Loss of < i > Mir146b < /i > with aging contributes to inflammation and mitochondrial dysfunction in thioglycollate-elicited peritoneal macrophages
Macrophages undergo programmatic changes with age leading to altered cytokine polarization and immune dysfunction, shifting these critical immune cells from protective sentinels to disease promoters. The molecular mechanisms underlying macrophage inflammaging are poorly understood. Using an unbiased RNA-seq approach, we identifiedMir146b as a microRNA whose expression progressively and unidirectionally declined with age in thioglycollate-elicited murine macrophages.Mir146b deficiency led to altered macrophage cytokine expression and reduced mitochondrial metabolic activity, two hallmarks of cellular aging. Single cell RNA ...
Source: eLife - August 23, 2021 Category: Biomedical Science Tags: Cell Biology Immunology and Inflammation Source Type: research
Systematic morphological and morphometric analysis of identified olfactory receptor neurons in < i > Drosophila melanogaster < /i >
The biophysical properties of sensory neurons are influenced by their morphometric and morphological features, whose precise measurements require high-quality volume electron microscopy (EM). However, systematic surveys of nanoscale characteristics for identified neurons are scarce. Here, we characterize the morphology ofDrosophila olfactory receptor neurons (ORNs) across the majority of genetically identified sensory hairs. By analyzing serial block-face electron microscopy (SBEM) images of cryofixed antennal tissues, we compile an extensive morphometric dataset based on 122 reconstructed 3D models for 33 of the 40 identi...
Source: eLife - August 23, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
An oomycete effector subverts host vesicle trafficking to channel starvation-induced autophagy to the pathogen interface
Eukaryotic cells deploy autophagy to eliminate invading microbes. In turn, pathogens have evolved effector proteins to counteract antimicrobial autophagy. How adapted pathogens co-opt autophagy for their own benefit is poorly understood. The Irish famine pathogenPhytophthora infestans secretes the effector protein PexRD54 that selectively activates an unknown plant autophagy pathway that antagonizes antimicrobial autophagy at the pathogen interface. Here, we show that PexRD54 induces autophagosome formation by bridging vesicles decorated by the small GTPase Rab8a with autophagic compartments labeled by the core autophagy p...
Source: eLife - August 23, 2021 Category: Biomedical Science Tags: Plant Biology Source Type: research
Hypoxia triggers collective aerotactic migration in < i > Dictyostelium discoideum < /i >
Using a self-generated hypoxic assay, we show that the amoebaDictyostelium discoideum displays a remarkable collective aerotactic behavior. When a cell colony is covered, cells quickly consume the available oxygen (O2) and form a dense ring moving outwards at constant speed and density. To decipher this collective process, we combined two technological developments: porphyrin-based O2 -sensing films and microfluidic O2 gradient generators. We showed thatDictyostelium cells exhibit aerotactic and aerokinetic response in a low range of O2 concentration indicative of a very efficient detection mechanism. Cell behaviors under ...
Source: eLife - August 20, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Physics of Living Systems Source Type: research
Probing the effect of clustering on EphA2 receptor signaling efficiency by subcellular control of ligand-receptor mobility
Clustering of ligand:receptor complexes on the cell membrane is widely presumed to have functional consequences for subsequent signal transduction. However, it is experimentally challenging to selectively manipulate receptor clustering without altering other biochemical aspects of the cellular system. Here, we develop a microfabrication strategy to produce substrates displaying mobile and immobile ligands that are separated by roughly one micron, and thus experience an identical cytoplasmic signaling state, enabling precision comparison of downstream signaling reactions. Applying this approach to characterize the ephrinA1:...
Source: eLife - August 20, 2021 Category: Biomedical Science Tags: Physics of Living Systems Structural Biology and Molecular Biophysics Source Type: research
An engineered transcriptional reporter of protein localization identifies regulators of mitochondrial and ER membrane protein trafficking in high-throughput CRISPRi screens
The trafficking of specific protein cohorts to correct subcellular locations at correct times is essential for every signaling and regulatory process in biology. Gene perturbation screens could provide a powerful approach to probe the molecular mechanisms of protein trafficking, but only if protein localization or mislocalization can be tied to a simple and robust phenotype for cell selection, such as cell proliferation or fluorescence-activated cell sorting (FACS). To empower the study of protein trafficking processes with gene perturbation, we developed a genetically-encoded molecular tool named HiLITR. HiLITR converts p...
