Steric trapping reveals a cooperativity network in the intramembrane protease GlpG.

Membrane proteins are assembled through balanced interactions among proteins, lipids and water. Studying their folding while maintaining the native lipid environment is necessary but challenging. Here we present methods for analyzing key elements of membrane protein folding including thermodynamic stability, compactness of the unfolded state and folding cooperativity under native conditions. The methods are based on steric trapping, which couples the unfolding of a doubly biotinylated protein to the binding of monovalent streptavidin (mSA). We further advanced this technology for general application by developing versatile biotin probes possessing spectroscopic reporters that are sensitized by mSA binding or protein unfolding. By applying these methods to the Escherichia coli intramembrane protease GlpG, we elucidated a widely unraveled unfolded state, subglobal unfolding of the region encompassing the active site, and a network of cooperative and localized interactions to maintain stability. These findings provide crucial insights into the folding energy landscape of membrane proteins

The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins

As a first-line vertebrate immune defense, the polymeric immunoglobulin receptor (pIgR) transports polymeric IgA and IgM across epithelia to mucosal secretions, where the cleaved ectodomain (secretory component; SC) becomes a component of secretory antibodies, or when unliganded, binds and excludes bacteria. Here we report the 2.6Å crystal structure of unliganded human SC (hSC) and comparisons with a 1.7Å structure of teleost fish SC (tSC), an early pIgR ancestor. The hSC structure comprises five immunoglobulin-like domains (D1-D5) arranged as a triangle, with an interface between ligand-binding domains D1 and D5. Electron paramagnetic resonance measurements confirmed the D1-D5 interface in solution and revealed that it breaks upon ligand binding. Together with binding studies of mutant and chimeric SCs, which revealed domain contributions to secretory antibody formation, these results provide detailed models for SC structure, address pIgR evolution, and demonstrate that SC uses multiple conformations to protect mammals from pathogens

Damage modelling: the current state and the latest progress on the development of creep damage constitutive equations for high Cr steels

This paper reviews the fundamentals of the development of creep damage constitutive equations for high Cr steels including (1) a concise summary of the characteristics of creep deformation and creep damage evolution and their dependence on the stress level and the importance of cavitation for the final fracture; (2) a critical review of the state of art of creep damage equation for high Cr steels; (3) some discussion and comments on the various approaches; (4) consideration and suggestion for future work. It emphasises the need for better understanding the nucleation, cavity growth and coalesces and the theory for coupling method between creep cavity damage and brittle fracture and generalisatio

Human Anti-Plague Monoclonal Antibodies Protect Mice from Yersinia pestis in a Bubonic Plague Model

Yersinia pestis is the etiologic agent of plague that has killed more than 200 million people throughout the recorded history of mankind. Antibiotics may provide little immediate relief to patients who have a high bacteremia or to patients infected with an antibiotic resistant strain of plague. Two virulent factors of Y. pestis are the capsid F1 protein and the low-calcium response (Lcr) V-protein or V-antigen that have been proven to be the targets for both active and passive immunization. There are mouse monoclonal antibodies (mAbs) against the F1- and V-antigens that can passively protect mice in a murine model of plague; however, there are no anti-Yersinia pestis monoclonal antibodies available for prophylactic or therapeutic treatment in humans. We identified one anti-F1-specific human mAb (m252) and two anti-V-specific human mAb (m253, m254) by panning a naïve phage-displayed Fab library against the F1- and V-antigens. The Fabs were converted to IgG1s and their binding and protective activities were evaluated. M252 bound weakly to peptides located at the F1 N-terminus where a protective mouse anti-F1 mAb also binds. M253 bound strongly to a V-antigen peptide indicating a linear epitope; m254 did not bind to any peptide from a panel of 53 peptides suggesting that its epitope may be conformational. M252 showed better protection than m253 and m254 against a Y, pestis challenge in a plague mouse model. A synergistic effect was observed when the three antibodies were combined. Incomplete to complete protection was achieved when m252 was given at different times post-challenge. These antibodies can be further studied to determine their potential as therapeutics or prophylactics in Y. pestis infection in humans

Fine Particulate Matter Concentrations in Urban Chinese Cities, 2005–2016: A Systematic Review

