 5' untranslated region and initiating methionine codon present in exon 1 and the remainder of the molecule in exon 2. Generation of an expressible cDNA for the mouse C5a receptor was accomplished using the polymerase chain reaction and a sense oligodeoxynucleotide primer which included an initiation codon just 5' to the sequence encoding the N-linked glycosylation site. When transfected into human 293 kidney epithelial cells the cloned cDNA directs expression of a binding site for human C5a anaphylatoxin with a binding constant of 2.5 +/- 0.3 nM; the human C5a receptor expressed under identical conditions has a Kd of 1.7 +/- 0.2 nM. Overall, the deduced amino acid sequences of the receptors are 65% identical given the analogous gene structures. Alignment of the sequences as seven transmembrane segment receptors reveals that the greatest structural diversity (approximately 70%) exists in the putative extracellular domains. In contrast, species differences among other members of this family of seven membrane-spanning receptors is generally only 10 to 20%, even for receptors whose ligands are relatively small and not expected to interact with sites on the extracellular surfaces. A high degree of structural identify is observed for the C5a receptors in the transmembrane segments and in all but one of the loops predicted to exist in the cytoplasm. Inasmuch as critical structures responsible for high affinity binding of the 74 amino acid polypeptide to both C5a receptors involve features conserved between species, these data provide the starting point for mutagenesis studies to determine the nature of the binding and activation sites for the chemotactic receptors. Additionally, these data provide a reagent for immunologic and molecular genetic studies on the role of C5a receptors in inflammatory models.

Amino Acid Sequence↗
PubMed1992

The Autographa californica baculovirus genome: evidence for multiple replication origins.

The Autographa californica multinucleocapsid nuclear polyhedrosis virus (AcMNPV), which is used for the overexpression of eukaryotic genes and is being engineered for possible use as a viral insecticide, has a circular, supercoiled genome of approximately 128 kilobases. Despite its widespread use, little is known about the mechanism by which AcMNPV replicates. Evidence is presented in this report that AcMNPV origins of DNA replication are repeated sequences each containing several closely related imperfect palindromes that are present in six regions distributed around the genome. Although AcMNPV infection-dependent plasmid replication was initiated by a single complete palindrome, the amount of replication was substantially increased in plasmids containing six or eight palindromes.

Baculoviridae↗
PubMed1979

Somitogenesis in amphibian embryos. I. Experimental evidence for an interaction between two temporal factors in the specification of somite pattern.

Somitogenesis is described in two species of anuran amphibians, Xenopus laevis and Rana temporaria, in which the cellular mechanics of somite formation are distinctly different. Heat shocks are employed to demonstrate a wave of cellular change which precedes somite formation down the body axis. This prior wave is shown to be kinematic. It is not a propagated wave. It is a consequence of the temporal activities of the cells laid out in space, but there is no evidence that these activities depend upon an interpretation of their position. Heat shocks cause characteristic segmental abnormalities over a zone of somites which is formed several hours after the shock. Evidence from double heat shock experiments suggests that the pattern of abnormality is the result of (i) a disturbance of co-ordination between pre-somitic cells, and (ii) the time available to those cells for recovery before they are recruited into a segmental pre-pattern at the time of passage of the prior wave. It is a temporal co-ordination that is disturbed and subsequently recovered following a heat shock. This temporal co-ordination of pre-somitic cells does not depend upon position along the axis. The evidence for two physiologically independent temporal patterns of cellular processes, which interact to specify the segmental pattern of somites (their size, shape and number), gives experimental support for the theoretical account of somitogenesis proposed by Cooke & Zeeman (1976).

Animals↗
PubMed1979

Somitogenesis in amphibia. II. Origins in early embryogenesis of two factors involved in somite specification.

