Membrane proteins with multiple transmembrane domains play critical roles in cell physiology, but little is known about the machinery coordinating their biogenesis at the endoplasmic reticulum. Here ...we describe a ~ 360 kDa ribosome-associated complex comprising the core Sec61 channel and five accessory factors: TMCO1, CCDC47 and the Nicalin-TMEM147-NOMO complex. Cryo-electron microscopy reveals a large assembly at the ribosome exit tunnel organized around a central membrane cavity. Similar to protein-conducting channels that facilitate movement of transmembrane segments, cytosolic and luminal funnels in TMCO1 and TMEM147, respectively, suggest routes into the central membrane cavity. High-throughput mRNA sequencing shows selective translocon engagement with hundreds of different multi-pass membrane proteins. Consistent with a role in multi-pass membrane protein biogenesis, cells lacking different accessory components show reduced levels of one such client, the glutamate transporter EAAT1. These results identify a new human translocon and provide a molecular framework for understanding its role in multi-pass membrane protein biogenesis.
Ubiquitin-specific protease 19 (USP19) is a member of the deubiquitinating (DUB) enzymes that catalyze removing the ubiquitin signals from target proteins. Our previous research has demonstrated that ...USP19 up-regulates the protein level and aggregation of polyQ-expanded huntingtin through the involvement of heat shock protein 90 (HSP90). Here, we present solution structures of the CS1, CS2 and UbL domains of USP19 and structural insights into their domain interactions. We found that the tandem CS domains fold back to interact with the C-terminal USP domain (USPD) intra-molecularly that leads to inhibition of the catalytic core of USP19, especially CS1 interacts with the embedded UbL domain and CS2 does with the CH2 catalytic core. Moreover, CS2 specifically interacts with the NBD domain of HSP90, which can activate the DUB enzyme. A mechanism of auto-inhibition of USP19 and activation by HSP90 is proposed, on which USP19 modulates the protein level of polyQ-expanded huntingtin in cells. This study provides structural and mechanistic insights into the modulation of protein level and aggregation by USP19 with the assistance of HSP90.
Abstract
Context
The association of maternal gestational diabetes mellitus (GDM) with neurodevelopmental outcomes remains controversial and evidence that maternal increasing levels of glucose during ...pregnancy associated with the risk for impaired neurodevelopment were limited.
Objective
To identify the continuous association of increasing maternal glucose levels with neurodevelopmental disorders in offspring and explore the potential contribution of cord metabolites to this association.
Methods
The prospective birth cohort study included 1036 mother-child pairs. Primary predictors were maternal exposure GDM and maternal glucose values at a 75-g oral-glucose-tolerance test at 24 to 28 weeks during pregnancy. Primary neurodevelopmental outcomes at 12 months in offspring were assessed by the Ages and Stages Questionnaires, Third Edition (ASQ-3).
Results
Maternal GDM was associated with failing the communication domain in offspring in the adjusted models relative risk (RR) with 95% CI: 1.97 (1.11, 3.52). Increasing levels of fasting plasma glucose (FPG), 1-h plasma glucose (1-h PG) and 2-h plasma glucose (2-h PG) with 1 SD change were at higher risks in failing the personal social domain of ASQ-3 RRs with 95% CI for FPG: 1.49 (1.09, 2.04); for 1-h PG: 1.70 (1.27, 2.29); for 2-h PG: 1.36 (1.01, 1.84). The linear association was also demonstrated. Compared with girls, boys exposed to higher maternal glucose levels were inclined to the failure of the personal social domain. Mediation analysis showed the contribution of maternal GDM to failure of communication domain mediated by C-peptide.
Conclusions
Maternal glucose levels below those diagnostic of diabetes are continuously associated with impaired neurodevelopment in offspring at 12 months.
The isothermal compression experiments with the strain rates of 0.01–10 s−1 and deformation temperature range of 300–420 °C are performed to investigate the hot deformation behavior of A356 aluminum ...alloy. Also, the complex deformation mechanisms are analyzed. It is found that, as the strain is gradually increased, the flow stress first rises, and then the stable stress appears without a tangible peak. The microstructures exhibit large elongated grains, and only a few small new grains appear under most deformation conditions. It is because the dynamic recovery (DRV) is the dominant softening mechanism. Based on the measured data, both the original Johnson–Cook (O–JC) model and modified Johnson–Cook model (M–JC) are built for the tested aluminum alloy. However, there are different deviations between the experimental and the predicted true stresses by O–JC model and M–JC model. Considering the obvious DRV features, an enhanced Johnson–Cook (EH–JC) model is proposed by introducing the stress–dislocation relation. The accuracy of the EH–JC model is validated because the correlation coefficient between the experimental and predicted results is as high as 0.997, whereas the average absolute relative error is merely 2.84%.
The hot compressive deformation behaviors of A356 aluminum alloy are studied. The main softening mechanism is dynamic recovery. Both the original Johnson–Cook model and modified Johnson–Cook model are built, but they cannot accurately describe the hot deformation behavior. Considering the obvious DRV feature, an enhanced Johnson–Cook model is proposed and validated.
