Otopetrins (Otop1-Otop3) comprise one of two known eukaryotic proton-selective channel families. Otop1 is required for otoconia formation and a candidate mammalian sour taste receptor. Here we report ...cryo-EM structures of zebrafish Otop1 and chicken Otop3 in lipid nanodiscs. The structures reveal a dimeric architecture, with each subunit forming 12 transmembrane helices divided into structurally similar amino (N) and carboxy (C) domains. Cholesterol-like molecules occupy various sites in Otop1 and Otop3 and occlude a central tunnel. In molecular dynamics simulations, hydrophilic vestibules formed by the N and C domains and in the intrasubunit interface between N and C domains form conduits for water entry into the membrane core, suggesting three potential proton conduction pathways. By mutagenesis, we tested the roles of charged residues in each putative permeation pathway. Our results provide a structural basis for understanding selective proton permeation and gating of this conserved family of proton channels.
Obesity, a known risk factor for cardiovascular disease and heart failure (HF), is associated with adverse cardiac remodeling in the general population. Little is known about how nutritional status ...modifies the relationship between obesity and outcomes. We aimed to investigate the association of obesity and nutritional status with clinical characteristics, echocardiographic changes, and clinical outcomes in the general community. We examined 5,300 consecutive asymptomatic Asian participants who were prospectively recruited in a cardiovascular health screening program (mean age 49.6 ± 11.4 years, 64.8% male) between June 2009 to December 2012. Clinical and echocardiographic characteristics were described in participants, stratified by combined subgroups of obesity and nutritional status. Obesity was indexed by body mass index (BMI) (low, less than or equal to25 kg/m.sup.2 lean; high, >25 kg/m.sup.2 obese) (WHO-recommended Asian cutoffs). Nutritional status was defined primarily by serum albumin (SA) concentration (low, <45 g/L malnourished; high, greater than or equal to45 g/L well-nourished), and secondarily by the prognostic nutritional index (PNI) and Global Leadership Initiative on Malnutrition (GLIM) criteria. Cox proportional hazard models were used to examine a 1-year composite outcome of hospitalization for HF or all-cause mortality while adjusting for age, sex, and other clinical confounders. Our community-based cohort consisted of 2,096 (39.0%) lean-well-nourished (low BMI, high SA), 1,369 (25.8%) obese-well-nourished (high BMI, high SA), 1,154 (21.8%) lean-malnourished (low BMI, low SA), and 681 (12.8%) obese-malnourished (high BMI, low SA) individuals. Obese-malnourished participants were on average older (54.5 ± 11.4 years) and more often women (41%), with a higher mean waist circumference (91.7 ± 8.8 cm), the highest percentage of body fat (32%), and the highest prevalence of hypertension (32%), diabetes (12%), and history of cardiovascular disease (11%), compared to all other subgroups (all p < 0.001). N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were substantially increased in the malnourished (versus well-nourished) groups, to a similar extent in lean (70.7 ± 177.3 versus 36.8 ± 40.4 pg/mL) and obese (73.1 ± 216.8 versus 33.2 ± 40.8 pg/mL) (p < 0.001 in both) participants. The obese-malnourished (high BMI, low SA) group also had greater left ventricular remodeling (left ventricular mass index, 44.2 ± 1.52 versus 33.8 ± 8.28 gm/m.sup.2 ; relative wall thickness 0.39 ± 0.05 versus 0.38 ± 0.06) and worse diastolic function (TDI-e' 7.97 ± 2.16 versus 9.87 ± 2.47 cm/s; E/e' 9.19 ± 3.01 versus 7.36 ± 2.31; left atrial volume index 19.5 ± 7.66 versus 14.9 ± 5.49 mL/m.sup.2) compared to the lean-well-nourished (low BMI, high SA) group, as well as all other subgroups (p < 0.001 for all). Over a median 3.6 years (interquartile range 2.5 to 4.8 years) of follow-up, the obese-malnourished group had the highest multivariable-adjusted risk of the composite outcome (hazard ratio HR 2.49, 95% CI 1.43 to 4.34, p = 0.001), followed by the lean-malnourished (HR 1.78, 95% CI 1.04 to 3.04, p = 0.034) and obese-well-nourished (HR 1.41, 95% CI 0.77 to 2.58, p = 0.27) groups (with lean-well-nourished group as reference). Results were similar when indexed by other anthropometric indices (waist circumference and body fat) and other measures of nutritional status (PNI and GLIM criteria). Potential selection bias and residual confounding were the main limitations of the study. In our cohort study among asymptomatic community-based adults in Taiwan, we found that obese individuals with poor nutritional status have the highest comorbidity burden, the most adverse cardiac remodeling, and the least favorable composite outcome.
Flycatcher1 (FLYC1), a MscS homolog, has recently been identified as a candidate mechanosensitive (MS) ion channel involved in Venus flytrap prey recognition. FLYC1 is a larger protein and its ...sequence diverges from previously studied MscS homologs, suggesting it has unique structural features that contribute to its function. Here, we characterize FLYC1 by cryo-electron microscopy, molecular dynamics simulations, and electrophysiology. Akin to bacterial MscS and plant MSL1 channels, we find that FLYC1 central core includes side portals in the cytoplasmic cage that regulate ion preference and conduction, by identifying critical residues that modulate channel conductance. Topologically unique cytoplasmic flanking regions can adopt 'up' or 'down' conformations, making the channel asymmetric. Disruption of an up conformation-specific interaction severely delays channel deactivation by 40-fold likely due to stabilization of the channel open state. Our results illustrate novel structural features and likely conformational transitions that regulate mechano-gating of FLYC1.
