Evolution of cytokine production capacity in ancient and modern European populations
In this study we built polygenic scores for heritable traits that influence the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increase...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Genetics and Genomics Immunology and Inflammation Source Type: research
Structural variability and concerted motions of the T cell receptor - CD3 complex
We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined byDong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15 ° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the C_ FG loop of the TCR, ...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research
Endothelial Pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure in mice
Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates of endothelial TRPV4 channels. We hypothesized that endothelial Panx1-ATP-TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress in...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research
Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
Over the past two decades, several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been isolated. Structural and biochemical characterization of these bnAbs has provided molecular insight into how they bind distinct antigens. However, our understanding of the evolutionary pathways leading to bnAbs, and thus how best to elicit them, remains limited. Here, we measure equilibrium dissociation constants of combinatorially complete mutational libraries for two naturally isolated influenza bnAbs (CR9114, 16 heavy-chain mutations; CR6261, 11 heavy-chain mutations), reconstruct...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research
The evolution of strategy in bacterial warfare via the regulation of bacteriocins and antibiotics
Bacteria inhibit and kill one another with a diverse array of compounds, including bacteriocins and antibiotics. These attacks are highly regulated, but we lack a clear understanding of the evolutionary logic underlying this regulation. Here, we combine a detailed dynamic model of bacterial competition with evolutionary game theory to study the rules of bacterial warfare. We model a large range of possible combat strategies based upon the molecular biology of bacterial regulatory networks. Our model predicts that regulated strategies, which use quorum sensing or stress responses to regulate toxin production, will readily e...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research
The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA Recognition Motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mR...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research
Ancient role of sulfakinin/cholecystokinin-type signalling in inhibitory regulation of feeding processes revealed in an echinoderm
Sulfakinin (SK)/cholecystokinin (CCK)-type neuropeptides regulate feeding and digestion in protostomes (e.g. insects) and chordates. Here, we characterised SK/CCK-type signalling for the first time in a non-chordate deuterostome – the starfishAsterias rubens (phylum Echinodermata). In this species, two neuropeptides (ArSK/CCK1, ArSK/CCK2) derived from the precursor protein ArSK/CCKP act as ligands for an SK/CCK-type receptor (ArSK/CCKR) and these peptides/proteins are expressed in the nervous system, digestive system, tube feet, and body wall. Furthermore, ArSK/CCK1 and ArSK/CCK2 cause dose-dependent contraction of cardi...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research
A simple regulatory architecture allows learning the statistical structure of a changing environment
Bacteria live in environments that are continuously fluctuating and changing. Exploiting any predictability of such fluctuations can lead to an increased fitness. On longer timescales, bacteria can ‘learn’ the structure of these fluctuations through evolution. However, on shorter timescales, inferring the statistics of the environment and acting upon this information would need to be accomplished by physiological mechanisms. Here, we use a model of metabolism to show that a simple generali zation of a common regulatory motif (end-product inhibition) is sufficient both for learning continuous-valued features of the stat...
Source: eLife - September 7, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Physics of Living Systems Source Type: research
Motor planning under uncertainty
Actions often require the selection of a specific goal amongst a range of possibilities, like when a softball player must precisely position her glove to field a fast-approaching ground ball. Previous studies have suggested that during goal uncertainty the brain prepares for all potential goals in parallel and averages the corresponding motor plans to command an intermediate movement that is progressively refined as additional information becomes available. Although intermediate movements are widely observed, they could instead reflect a neural decision about the single best action choice given the uncertainty present. Her...
Source: eLife - September 6, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome
The chromatin remodeler ALC1 is recruited to and activated by DNA damage-induced poly(ADP-ribose) (PAR) chains deposited by PARP1/PARP2/HPF1 upon detection of DNA lesions. ALC1 has emerged as a candidate drug target for cancer therapy as its loss confers synthetic lethality in homologous recombination-deficient cells. However, structure-based drug design and molecular analysis of ALC1 have been hindered by the requirement for PARylation and the highly heterogeneous nature of this post-translational modification. Here, we reconstituted an ALC1 and PARylated nucleosome complex modifiedin vitro using PARP2 and HPF1. This comp...
Source: eLife - September 6, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Structural Biology and Molecular Biophysics Source Type: research
Information content differentiates enhancers from silencers in mouse photoreceptors
Enhancers and silencers often depend on the same transcription factors (TFs) and are conflated in genomic assays of TF binding or chromatin state. To identify sequence features that distinguish enhancers and silencers, we assayed massively parallel reporter libraries of genomic sequences targeted by the photoreceptor TF CRX in mouse retinas. Both enhancers and silencers contain more TF motifs than inactive sequences, but relative to silencers, enhancers contain motifs from a more diverse collection of TFs. We developed a measure of information content that describes the number and diversity of motifs in a sequence and foun...
Source: eLife - September 6, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Genetics and Genomics Source Type: research
Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines
In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1,299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-t...
Source: eLife - September 6, 2021 Category: Biomedical Science Tags: Cancer Biology Computational and Systems Biology Source Type: research
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids
Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterised endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epit...
Source: eLife - September 6, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research
HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain
Aberrant liquid-to-solid phase transitions of biomolecular condensates have been linked to various neurodegenerative diseases. However, the underlying molecular interactions that drive aging remain enigmatic. Here, we develop quantitative time-resolved crosslinking mass spectrometry to monitor protein interactions and dynamics inside condensates formed by the protein fused in sarcoma (FUS). We identify misfolding of the RNA recognition motif (RRM) of FUS as a key driver of condensate ageing. We demonstrate that the small heat shock protein HspB8 partitions into FUS condensates via its intrinsically disordered domain and pr...
Source: eLife - September 6, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research
Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease
Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified. (Source: eLife)
Source: eLife - September 6, 2021 Category: Biomedical Science Tags: Medicine Source Type: research
