Concerted conformational dynamics and water movements in the ghrelin G protein-coupled receptor
There is increasing support for water molecules playing a role in signal propagation through G protein-coupled receptors (GPCRs). However, exploration of the hydration features of GPCRs is still in its infancy. Here, we combined site-specific labeling with unnatural amino acids to molecular dynamics to delineate how local hydration of the ghrelin receptor growth hormone secretagogue receptor (GHSR) is rearranged upon activation. We found that GHSR is characterized by a specific hydration pattern that is selectively remodeled by pharmacologically distinct ligands and by the lipid environment. This process is directly relate...
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research
Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells
This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way forin vivocochlear repair via SC transdifferentiation. (Source: eLife)
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research
Functional independence of endogenous µ- and δ-opioid receptors co-expressed in cholinergic interneurons
This study aims to evaluate possible functional interplay of endogenous µ- and d-Opioid receptors (MORs and DORs) in mouse neurons. Detecting GPCR dimers in native tissues however has been challenging. Previously, MORs and DORs co-expressed in transfected cells have been reported to form heterodimers, and their possible co-localization in neurons has been studied in kn ock-in mice expressing genetically engineered receptors fused to fluorescent proteins. Here we find that single cholinergic neurons in the mouse striatum endogenously express both MORs and DORs. The receptors on neurons from live brain slices were fluoresce...
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Inequalities in the distribution of National Institutes of Health research project grant funding
Previous reports have described worsening inequalities of National Institutes of Health (NIH) funding. We analyzed Research Project Grant data through the end of Fiscal Year 2020, confirming worsening inequalities beginning at the time of the NIH budget doubling (1998-2003), while finding that trends in recent years have reversed for both investigators and institutions, but only to a modest degree. We also find that career-stage trends have stabilized, with equivalent proportions of early-, mid-, and late-career investigators funded from 2017 to 2020. The fraction of women among funded PIs continues to increase, but they a...
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research
Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
Background: Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations. (Source: eLife)
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Medicine Source Type: research
Neuronal regulated < i > ire < /i > - < i > 1 < /i > -dependent mRNA decay controls germline differentiation in < i > Caenorhabditis elegans < /i >
Understanding the molecular events that regulate cell pluripotency versus acquisition of differentiated somatic cell fate is fundamentally important. Studies inCaenorhabditis elegans demonstrate that knockout of the germline-specific translation repressorgld-1 causes germ cells within tumorous gonads to form germline-derived teratoma. Previously we demonstrated that endoplasmic reticulum (ER) stress enhances this phenotype to suppress germline tumor progression(Levi-Ferber et al., 2015). Here, we identify a neuronal circuit that non-autonomously suppresses germline differentiation and show that it communicates with the gon...
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research
LIN37-DREAM prevents DNA end resection and homologous recombination at DNA double-strand breaks in quiescent cells
DNA double-strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to the expression of HR proteins, including BRCA1, BRCA2, PALB2, and RAD51, and promotes DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection...
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Cell Biology Chromosomes and Gene Expression Source Type: research
Environmental fluctuations reshape an unexpected diversity-disturbance relationship in a microbial community
Environmental disturbances have long been theorized to play a significant role in shaping the diversity and composition of ecosystems. However, an inability to specify the characteristics of a disturbance experimentally has produced an inconsistent picture of diversity-disturbance relationships (DDRs). Here, using a high-throughput programmable culture system, we subjected a soil-derived bacterial community to dilution disturbance profiles with different intensities (mean dilution rates), applied either constantly or with fluctuations of different frequencies. We observed an unexpected U-shaped relationship between communi...
Source: eLife - September 3, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research
Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes
Tissue-resident intestinal intraepithelial T lymphocytes (T-IEL) patrol the gut and have important roles in regulating intestinal homeostasis. T-IEL include both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural IEL, which are developmentally targeted to the intestine. While the processes driving T-IEL development have been elucidated, the precise roles of the different subsets and the processes driving activation and regulation of these cells remain unclear. To gain functional insights into these enigmatic cells, we used high-resolution, quantitative mass spectrometry to compare the proteom...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research
Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration
Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma inC. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive ...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research
L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans
Learning to be safe is central for adaptive behaviour when threats are no longer present. Detecting the absence of an expected threat is key for threat extinction learning and an essential process for the behavioural treatment of anxiety related disorders. One possible mechanism underlying extinction learning is a dopaminergic mismatch signal that encodes the absence of an expected threat. Here we show that such a dopamine-related pathway underlies extinction learning in humans. Dopaminergic enhancement via administration of L-DOPA (vs. Placebo) was associated with reduced retention of differential psychophysiological thre...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Understanding patterns of HIV multi-drug resistance through models of temporal and spatial drug heterogeneity
We describe how these observations might emerge under two models of HIV drugs varying in space or time. Despite decades of work in this area, much opportunity remains to create models with realistic parameters for three drugs, and to match model outcomes to resistance rates and genetic patterns from individuals on triple-drug therapy. Further, lessons from HIV may inform other systems. (Source: eLife)
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research
Muscle-specific economy of force generation and efficiency of work production during human running
Human running features a spring-like interaction of body and ground, enabled by elastic tendons that store mechanical energy and facilitate muscle operating conditions to minimize the metabolic cost. By experimentally assessing the operating conditions of two important muscles for running, the soleus and vastus lateralis, we investigated physiological mechanisms of muscle work production and muscle force generation. We found that the soleus continuously shortened throughout the stance phase, operating as work generator under conditions that are considered optimal for work production: high force-length potential and high en...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research
Crosstalk between the chloroplast protein import and SUMO systems revealed through genetic and molecular investigation in < i > Arabidopsis < /i >
The chloroplast proteome contains thousands of different proteins that are encoded by the nuclear genome. These proteins are imported into the chloroplast via the action of the TOC translocase and associated downstream systems. Our recent work has revealed that the stability of the TOC complex is dynamically regulated by the ubiquitin-dependent chloroplast-associated protein degradation (CHLORAD) pathway. Here, we demonstrate that the TOC complex is also regulated by the SUMO system.Arabidopsis mutants representing almost the entire SUMO conjugation pathway can partially suppress the phenotype ofppi1, a pale-yellow mutant ...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Cell Biology Plant Biology Source Type: research
Hybrid protein assembly-histone modification mechanism for PRC2-based epigenetic switching and memory
The histone modification H3K27me3 plays a central role in Polycomb-mediated epigenetic silencing. H3K27me3 recruits and allosterically activates Polycomb Repressive Complex 2 (PRC2), which adds this modification to nearby histones, providing a read/write mechanism for inheritance through DNA replication. However, for some PRC2 targets, a purely histone-based system for epigenetic inheritance may be insufficient. We address this issue at the Polycomb targetFLOWERING LOCUS C (FLC) inArabidopsis thaliana, as a narrow nucleation region of only ~three nucleosomes withinFLC mediates epigenetic state switching and subsequent memo...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research
