NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory < i > C. elegans < /i > mutants
Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory defectiveCaenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein geneosm-3 were significantly protected from tunicamycin-induced ER stress. Whileosm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not.osm-3 mutants are protected from bacterial pathogens, which ispmk-1 p38 MAP kinase dependent while TM resistance waspmk-1 independent. Expression...
Source: eLife - August 27, 2021 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research
Sleeping at the Switch
Sleep slow waves are studied for their role in brain plasticity, homeostatic regulation and their changes during aging. Here, we address the possibility that two types of slow waves co-exist in humans. Thirty young and 29 older adults underwent a night of polysomnographic recordings. Using theTransition frequency, slow waves with a slow transition (slow switchers) and with a fast transition (fast switchers) were discovered. Slow switchers had a high EEG connectivity along their depolarization transition while fast switchers had a lower connectivity dynamic and dissipated faster during the night. Aging was associated with l...
Source: eLife - August 27, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
MACF1 controls skeletal muscle function through the microtubule-dependent localization of extra-synaptic myonuclei and mitochondria biogenesis
Skeletal muscles are composed of hundreds of multinucleated muscle fibers (myofibers) whose myonuclei are regularly positioned all along the myofiber's periphery except the few ones clustered underneath the neuromuscular junction (NMJ) at the synaptic zone. This precise myonuclei organization is altered in different types of muscle disease, including centronuclear myopathies (CNMs). However, the molecular machinery regulating myonuclei position and organization in mature myofibers remains largely unknown. Conversely, it is also unclear how peripheral myonuclei positioning is lost in the related muscle diseases. Here, we de...
Source: eLife - August 27, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research
Parallel evolution between genomic segments of seasonal human influenza viruses reveals RNA-RNA relationships
This study illustrates how putative RNA interactions underlying selective assembly of IAV can be interrogated with phylogenetics. (Source: eLife)
Source: eLife - August 27, 2021 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research
Apical contacts stemming from incomplete delamination guide progenitor cell allocation through a dragging mechanism
The developmental strategies used by progenitor cells to allow a safe journey from their induction place towards the site of terminal differentiation are still poorly understood. Here we uncovered a mechanism of progenitor cell allocation that stems from an incomplete process of epithelial delamination that allows progenitors to coordinate their movement with adjacent extra-embryonic tissues. Progenitors of the zebrafish laterality organ originate from the superficial epithelial enveloping layer by an apical constriction process of cell delamination. During this process, progenitors retain long-lasting apical contacts that...
Source: eLife - August 27, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research
PRMT5 & gt;regulates ovarian follicle development by facilitating < i > Wt1 < /i > translation
Protein arginine methyltransferase 5 (Prmt5) is the major type II enzyme responsible for symmetric dimethylation of arginine. Here, we found PRMT5 was expressed at high level in ovarian granulosa cells of growing follicles. Inactivation ofPrmt5 in granulosa cells resulted in aberrant follicle development and female infertility. InPrmt5-knockout mice, follicle development was arrested with disorganized granulosa cells in which WT1 expression was dramatically reduced and the expression of steroidogenesis-related genes was significantly increased. The premature differentiated granulosa cells were detached from oocytes and fol...
Source: eLife - August 27, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research
Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand the human ACE2 receptor on binding affinity and kinetics
The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD are present in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K and S477N) and two common ACE2 mutations (S1...
Source: eLife - August 26, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Microbiology and Infectious Disease Source Type: research
Disintegration promotes protospacer integration by the Cas1-Cas2 complex
‘Disintegration’—the reversal of transposon DNA integration at a target site—is regarded as an abortive off-pathway reaction. Here, we challenge this view with a biochemical investigation of the mechanism of protospacer insertion, which is mechanistically analogous to DNA transposition, by t heStreptococcus pyogenes Cas1-Cas2 complex. In supercoiled target sites, the predominant outcome is the disintegration of one-ended insertions that fail to complete the second integration event. In linear target sites, one-ended insertions far outnumber complete protospacer insertions. The second insertion event is most often a...
