The ability to sense physical forces is conserved across all organisms. Cells convert mechanical stimuli into electrical or chemical signals via mechanically activated ion channels. In recent years, ...the identification of new families of mechanosensitive ion channels-such as PIEZO and OSCA/TMEM63 channels-along with surprising insights into well-studied mechanosensitive channels have driven further developments in the mechanotransduction field. Several well-characterized mechanosensory roles such as touch, blood-pressure sensing and hearing are now linked with primary mechanotransducers. Unanticipated roles of mechanical force sensing continue to be uncovered. Furthermore, high-resolution structures representative of nearly every family of mechanically activated channel described so far have underscored their diversity while advancing our understanding of the biophysical mechanisms of pressure sensing. Here we summarize recent discoveries in the physiology and structures of known mechanically activated ion channel families and discuss their implications for understanding the mechanisms of mechanical force sensing.
Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit ...RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics.
The envelope glycoprotein trimer (Env) on the surface of HIV-1 recognizes CD4⁺ T cells and mediates viral entry. During this process, Env undergoes substantial conformational rearrangements, making ...it difficult to study in its native state. Soluble stabilized trimers have provided valuable insights into the Env structure, but they lack the hydrophobic membrane proximal external region (MPER, an important target of broadly neutralizing antibodies), the transmembrane domain, and the cytoplasmic tail. Here we present (i) a cryogenic electron microscopy (cryo-EM) structure of a clade B virus Env, which lacks only the cytoplasmic tail and is stabilized by the broadly neutralizing antibody PGT151, at a resolution of 4.2 angstroms and (ii) a reconstruction of this form of Env in complex with PGT151 and MPER-targeting antibody 10E8 at a resolution of 8.8 angstroms. These structures provide new insights into the wild-type Env structure.
Summary
Structure determination of the HIV‐1 envelope glycoprotein (Env) presented a number of challenges, but several high‐resolution structures have now become available. In 2013, cryo‐EM and x‐ray ...structures of soluble, cleaved SOSIP Env trimers from the clade A BG505 strain provided the first glimpses into the Env trimer fold as well as more the variable regions. A recent cryo‐EM structure of a native full‐length trimer without any stabilizing mutations had the same core structure, but revealed new insights and features. A more comprehensive and higher resolution understanding of the glycan shield has also emerged, enabling a more complete representation of the Env glycoprotein structure. Complexes of Env trimers with broadly neutralizing antibodies have surprisingly illustrated that most of the Env surface can be targeted in natural infection and that the neutralizing epitopes are almost all composed of both peptide and glycan components. These structures have also provided further evidence of the inherent plasticity of Env and how antibodies can exploit this flexibility by perturbing or even stabilizing the trimer to facilitate neutralization. These breakthroughs have stimulated further design and stabilization of Env trimers as well as other platforms to generate trimers that now span multiple subtypes. These Env trimers when used as immunogens, have led to the first vaccine‐induced neutralizing antibodies for structural and functional analyses.
Primary production in over half of the world’s oceans is limited by fixed nitrogen availability. The main loss term from the fixed nitrogen inventory is the production of dinitrogen gas (N2) by ...heterotrophic denitrification or the more recently discovered autotrophic process, anaerobic ammonia oxidation (anammox). Oceanic oxygen minimum zones (OMZ) are responsible for about 35% of oceanic N2 production and up to half of that occurs in the Arabian Sea. Although denitrification was long thought to be the only loss term, it has recently been argued that anammox alone is responsible for fixed nitrogen loss in the OMZs. Here we measure denitrification and anammox rates and quantify the abundance of denitrifying and anammox bacteria in the OMZ regions of the Eastern Tropical South Pacific and the Arabian Sea. We find that denitrification rather than anammox dominates the N2 loss term in the Arabian Sea, the largest and most intense OMZ in the world ocean. In seven of eight experiments in the Arabian Sea denitrification is responsible for 87–99% of the total N2 production. The dominance of denitrification is reproducible using two independent isotope incubation methods. In contrast, anammox is dominant in the Eastern Tropical South Pacific OMZ, as detected using one of the isotope incubation methods, as previously reported. The abundance of denitrifying bacteria always exceeded that of anammox bacteria by up to 7- and 19-fold in the Eastern Tropical South Pacific and Arabian Sea, respectively. Geographic and temporal variability in carbon supply may be responsible for the different contributions of denitrification and anammox in these two OMZs. The large contribution of denitrification to N2 loss in the Arabian Sea indicates the global significance of denitrification to the oceanic nitrogen budget.
The authors examined the prospective relationship between physical activity and incident depression and explored potential moderators.