Background: Particulate matter pollution has become a growing health concern over the past few decades globally. The problem is especially evident in China, where particulate matter levels prior to 2013 are publically unavailable. We conducted a systematic review of scientific literature that reported fine particulate matter (PM2.5) concentrations in different regions of China from 2005 to 2016. Methods: We searched for English articles in PubMed and Embase and for Chinese articles in the China National Knowledge Infrastructure (CNKI). We evaluated the studies overall and categorized the collected data into six geographical regions and three economic regions. Results: The mean (SD) PM2.5 concentration, weighted by the number of sampling days, was 60.64 (33.27) µg/m3 for all geographic regions and 71.99 (30.20) µg/m3 for all economic regions. A one-way ANOVA shows statistically significant differences in PM2.5 concentrations between the various geographic regions (F = 14.91, p < 0.0001) and the three economic regions (F = 4.55, p = 0.01). Conclusions: This review identifies quantifiable differences in fine particulate matter concentrations across regions of China. The highest levels of fine particulate matter were found in the northern and northwestern regions and especially Beijing. The high percentage of data points exceeding current federal regulation standards suggests that fine particulate matter pollution remains a huge problem for China. As pre-2013 emissions data remain largely unavailable, we hope that the data aggregated from this systematic review can be incorporated into current and future models for more accurate historical PM2.5 estimates

A county-level estimate of PM2.5 related chronic mortality risk in China based on multi-model exposure data

BACKGROUND: Ambient fine particulate matter (PM2.5) pollution is currently a serious environmental problem in China, but evidence of health effects with higher resolution and spatial coverage is insufficient. OBJECTIVE: This study aims to provide a better overall understanding of long-term mortality effects of PM2.5 pollution in China and a county-level spatial map for estimating PM2.5 related premature deaths of the entire country. METHOD: Using four sets of satellite-derived PM2.5 concentration data and the integrated exposure-response model which has been employed by the Global Burden of Disease (GBD) to estimate global mortality of ambient and household air pollution in 2010, we estimated PM2.5 related premature mortality for five endpoints across China in 2010. RESULT: Premature deaths attributed to PM2.5 nationwide amounted to 1.27million in total, and 119,167, 83,976, 390,266, 670,906 for adult chronic obstructive pulmonary disease, lung cancer, ischemic heart disease, and stroke, respectively; 3995 deaths for acute lower respiratory infections were estimated in children under the age of 5. About half of the premature deaths were from counties with annual average PM2.5 concentrations above 63.61μg/m3, which cover 16.97% of the Chinese territory. These counties were largely located in the Beijing-Tianjin-Hebei region and the North China Plain. High population density and high pollution areas exhibited the highest health risks attributed to air pollution. On a per capita basis, the highest values were mostly located in heavily polluted industrial regions. CONCLUSION: PM2.5-attributable health risk is closely associated with high population density and high levels of pollution in China. Further estimates using long-term historical exposure data and concentration-response (C-R) relationships should be completed in the future to investigate longer-term trends in the effects of PM2.5

Biophysical and Biochemical Characterization of Avian Secretory Component Provides Structural Insights into the Evolution of the Polymeric Ig Receptor

The polymeric Ig receptor (pIgR) transports polymeric Abs across epithelia to the mucosa, where proteolytic cleavage releases the ectodomain (secretory component [SC]) as an integral component of secretory Abs, or as an unliganded protein that can mediate interactions with bacteria. SC is conserved among vertebrates, but domain organization is variable: mammalian SC has five domains (D1-D5), whereas avian, amphibian, and reptilian SC lack the D2 domain, and fish SC lacks domains D2-D4. In this study, we used double electron–electron resonance spectroscopy and surface plasmon resonance binding studies to characterize the structure, dynamics, and ligand binding properties of avian SC, avian SC domain variants, and a human SC (hSC) variant lacking the D2 domain. These experiments demonstrated that, unlike hSC, which adopts a compact or “closed” domain arrangement, unliganded avian SC is flexible and exists in both closed and open states, suggesting that the mammalian SC D2 domain stabilizes the closed conformation observed for hSC D1-D5. Experiments also demonstrated that avian and mammalian pIgR share related, but distinct, mechanisms of ligand binding. Together, our data reveal differences in the molecular recognition mechanisms associated with evolutionary changes in the pIgR protein

Short- and intermediate-term exposure to NO2 and mortality: A multi-county analysis in China