Source: eLife - August 20, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research
SARS-CoV-2 shedding dynamics across the respiratory tract, sex, and disease severity for adult and pediatric COVID-19
(Source: eLife)
Source: eLife - August 20, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Microbiology and Infectious Disease Source Type: research
Understanding neural signals of post-decisional performance monitoring: An integrative review
Performance monitoring is a key cognitive function, allowing to detect mistakes and adapt future behavior. Post-decisional neural signals have been identified that are sensitive to decision accuracy, decision confidence and subsequent adaptation. Here, we review recent work that supports an understanding of late error/confidence signals in terms of the computational process of post-decisional evidence accumulation. We argue that the error positivity, a positive-going centro-parietal potential measured through scalp electrophysiology, reflects the post-decisional evidence accumulation process itself, which follows a boundar...
Source: eLife - August 20, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Physiology and ecology combine to determine host andvector importance for Ross River virus
We present a nested approach for quantifying the importance of host and vectors that integrates species' physiological competence with their ecological traits. We apply this framework to a medically important arbovirus, Ross River virus (RRV), in Brisbane, Australia. We find that vertebrate hosts with high physiological competence are not the most important for community transmission; interactions between hosts and vectors largely underpin the importance of host species. For vectors, physiological competence is highly important. Our results identify primary and secondary vectors of RRV and suggest two potential transmissio...
Source: eLife - August 20, 2021 Category: Biomedical Science Tags: Ecology Epidemiology and Global Health Source Type: research
N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2
SARS-CoV-2 is spreading around the world for the past year. Recently, several variants such as B.1.1.7 (Alpha), B.1.351 (Beta), and P.1 (Gamma), sharing a key mutation N501Y on the RBD, appear to be more infectious to humans. To understand the underlying mechanism, we performed cell surface binding assay, kinetics study, single-molecule technique, and computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and slower dissociation rate. Consistently, atomic force microscop...
Source: eLife - August 20, 2021 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research
Neural dynamics between anterior insular cortex and right supramarginal gyrus dissociate genuine affect sharing from perceptual saliency of pretended pain
In this study, we addressed the highly debated question of whether neural responses previously linked to affect sharing could result from the perception of salient affective displays. Moreover, we investigated how the brain network involved in affect sharing and self-other distinction underpinned our response to a pain that is either perceived as genuine or pretended (while in fact both were acted for reasons of experimental control). We found stronger activations in regions associated with affect sharing (anterior insula, aIns, and anterior mid-cingulate cortex, aMCC) as well as with affective self-other distinction (righ...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Characterization of the ABC methionine transporter from < i > Neisseria meningitidis < /i > reveals that lipidated MetQ is required for interaction
NmMetQ is a substrate-binding protein (SBP) from Neisseria meningitidis that has been identified as a surface-exposed candidate antigen for meningococcal vaccines. However, this location for NmMetQ challenges the prevailing view that SBPs in Gram-negative bacteria are localized to the periplasmic space to promote interaction with their cognate ABC transporter embedded in the bacterial inner membrane. To elucidate the roles of NmMetQ, we characterized NmMetQ with and without its cognate ABC transporter (NmMetNI). Here, we show that NmMetQ is a lipoprotein (lipo-NmMetQ) that binds multiple methionine analogs and stimulates t...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research
An essential, kinetoplastid-specific GDP-Fuc: β- < i > D < /i > -Gal α-1,2-fucosyltransferase is located in the mitochondrion of < i > Trypanosoma brucei < /i >
Fucose is a common component of eukaryotic cell-surface glycoconjugates, generally added by Golgi-resident fucosyltransferases. Whereas fucosylated glycoconjugates are rare in kinetoplastids, the biosynthesis of the nucleotide sugar GDP-Fuc has been shown to be essential inTrypanosoma brucei. Here we show that the single identifiableT. brucei fucosyltransferase (TbFUT1) is a GDP-Fuc: β-D-galactose α-1,2-fucosyltransferase with an apparent preference for a Galβ1,3GlcNAcβ1-O-R acceptor motif. Conditional null mutants ofTbFUT1 demonstrated that it is essential for both the mammalian-infective bloodstream form and the inse...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Microbiology and Infectious Disease Source Type: research
GIV/Girdin, a non-receptor modulator for G αi/s, regulates spatiotemporal signaling during sperm capacitation and is required for male fertility
For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of conditional knockout (cKO) mice and cell-penetrating peptides, we show that GIV (CCDC88A), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research
TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells
TMEM120A, a member of the Transmembrane protein 120 (TMEM120) family, has pivotal function in adipocyte differentiation and metabolism, and may also contribute to sensing mechanical pain by functioning as an ion channel named TACAN. Here we report that expression of TMEM120A is not sufficient in mediating poking- or stretch-induced currents in cells, and have solved cryo-EM structures of human TMEM120A (HsTMEM120A) in complex with an endogenous metabolic cofactor (coenzyme A, CoASH) and in the apo form.HsTMEM120A forms a symmetrical homodimer with each monomer containing an amino-terminal coiled-coil motif followed by a tr...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Neuroscience Structural Biology and Molecular Biophysics Source Type: research