Source: eLife - August 26, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research
Development and genetics of red coloration in the zebrafish relative < i > Danio albolineatus < /i >
Animal pigment patterns play important roles in behavior and, in many species, red coloration serves as an honest signal of individual quality in mate choice. AmongDanio fishes, some species develop erythrophores, pigment cells that contain red ketocarotenoids, whereas other species, like zebrafish (D. rerio) only have yellow xanthophores. Here, we use pearl danio (D. albolineatus) to assess the developmental origin of erythrophores and their mechanisms of differentiation. We show that erythrophores in the fin ofD. albolineatus share a common progenitor with xanthophores and maintain plasticity in cell fate even after diff...
Source: eLife - August 26, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research
The pro-regenerative effects of HyperIL6 in drug induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling
It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation a...
Source: eLife - August 26, 2021 Category: Biomedical Science Tags: Cell Biology Stem Cells and Regenerative Medicine Source Type: research
The structure of photosystem I from a high-light tolerant Cyanobacteria
Photosynthetic organisms have adapted to survive a myriad of extreme environments from the earth ’s deserts to its poles, yet the proteins that carry out the light reactions of photosynthesis are highly conserved from the cyanobacteria to modern day crops. To investigate adaptations of the photosynthetic machinery in cyanobacteria to excessive light stress, we isolated a new strain of cyanoba cteria,Cyanobacteriumaponinum 0216, from the extreme light environment of the Sonoran Desert. Here we report the biochemical characterization and the 2.7 Å resolution structure of trimeric photosystem I from this high-light toleran...
Source: eLife - August 26, 2021 Category: Biomedical Science Tags: Plant Biology Structural Biology and Molecular Biophysics Source Type: research
The roles of history, chance, and natural selection in the evolution of antibiotic resistance
History, chance, and selection are the fundamental factors that drive and constrain evolution. We designed evolution experiments to disentangle and quantify effects of these forces on the evolution of antibiotic resistance. Previously we showed that selection of the pathogenAcinetobacter baumanniiin both structured and unstructured environments containing the antibiotic ciprofloxacin produced distinct genotypes and phenotypes, with lower resistance in biofilms as well as collateral sensitivity to b-lactam drugs (Santos-Lopez et al. 2019). Here we study how this prior history influences subsequent evolution in new b-lactam ...
Source: eLife - August 25, 2021 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research
Endothelial junctional membrane protrusions serve as hotspots for neutrophil transmigration
Upon inflammation, leukocytes rapidly transmigrate across the endothelium to enter the inflamed tissue. Evidence accumulates that leukocytes use preferred exit sites, though it is not yet clear how these hotspots in the endothelium are defined and how they are recognized by the leukocyte. Using lattice light sheet microscopy, we discovered that leukocytes prefer endothelial membrane protrusions at cell junctions for transmigration. Phenotypically, these junctional membrane protrusions are present in an asymmetric manner, meaning that one endothelial cell shows the protrusion and the adjacent one does not. Consequently, leu...
Source: eLife - August 25, 2021 Category: Biomedical Science Tags: Cell Biology Immunology and Inflammation Source Type: research
HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis
Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present....
Source: eLife - August 25, 2021 Category: Biomedical Science Tags: Cancer Biology Chromosomes and Gene Expression Source Type: research
Crosstalk between nitric oxide and retinoic acid pathways is essential for amphioxus pharynx development
During animal ontogenesis, body axis patterning is finely regulated by complex interactions among several signaling pathways. Nitric oxide (NO) and retinoic acid (RA) are potent morphogens that play a pivotal role in vertebrate development. Their involvement in axial patterning of the head and pharynx shows conserved features in the chordate phylum. Indeed, in the cephalochordate amphioxus, NO and RA are crucial for the correct development of pharyngeal structures. Here, we demonstrate the functional cooperation between NO and RA that occurs during amphioxus embryogenesis. During neurulation, NO modulates RA production thr...
Source: eLife - August 25, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research
