Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination
Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence ofPhb1, likely a...
Source: eLife - September 14, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Filopodia powered by class X myosin promote fusion of mammalian myoblasts
Skeletal muscle fibers are multinucleated cellular giants formed by the fusion of mononuclear myoblasts. Several molecules involved in myoblast fusion have been discovered, and finger-like projections coincident with myoblast fusion have also been implicated in the fusion process. The role of these cellular projections in muscle cell fusion was investigated herein. We demonstrate that these projections are filopodia generated by class X myosin (Myo10), an unconventional myosin motor protein specialized for filopodia. We further show that Myo10 is highly expressed by differentiating myoblasts, and Myo10 ablation inhibits bo...
Source: eLife - September 14, 2021 Category: Biomedical Science Tags: Cell Biology Stem Cells and Regenerative Medicine Source Type: research
A XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
We developed aXrcc4M61R separation of function mouse line to overcome the embryonic lethality of Xrcc4 deficient mice. XRCC4M61R protein does not interact with Xlf, thus obliterating XRCC4-Xlf filament formation while preserving the ability to stabilize DNA Ligase IV. X4M61R mice, which are DNA repair deficient, phenocopy theNhej1-/- (known asXlf -/-) setting with a minor impact on the development of the adaptive immune system. The core NHEJ DNA repair factor XRCC4 is therefore not mandatory for V(D)J recombination aside from its role in stabilizing DNA ligase IV. In contrast,Xrcc4M61R mice crossed onPaxx-/-,Nhej1-/-, orAt...
Source: eLife - September 14, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Developmental Biology Source Type: research
Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace
The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a uniquepartial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. St...
Source: eLife - September 14, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research
Optimal plasticity for memory maintenance during ongoing synaptic change
Synaptic connections in many brain circuits fluctuate, exhibiting substantial turnover and remodelling over hours to days. Surprisingly, experiments show that most of this flux in connectivity persists in the absence of learning or known plasticity signals. How can neural circuits retain learned information despite a large proportion of ongoing and potentially disruptive synaptic changes? We address this question from first principles by analysing how much compensatory plasticity would be required to optimally counteract ongoing fluctuations, regardless of whether fluctuations are random or systematic. Remarkably, we find ...
Source: eLife - September 14, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research
Translational control of polyamine metabolism by CNBP is required for < i > Drosophila < /i > locomotor function
Microsatellite expansions of CCTG repeats in the cellular nucleic acid-binding protein (CNBP) gene leads to accumulation of toxic RNA and have been associated with myotonic dystrophy type 2 (DM2). However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA-binding protein that regulates translation and is required for mammalian development. Here, we show that depletion ofDrosophila CNBP in muscles causes ageing-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase ...
Source: eLife - September 14, 2021 Category: Biomedical Science Tags: Genetics and Genomics Neuroscience Source Type: research
Microbiome-pathogen interactions drive epidemiological dynamics of antibiotic resistance: a modelling study applied to nosocomial pathogen control
The human microbiome can protect against colonization with pathogenic antibiotic-resistant bacteria (ARB), but its impacts on the spread of antibiotic resistance are poorly understood. We propose a mathematical modelling framework for ARB epidemiology formalizing within-host ARB-microbiome competition, and impacts of antibiotic consumption on microbiome function. Applied to the healthcare setting, we demonstrate a trade-off whereby antibiotics simultaneously clear bacterial pathogens and increase host susceptibility to their colonization, and compare this framework with a traditional strain-based approach. At the populatio...
Source: eLife - September 14, 2021 Category: Biomedical Science Tags: Ecology Epidemiology and Global Health Source Type: research
Addressing shortfalls of laboratory HbA < sub > 1c < /sub > using a model that incorporates red cell lifespan
Laboratory HbA1c does not always predict diabetes complications and our aim was to establish a glycaemic measure that better reflects intracellular glucose exposure in organs susceptible to complications. Six months of continuous glucose monitoring data and concurrent laboratory HbA1c were evaluated from 51 type 1 diabetes (T1D) and 80 type 2 diabetes (T2D) patients. Red blood cell (RBC) lifespan was estimated using a kinetic model of glucose and HbA1c, allowing the calculation of person-specific adjusted HbA1c (aHbA1c). Median (IQR) RBC lifespan was 100 (86 –102) and 100 (83–101) days in T1D and T2D, respectively. The...
Source: eLife - September 13, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Computational and Systems Biology Source Type: research
In situ cryo-ET structure of phycobilisome –photosystem II supercomplex from red alga
Phycobilisome (PBS) is the main light-harvesting antenna in cyanobacteria and red algae. How PBS transfers the light energy to photosystem II (PSII) remains to be elucidated. Here we report the in situ structure of the PBS –PSII supercomplex fromPorphyridium purpureum UTEX 2757 using cryo-electron tomography and subtomogram averaging. Our work reveals the organized network of hemiellipsoidal PBS with PSII on the thylakoid membrane in the native cellular environment. In the PBS –PSII supercomplex, each PBS interacts with six PSII monomers, of which four directly bind to the PBS, and two bind indirectly. Additional three...
Source: eLife - September 13, 2021 Category: Biomedical Science Tags: Plant Biology Structural Biology and Molecular Biophysics Source Type: research
Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study
Background: Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population. (Source: eLife)
Source: eLife - September 13, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Genetics and Genomics Source Type: research
RNA splicing programs define tissue compartments and cell types at single cell resolution
The extent splicing is regulated at single-cell resolution has remained controversial due to both available data and methods to interpret it. We apply the SpliZ, a new statistical approach, to detect cell-type-specific splicing in>110K cells from 12 human tissues. Using 10x data for discovery, 9.1% of genes with computable SpliZ scores are cell-type-specifically spliced, including ubiquitously expressed genesMYL6 andRPS24. These results are validated with RNA FISH, single-cell PCR, and Smart-seq2. SpliZ analysis reveals 170 genes with regulated splicing during human spermatogenesis, including examples conserved in mouse...
Source: eLife - September 13, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Genetics and Genomics Source Type: research
Comparison of transcriptional initiation by RNA polymerase II across eukaryotic species
The preinitation complex (PIC) for transcriptional initiation by RNA polymerase (Pol) II is composed of general transcription factors that are highly conserved. However, analysis of ChIP-seq datasets reveals kinetic and compositional differences in the transcriptional initiation process among eukaryotic species. In yeast, Mediator associates strongly with activator proteins bound to enhancers, but it transiently associates with promoters in a form that lacks the kinase module. In contrast, in human, mouse, and fly cells, Mediator with its kinase module stably associates with promoters, but not with activator-binding sites....
Source: eLife - September 13, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research
Western diet shifts immune cell balance
The immune cells of macaques fed a Western-like diet adopt a pro-inflammatory profile. (Source: eLife)
Source: eLife - September 13, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Immunology and Inflammation Source Type: research
Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya
Background: Understanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control. (Source: eLife)
Source: eLife - September 13, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Microbiology and Infectious Disease Source Type: research
A Tad-like apparatus is required for contact-dependent prey killing in predatory social bacteria
This study further reveals a novel cell-cell interaction function for bacterial pili-like assemblages. (Source: eLife)
Source: eLife - September 10, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research