Abstract
Background
Haemaphysalis
longicornis
is an obligate hematophagous ectoparasite that transmits a variety of pathogens causing life-threatening diseases in humans and animals. Paramyosin (Pmy) ...is not only an invertebrate-specific myofibrillar protein but also an important immunomodulatory protein. Therefore, it is one of the ideal candidate antigens for vaccines.
Methods
We conducted two vaccine trials to evaluate the protective efficacy of Pmy recombinant protein (rPmy) and peptide vaccine (KLH-LEE). Each rabbit was immunized with three doses of rPmy or KLH-LEE adjuvanted with Freund’s complete/incomplete at 500 μg/dose at 2-week intervals before challenge with 40 female
H.
longicornis/
rabbit. PBS plus adjuvant, Trx or KLH was used as control group. The antibodies of rabbits were detected by ELISA. Then, female ticks were fed on the rabbits until detachment.
Results
ELISA results showed that both vaccines induced rabbits to produce antibodies. Compared with the Trx group, the engorgement weight, oviposition and hatchability of the rPmy group decreased by 8.87%, 26.83% and 38.86%, respectively. On the other hand, engorgement weight, oviposition and hatchability of female ticks in the KLH-LEE group correspondingly resulted in 27.03%, 53.15% and 38.40% reduction compared with that of the KLH group. Considering the cumulative effect of vaccination on the evaluated parameters, results showed 60.37% efficacy of the rPmy vaccine formulation and 70.86% efficacy in the KLH-LEE group.
Conclusions
Pmy and particularly epitope LEE have potential for further development of an effective candidate vaccine to protect the host against tick infection.
Graphical Abstarct
Chloromethylisothiazolinone (CMIT) has been extensively used as antimicrobial in cosmetics, detergents, wall paints, and anti-fouling products. To prevent the potential ecological and health risks, ...the degradation mechanisms and toxicity changes of CMIT by Vacuum-Ultraviolet/Ultraviolet (VUV/UV) irradiation were investigated in this study. VUV/UV irradiation showed better performance on CMIT degradation compared to sole UV photolysis. The removal efficiency of CMIT with photon fluence of 0.6 μEinstein/cm2 was 8% and 100% by UV or VUV/UV irradiation, respectively. Radical quenching experiments indicated that 254 nm photolysis, 185 nm photolysis, and •OH oxidation contributed to CMIT degradation during VUV/UV process, with fluence-based apparent rate constants of 0.16, 0.13, and 4.9 μEinstein−1cm2, respectively. The formation of H2O2 during VUV/UV process increased to 0.7 mg/L at 4.5 min, and the concentration of •OH ranged within 1.0–3.8 × 10−12 M. The degradation of CMIT by VUV/UV irradiation in neutral condition was slightly higher than that in acidic and basic conditions. The removal efficiency of CMIT with reaction time of 2 min decreased from 92.2% to 34.3% when the concentration of HCO3−/CO32− increased to 1 mM. The degradation of CMIT by VUV/UV irradiation in secondary effluents was lower than that in ultrapure water because of the •OH scavenging effects, but still 2.9 times higher than that by UV photolysis. Four main degradation mechanisms of CMIT were observed during VUV/UV process, including the oxidation of sulfur, addition of hydroxyl groups on the double-carbon-bond, demethylation on the nitrogen, and substitution of organochlorine atom by hydroxyl group. Based on the quantitative structure activity relationship analysis, most products of CMIT underwent complete detoxification to fish and daphnia. 40% of products still showed acute toxicity to algae, but most of them were less toxic than CMIT.
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•VUV/UV irradiation outperformed UV photolysis for CMIT removal in wastewater effluent.•VUV/UV degraded CMIT by 185 nm photolysis, 254 nm photolysis and .•OH oxidation•The formation of hydrogen peroxide and hydroxyl radicals was quantified.•CMIT was degraded by dechlorination, N-demethylation, oxidation of sulfur and alkene.•Most products were partially or completely detoxified to fish, daphnia and algae.
25 models are designed according to the orthogonal table, to study the comprehensive relationship between heat transfer and sealing characteristics in straight-through labyrinth seals with different ...geometrical parameters. The experimental investigations are carried out at different pressure ratios of 1.2, 1.3, 1.4, 1.6, 1.8. The results show that different geometry parameters brought obvious different influence on both leakage efficiency and heat transfer characteristics, and in which the parameters (H, c,β) have the most significant influence on leakage efficiency, and heat transfer characteristics under different pressure ratios, whose small changes in size can lead to performance optimization in leakage and heat transfer. The geometrical parameters always show consistent influence on leakage efficiency and heat transfer characteristics, while heat transfer characteristics show larger vibration with the increase of pressure ratio.