A somite pre-pattern is established shortly before visible segmentation. The pre-pattern results from the interaction of two components: a wave of cell behavioural change that passes along the axis, and, an underlying co-ordination of the cells that is the basis for their association into large somite-sized groupings. The evidence is derived from studies of the zones of abnormal segmentation that follow temperature shocks delivered between the neurula and tail-bud stages (Pearson & Elsdale, 1979). Temperature shock given earlier at the mid-gastrula stage is however ineffective in inducing abnormalities in somitogenesis. Shocks given before the mid-gastrula stage reveal a prior period of sensitivity stretching back into the blastula. Thus early and late sensitive periods can be defined separated by a short refactory period. Quite different patterns in the distribution of somite abnormalities characterize the results of shock during the two sensitive periods, suggesting different aetiologies. It is concluded that the wave of rapid cell change is set up early in embryogenesis during the blastula stage, and each cell of the prospective paraxial mesoderm carries a determination to change after a specific length of time, i.e. a countdown is set in each cell. As a result of the movements of gastrulation, the prospective paraxial mesoderm cells become laid out along the axis of the neurula in the order (antero-posterior sequence) in which they will change. The achievement of the correct redistribution of the cells depends crucially on the conservation of the sequence in the blastula by the maintenance of topological integrity throughout gastrulation. It is suggested that early shock disturbs gastrulation movements, causing some mixing up of the cells resulting in incoherence of the wavefront. Whereas early shocks are thus assumed to affect the wave, the evidence suggests that late shock undergoes co-ordination. It is concluded therefore that co-ordination is established later, after the refractory period, around the late gastrula stage.

Animals↗
PubMed1977

Effect of oil composition on both adjuvant-induced arthritis and delayed hypersensitivity to purified protein derivative and peptidoglycans in various rat strains.

We confirmed that, when immunized with a conventional complete Freund adjuvant (water in oil), Lewis rats were highly susceptible to adjuvant arthritis, Fisher rats were less susceptible, and Buffalo rats were much less susceptible. However, mycobacterial delipidated cells in squalane (squalane-type adjuvant) produced severe arthritis with almost 100% incidence even in the less susceptible rat strains except for Buffalo rats. With regard to an immune response, Freund complete adjuvant induced strong delayed hypersensitivity to purified protein derivative (PPD) and peptidoglycan (PG) in all rat strains used, Whereas the squalane-type adjuvant induced these hypersensitivities only in Lewis and Buffalo rats, but not in Fisher and Brown Norway rats. No correlation was found between development of arthritis and delayed hypersensitivity to either PPD or PG, or both. It seems that PPD hypersensitivity may be inherited differently from PG hypersensitivity.

Animals↗
PubMed1977

Mitral regurgitation in coronary heart disease.

Mitral reguritation is a relatively common finding in coronary heart disease. In this series of 127 patients, selected with a view to coronary or left ventricular surgery on the basis of severity of symptoms, the incidence was 39 (31%). Mitral regurgitation is significantly more common in patients with a history or electrocardiographic evidence of previous myocardial infarction. Clinically it may present as a pan- or late systolic or even a mid-systolic, ejection type murmur at the apex or at the left sternal edge; but in 39 per cent of the patients with angiographic mitral regurgitation no murmur was present. Angiographically important mitral regurgitation (grades 2-4/4) was usually associated with a systolic murmur; this finding was independent of ejection fractions. Left ventricular enlargement clinically or radiographically is likely to accompany mitral regurgitation but left atrial enlargement (electrocardiographically or on chest x-ray) is a more reliable pointer to mitral regurgitation and pulmonary venous hypertension is even more strongly suggestive of its presence. The electrocardiographic signs of papillary muscle infarction were rare in this series (15%) and were not related to angiographic mitral regurgitation. There was no difference in the incidence of mitral regurgitation in association with anterior or inferior myocardial infarction or in distribution of coronary artery disease. There is, however, a higher incidence of mitral regurgitation in more severe coronary arterial disease (P less than 0-05). The incidence of mitral regurgitation is significantly higher with reduction in left ventricular ejection fraction (P less than 0-001), with rise in the left ventricular end-diastolic pressure (P less than 0-02), and with abnormal contraction patterns, but the severity of mitral regurgitation is not significantly related to these findings.

Adult↗
PubMed1976

Abnormalities in somite segmentation following heat shock to Xenopus embryos.

The typical abnormality induced by a 15 min shock at 37degreesC is a single discrete length along the somite file within which segmental boundaries are absent or irregular. The two sides of the same embryo present a similar but not necessarily identical appearance. Usually all the embryos in a treated batch show abnormalities of similar severity. Survival of treated embryos, the details of the visible malformations, and temporal aspects of the phenomenon have been studied. The results indicate a temperature sensitive period that traverses the neurula, from head to tail at about the same rate as the somites form, but some hours beforehand. The temperature sensitive process is not associated with cell determination and differentiation, and there are reasons for thinking that the specification of the normal somite number occurs independently. The results are discussed in relation to Cooke & Zeeman's model of a wave front interacting with an oscillator.

Animals↗