Nitrogen dioxide (NO2) is a well-established traffic emissions tracer and has been associated with multiple adverse health outcomes. Short- and long-term exposure to NO2 has been studied and is well-documented in existing literature, but information on intermediate-term NO2 effects and mortality is lacking, despite biological plausibility. We obtained daily NO2 and mortality data from 42 counties in China from 2013 to 2015. Distributed-lag non-linear models were employed to investigate the relationship between non-accidental mortality and NO2 up to 30 days before the event, including PM2.5, temperature, relative humidity, and holidays as covariates in a random effects meta-analysis pooling county-specific estimates. We repeated the analysis for cardiovascular- and respiratory-related mortality, and explored sex-stratified associations. Per 10 μg/m3 increase in NO2, we estimated a 0.13% (95%CI: 0.03, 0.23%), 0.57% (95%CI: -0.04, 1.18%), and -0.14% (95%CI: -1.63, 1.37%) change in non-accidental mortality for same-day and previous-day NO2 (lag0-1 cumulated), in the preceding 7 days (lag0-7 cumulated), and in the preceding 30 days (lag0-30 cumulated), respectively. The strongest estimate was observed for respiratory-related mortality in the lag0-30 cumulated effect for women (3.12%; 95%CI: -1.66, 8.13%). We observed a trend of higher effect estimates of intermediate-term NO2 exposure on respiratory mortality compared to that of the short-term, although the differences were not statistically significant. Our results at longer lags for all-cause and cardiovascular mortality were sensitive to modeling choices. Future work should further investigate intermediate-term air pollution exposure given their potential biological relevance, but in larger scale settings. Keywords: air pollution; epidemiology; intermediate-term effects; nitrogen dioxide; random-effects meta-analysi

Hypoglycemia and Death in Mice Following Experimental Exposure to an Extract of Trogia venenata Mushrooms

BACKGROUND: Clusters of sudden unexplained death (SUD) in Yunnan Province, China, have been linked to eating Trogia venenata mushrooms. We evaluated the toxic effect of this mushroom on mice. METHODS: We prepared extracts of fresh T. venenata and Laccaria vinaceoavellanea mushrooms collected from the environs of a village that had SUD. We randomly allocated mice into treatment groups and administered mushroom extracts at doses ranging from 500 to 3500 mg/kg and water (control) via a gavage needle. We observed mice for mortality for 7 days after a 3500 mg/kg dose and for 24 hours after doses from 500 to 3000 mg/kg. We determined biochemical markers from serum two hours after a 2000 mg/kg dose. RESULTS: Ten mice fed T. venenata extract (3500 mg/kg) died by five hours whereas all control mice (L. vinaceoavellanea extract and water) survived the seven-day observation period. All mice died by five hours after exposure to single doses of T. venenata extract ranging from 1500 to 3000 mg/kg, while the four mice exposed to a 500 mg/kg dose all survived. Mice fed 2000 mg/kg of T. venenata extract developed profound hypoglycemia (median= 0.66 mmol/L) two hours after exposure. DISCUSSION: Hypoglycemia and death within hours of exposure, a pattern unique among mushroom toxicity, characterize T. venenata poisoning

Mid-21st century ozone air quality and health burden in China under emissions scenarios and climate change

Despite modest emissions reductions of air pollutants in recent years, China still suffers from poor air quality, and the outlook for future air quality in China is uncertain. We explore the impact of two disparate 2050 emissions scenarios relative to 2015 in the context of a changing climate with the Geophysical Fluid Dynamics Laboratory Atmospheric Model version 3 (GFDL-AM3) chemistry-climate model. We impose the same near-term climate change for both emission scenarios by setting global sea surface temperature (SST) and sea ice cover (SIC) to the average over 2010–2019 and 2046–2055, respectively, from a three-member ensemble of GFDL coupled climate model simulations under the RCP8.5 (Representative Concentration Pathway) scenario. By the 2050s, annual mean surface ozone increases throughout China by up to 8 ppbv from climate change alone (estimated by holding air pollutants at 2015 levels while setting SIC and SST to 2050 conditions in the model) and by 8–12 ppbv in a scenario in which emissions of ozone precursors nitrogen oxides (NO x ) and anthropogenic volatile organic compounds (VOCs) increase by ~10%. In a scenario in which NO x and anthropogenic VOC emissions decline by 60%, annual mean surface ozone over China decreases by 16–20 ppbv in the 2050s relative to the 2010s. The ozone increase from climate change alone results in an additional 62 000 premature deaths in China as compared to 330 000 fewer premature deaths by the 2050s under a strong emissions mitigation scenario. In springtime over Southwestern China in the 2050s, the model projects 9–12 ppbv enhancements to surface ozone from the stratosphere (diagnosed with a model tracer) and from international anthropogenic emissions (diagnosed by differencing AM3 simulations with the same emissions within China but higher versus lower emissions in the rest of the world). Our findings highlight the effectiveness of emissions controls in reducing the health burden in China due to air pollution, and also the potential for climate change and rising global emissions to offset, at least partially, some of the ozone decreases attained with regional emission reductions in China