Cushioning materials generally absorb kinetic mechanical energy under compression actions at a relatively constant stress over a large range of displacement. However, cushioning materials widely used ...today are polyurethane (PU) foams with low moisture transmission. As a new class of three-dimensional textile structures, warp-knitted spacer fabrics not only have much better moisture transmission property than PU foams, but also have the similar cushioning performance if appropriate structural parameters are adopted. This paper reports an experimental study on the compression behavior of a series of warp-knitted fabrics made for cushioning applications. These fabrics were produced on a double-needle bar warp knitting machine of gauge 18 by varying different structural parameters including spacer yarn inclination angle and fineness, fabric thickness, and outer layer structure. Both the compression stress-strain curves and energy efficiency diagrams from the testing results were used to analyze the compression behavior of these fabrics and the effect of each structural parameter. The results indicate that warp-knitted spacer fabrics are an ideal class of the energy absorbers for cushioning applications and their energy-absorption capacity can easily be tailored to meet specific end-use requirements by simply varying their structural parameters with the help of efficiency diagrams.
Background
Skeletal muscle mass and quality assessed by computed tomography (CT) images of the third lumbar vertebra (L3) level have been established as risk factors for poor clinical outcomes in ...several illnesses, but the relevance for dialysis patients is unclear. A few studies have suggested a correlation between CT‐determined skeletal muscle mass and quality at the first lumbar vertebra (L1) level and adverse outcomes. Generally, chest CT does not reach beyond L1. We aimed to determine whether opportunistic CT scan (chest CT)‐determined skeletal muscle mass and quality at L1 are associated with mortality in initial‐dialysis patients.
Methods
This 3‐year multicentric retrospective study included initial‐dialysis patients from four centres between 2014 and 2017 in China. Unenhanced CT images of the L1 and L3 levels were obtained to assess skeletal muscle mass by skeletal muscle index, (SMI), cm2/m2 and quality by skeletal muscle density (SMD), HU. Skeletal muscle measures at L1 were compared with those at L3. The sex‐specific optimal cutoff values of L1 SMI and L1 SMD were determined in relation to all‐cause mortality. The outcomes were all‐cause death and cardiac death. Cox regression models were applied to investigate the risk factors for death.
Results
A total of 485 patients were enrolled, of whom 257 had both L1 and L3 images. Pearson's correlation coefficient between L1 and L3 SMI was 0.84 (P < 0.001), and that between L1 and L3 SMD was 0.90 (P < 0.001). No significant association between L1 SMI and mortality was observed (P > 0.05). Low L1 SMD (n = 280, 57.73%) was diagnosed based on the optimal cutoff value (<39.56 HU for males and <33.06 HU for females). Multivariate regression analysis revealed that the low L1 SMD group had higher risks of all‐cause death (hazard ratio 1.80; 95% confidence interval 1.05–3.11, P = 0.034) and cardiac death (hazard ratio 3.74; 95% confidence interval 1.43–9.79, P = 0.007).
Conclusions
In initial‐dialysis patients, there is high agreement between the L1 and L3 measures for SMI and SMD. Low SMD measured at L1, but not low SMI, is an independent predictor of both all‐cause death and cardiac death.
•VUV/UV/chlorine showed synergistic effect on DDBAC degradation than chlorine, UV, VUV/UV, UV/chlorine.•DDBAC degraded through both UV photolysis and radical oxidation during VUV/UV/chlorine.•The ...concentration and contribution of OH and Cl during VUV/UV/chlorine oxidation were calculated.•Degradation pathway of DDBAC during VUV/UV/chlorine oxidation was proposed.
Quaternary ammonium compounds (QACs) are crucial ingredients in many cleaning agents, disinfectants and personal care products. They are widely detected in aquatic environments. In this study, vacuum ultraviolet (VUV)/UV/chlorine was used to degrade dodecyl dimethyl benzyl ammonium chloride (DDBAC, a typical QAC). The degradation efficiency of VUV/UV/chlorine on DDBAC was the highest among chlorine, UV, VUV/UV, UV/chlorine and VUV/UV/chlorine. During the VUV/UV/chlorine process, with chlorine concentration increasing from 0 to 700 μM, the degradation rate constant of DDBAC increased from 0.16 to 0.22 min−1 then decreased to 0.17 min−1. When the chloride concentration was 10 mM and 50 mM, the degradation rate constant of DDBAC decreased by 31% and 55%, respectively. Inorganic anions and organic compounds in the reverse osmosis concentrate inhibited the degradation of DDBAC by quenching radicals. The degradation mechanisms of DDBAC degradation during the VUV/UV/chlorine process include UV photolysis and oxidation by OH, Cl and other reactive species. With the increase in pH from 5 to 10, the OH concentration decreased from 18.7 × 10−14 M to 7.5 × 10−14 M, and the Cl concentration decreased from 8.8 × 10−14 M to 2.1 × 10−14 M. At pH 5–10, contributions of OH and Cl to DDBAC degradation were 30%−44% and 18%−37%, respectively. Degradation mechanisms of DDBAC mainly include hydrogen abstraction, hydroxylation, and cleavage of the C-N bond. The concentrations of four chlorinated products (trichloromethane, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid) mostly initially increased and then decreased.
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