Biology subjects

Harris, N. S.

Publications and source records attributed to Harris, N. S..

5 recordsLinked to original sources

bioRxiv2024

MEK1/2 and ERK1/2 mediated lung endothelial injury and altered hemostasis promote diffuse alveolar hemorrhage in murine lupus

ObjectiveAbout 3% of lupus patients develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. B6 mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of TLR signaling and other inflammatory pathways. This study examined the role of the mitogen-activated protein kinase pathway (MEK1/2-ERK1/2, JNK, p38). MethodsB6 and BALB/c mice were treated with pristane {+/-} inhibitors of MEK1/2 (trametinib/GSK1120212, "GSK"), ERK1/2 (SCH772984, "SCH"), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined. ResultsGSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung from pristane-treated mice, but not mice receiving pristane+GSK and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factor Egr1 increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes Tfpi (tissue factor pathway inhibitor) and Thbd (thrombomodulin) in B6 mice. The ratio of tissue factor (F3) to Tfpi increased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating Thbd protein increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice. ConclusionPristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in SLE and may help to optimize therapy.

immunology↗

bioRxiv2020

Sharing of weak signals of positive selection across the genome

Selection in humans often leaves subtle signatures at individual loci. Few studies have measured the extent to which these signals are shared among human populations. Here a new method is developed to compare weak signals of selection in aggregate across the genome using the 1000 Genomes Phase 3 Data. Results presented here show that selection producing weak selection serves to increase population differences around coding areas of the genome.

genomics↗

bioRxiv2020

Genomic regions linked to soft sweeps approximate neutrality when inferring population history from site pattern frequencies

Recent studies have suggested that selection is widespread throughout the genome and largely uncompensated for in inferences of population history. To address this potential issue, we estimated site pattern frequencies for neutral and selection associated areas of the genome. There are notable differences in these frequencies between neutral regions and those affected by selection. However, these differences have relatively small effects when inferring population history.

genomics↗

bioRxiv2020

Detecting shared independent selection

Signals of selection are not often shared between populations. When a mutual signal is detected, it is often not known if selection occurred before or after populations split. Here we develop a method to detect genomic regions at which selection has favored different haplotypes in two populations. This method is verified through simulations and tested on small regions of the genome. This method was then expanded to scan the phase 3 genomes of the 1000 Genomes Project populations for regions in which the evidence for independent selection is strongest. We identify several genes which likely underwent selection independently in different populations.

genomics↗

bioRxiv2019

Neanderthal-Denisovan ancestors interbred with a distantly-related hominin

Previous research has shown that modern Eurasians interbred with their Neanderthal and Denisovan predecessors. We show here that hundreds of thousands of years earlier, the ancestors of Neanderthals and Denisovans interbred with their own Eurasian predecessors--members of a \"superarchaic\" population that separated from other humans about 2 mya. The superarchaic population was large, with an effective size between 20 and 50 thousand individuals. We confirm previous findings that: (1) Denisovans also interbred with superarchaics, (2) Neanderthals and Denisovans separated early in the middle Pleistocene, (3) their ancestors endured a bottleneck of population size, and (4) the Neanderthal population was large at first but then declined in size. We provide qualified support for the view that (5) Neanderthals interbred with the ancestors of modern humans.\n\nOne-sentence summaryWe document the earliest known interbreeding between ancient human populations and an expansion out of Africa early in the middle Pleistocene.

evolutionary biology↗