Prospective cohort studies evaluating incident depression were ...searched from database inception through Oct. 18, 2017, on PubMed, PsycINFO, Embase, and SPORTDiscus. Demographic and clinical data, data on physical activity and depression assessments, and odds ratios, relative risks, and hazard ratios with 95% confidence intervals were extracted. Random-effects meta-analyses were conducted, and the potential sources of heterogeneity were explored. Methodological quality was assessed using the Newcastle-Ottawa Scale.
A total of 49 unique prospective studies (N=266,939; median proportion of males across studies, 47%) were followed up for 1,837,794 person-years. Compared with people with low levels of physical activity, those with high levels had lower odds of developing depression (adjusted odds ratio=0.83, 95% CI=0.79, 0.88; I
=0.00). Furthermore, physical activity had a protective effect against the emergence of depression in youths (adjusted odds ratio=0.90, 95% CI=0.83, 0.98), in adults (adjusted odds ratio=0.78, 95% CI=0.70, 0.87), and in elderly persons (adjusted odds ratio=0.79, 95% CI=0.72, 0.86). Protective effects against depression were found across geographical regions, with adjusted odds ratios ranging from 0.65 to 0.84 in Asia, Europe, North America, and Oceania, and against increased incidence of positive screen for depressive symptoms (adjusted odds ratio=0.84, 95% CI=0.79, 0.89) or major depression diagnosis (adjusted odds ratio=0.86, 95% CI=0.75, 0.98). No moderators were identified. Results were consistent for unadjusted odds ratios and for adjusted and unadjusted relative risks/hazard ratios. Overall study quality was moderate to high (Newcastle-Ottawa Scale score, 6.3). Although significant publication bias was found, adjusting for this did not change the magnitude of the associations.
Available evidence supports the notion that physical activity can confer protection against the emergence of depression regardless of age and geographical region.
Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaws (MRONJ) – formerly referred to as bisphosphonate-related osteonecrosis of the jaws ...(BRONJ)—were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007, 2009 and 2014. The position papers were developed by a committee appointed by the AAOMS Board of Trustees and comprising clinicians with extensive experience in caring for these patients, as well as clinical and basic science researchers. The knowledge base and experience in addressing MRONJ continues to evolve and expand, necessitating modifications and refinements to the previous position papers. Three members of the AAOMS Committee on Oral, Head, and Neck Oncologic and Reconstructive Surgery (COHNORS) and three authors of the 2014 position paper were appointed to serve as a working group to analyze the current literature and revise the guidance as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis and management strategies and highlights the current research status. AAOMS maintains that it is vitally important for this information to be disseminated to other relevant healthcare professionals and organizations.
Piezo1 and Piezo2 are mechanically activated ion channels that mediate touch perception, proprioception and vascular development. Piezo proteins are distinct from other ion channels and their ...structure remains poorly defined, which impedes detailed study of their gating and ion permeation properties. Here we report a high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer. The detergent-solubilized complex adopts a three-bladed propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-transmembrane helical bundles that we term Piezo repeats. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo repeats to the pore, and are poised to control gating allosterically. The structure provides a foundation to dissect further how Piezo channels are regulated by mechanical force.
Hippocampal volume increase in response to aerobic exercise has been consistently observed in animal models. However, the evidence from human studies is equivocal. We undertook a systematic review to ...identify all controlled trials examining the effect of aerobic exercise on the hippocampal volumes in humans, and applied meta-analytic techniques to determine if aerobic exercise resulted in volumetric increases. We also sought to establish how volume changes differed in relation to unilateral measures of left/right hippocampal volume, and across the lifespan. A systematic search identified 4398 articles, of which 14 were eligible for inclusion in the primary analysis. A random-effects meta-analysis showed no significant effect of aerobic exercise on total hippocampal volume across the 737 participants. However, aerobic exercise had significant positive effects on left hippocampal volume in comparison to control conditions. Post-hoc analyses indicated effects were driven through exercise preventing the volumetric decreases which occur over time. These results provide meta-analytic evidence for exercise-induced volumetric retention in the left hippocampus. Aerobic exercise interventions may be useful for preventing age-related hippocampal deterioration and maintaining neuronal health.
We present an estimation of the theoretical precision of low angle Bhabha scattering at the proposed future ILC collider at 500 GeV. The analysis is an extension of the previous analysis done for the ...FCCee collider at
s
=
M
Z
. As the state-of-the-art and the reference point we use the BHLUMI Monte Carlo event generator. Based on the current precision status of BHLUMI for LEP analysis, we estimate how various error components evolve from the LEP to ILC setups. The conclusion of our work is that for the ILC the precision of the current version of BHLUMI 4.04 deteriorates to 0.5%, by more than an order of magnitude w.r.t. the present precision for LEP. With the expected future improvements, the precision of BHLUMI can change to 0.016%, nearly as good as for the FCCee at the
M
Z
setup (0.01%). Based on the developed methodology we present also results for ILC
1000
, FCCee
350
and CLIC
3000
setups.
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