We aimed to evaluate the impact of early initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) with known or at risk of ...atherosclerotic cardiovascular disease (ASCVD). T2D with first prescription of SGLT2i (Dx-to-Rx time) less than or equal to12 months were matched with >12 months using propensity score derived from logistic regression. T2D were divided into 3 groups: (i) known ASCVD; (ii) additional CV risk factor(s) and; (iii) without ASCVD or additional CV risk factors. Incidence rates of 3-point major adverse cardiovascular events (MACE, including non-fatal stroke, non-fatal myocardial infarction and CV death) were compared between Dx-to-Rx time less than or equal to12 months and >12 months across 3 subgroups. Median follow-up was 2.8 years (IQR 2.2 to 3.4). Among 29,309 T2D (mean age 57.6±11.4 years, 59.0% men), 23.6% had established ASCVD and 66.6% had additional CV risk factors. Overall, 19.0% of patients had Dx-to-Rx time less than or equal to12 month which was associated with lower rates of MACE hazard ratio (HR) = 0.27, 95%CI: 0.17-0.42. Benefits of early initiation of SGLT2i was observed in patients with additional CV risk factors or known ASCVD but not in those without CV risk factors or ASCVD (P for interaction = 0.001). Early initiation of SGLT2 inhibitor was associated with lower MACE rates in T2D with known or at risk of ASCVD.
Isothermal compression tests of a new type Al–Zn–Mg–Er–Zr alloy are carried out on a Gleeble-3800 thermal simulator at temperatures varying from 300 to 460°C and strain rates ranging from 0.001 to ...10s−1. A comprehensive and scientific constitutive models based on the Arrhenius type equation have been developed from the experimentally measured data. The deformation temperature and strain rate have significant effect on flow stress and the material constants, such as α, β, n, lnA and Q are the functions of the strain. The flow stress calculated by the developed constitutive equation shows a close agreement with the experimental value, which indicates that the proposed constitutive equation can precisely analyze the hot deformation behavior of the Al–Zn–Mg–Er–Zr alloy. Due to the presence of coherent L12-structured Al3(Er,Zr) precipitates, the dominant softening mechanism is dynamic recovery during isothermal compression.
•We investigate the precipitation evolution of dilute Al–Er–Zr at 450 and 500°C.•The coarsening is controlled by the diffusion of solute atoms in the outer layer.•Precipitates in Al–Er–Zr have ...enhanced coarsening resistance compared with Al3Er.•Precipitates in Al–0.04Er–0.08Zr transform to D023 after aging at 500°C for 100h.
The temporal evolution of the Al3(ErZr) precipitates is investigated in Al–0.04Er–0.04Zr and Al–0.04Er–0.08Zr alloys during aging at elevated temperature of 450 and 500°C. The results show that the coarsening behavior of the precipitates in both alloys is similar, due to the core–shell structure with Zr segregated in the shell of the Al3(ErZr) precipitates. With the increase of the amount of Zr addition, the misfit between the precipitate and the Al matrix decreases, consequently the coherency transition size of the precipitates in Al–0.04Er–0.08Zr is larger than that of Al–0.04Er–0.04Zr. After aging at 500°C for 100h, some of the precipitates in Al–0.04Er–0.08Zr transform to D023 structure due to the high Zr/Er ratio, while the precipitates in Al–0.04Er–0.04Zr keep the L12 structure.
Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid ...parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
Background and purpose
Physical activity is associated with a reduced incidence of first‐time stroke. However, few studies have examined the effect of pre‐stroke physical activity on post‐stroke ...complications and clinical outcomes.
Methods
A total of 39 835 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2009 were analyzed according to five levels of severity as determined by National Institutes of Health Stroke Scale score upon hospital admission. Pre‐stroke physical activity was defined in the Taiwan Stroke Registry as dedicated leisure‐time physical activity for at least 30 min/day for 3 days/week for more than 6 months. A Cox model was used to compare complications and outcomes between active and inactive groups.
Results
The active and inactive groups were similar in age distribution and stroke type distribution, but the active group had better National Institutes of Health Stroke Scale scores upon admission. The active group also had significantly fewer post‐stroke complications. Active patients had lower hospital mortality and better functional outcomes upon discharge as per the modified Rankin Scale. Improved functional status in the active group was significant at 1, 3 and 6 months post‐stroke.
Conclusion
Dedicated leisure‐time physical activity for at least 30 min/day, at least three times per week for more than 6 months was associated with decreased stroke severity, fewer post‐stroke complications, lower mortality and better outcomes.
The precipitation hardening of dilute Al–Er, Al–Zr and Al–Er–Zr alloys was investigated by microhardness measurements and transmission electron microscopy. The Al–0.04Er (at.%) alloy obtains its ...maximum aging hardness of 400
MPa due to the precipitation of Al
3Er. The Al–0.04Er–0.08Zr obtains a maximum hardness of 560
MPa, which is significant greater than that of the Al–Er and Al–Zr alloys. The synergetic effect of Er and Zr on the precipitation hardening of Al–Er–Zr alloys is discussed.
Mast cells (MCs) are central effector cells in allergic reactions that are often mediated by immunoglobulin E (IgE). Allergies commonly start at an early age, and both MCs and IgE are detectable in ...fetuses. However, the origin of fetal IgE and whether fetal MCs can degranulate in response to IgE-dependent activation are presently unknown. Here, we show that human and mouse fetal MCs phenotypically mature through pregnancy and can be sensitized by maternal IgE. IgE crossed the placenta, dependent on the fetal neonatal Fc receptor (FcRN), and sensitized fetal MCs for allergen-specific degranulation. Both passive and active prenatal sensitization conferred allergen sensitivity, resulting in postnatal skin and airway inflammation after the first allergen encounter. We report a role for MCs within the developing fetus and demonstrate that fetal MCs may contribute to antigen-specific vertical transmission of allergic disease.
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