The Prospects for Immigration Amendments

Obg proteins are a family of P-loop GTPases, conserved from bacteria to human. The Obg protein in Escherichia coli (ObgE) has been implicated in many diverse cellular functions, with proposed molecular roles in two global processes, ribosome assembly and stringent response. Here, using pre-steady state fast kinetics we demonstrate that ObgE is an anti-association factor, which prevents ribosomal subunit association and downstream steps in translation by binding to the 50S subunit. ObgE is a ribosome dependent GTPase; however, upon binding to guanosine tetraphosphate (ppGpp), the global regulator of stringent response, ObgE exhibits an enhanced interaction with the 50S subunit, resulting in increased equilibrium dissociation of the 70S ribosome into subunits. Furthermore, our cryo-electron microscopy (cryo-EM) structure of the 50S? ObgE? GMPPNP complex indicates that the evolutionarily conserved N-terminal domain (NTD) of ObgE is a tRNA structural mimic, with specific interactions with peptidyl-transferase center, displaying a marked resemblance to Class I release factors. These structural data might define ObgE as a specialized translation factor related to stress responses, and provide a framework towards future elucidation of functional interplay between ObgE and ribosome-associated (p) ppGpp regulators. Together with published data, our results suggest that ObgE might act as a checkpoint in final stages of the 50S subunit assembly under normal growth conditions. And more importantly, ObgE, as a (p) ppGpp effector, might also have a regulatory role in the production of the 50S subunit and its participation in translation under certain stressed conditions. Thus, our findings might have uncovered an under-recognized mechanism of translation control by environmental cues

Thin film nanocomposite membranes of PIM-1 and graphene oxide/ZIF-8 nanohybrids for organophilic pervaporation

In this work, thin film nanocomposite (TFN) membranes of super-glassy polymer PIM-1 containing zeolitic imidazolate framework-8 (ZIF-8)/graphene oxide (GO) composites (ZG) have been prepared by dip-coating onto water pre-impregnated polyvinylidene fluoride (PVDF) substrates. Higher flux and improved separation factors as compared to bare PIM-1 thin film composite (TFC) membranes have been achieved in organophilic pervaporation; for an aqueous feed solution with 5 wt% of butanol at 65 °C, a total permeate flux of 7.9 ± 0.69 kg m−2h−1 and a separation factor (βBtOH/H2O) of 29.9 ± 1.99 have been obtained with a TFC membrane containing 0.5 wt% of ZG filler. The pervaporation separation index (PSI) of this membrane (228 kg m−2h−1) is amongst the highest values reported in the literature. This excellent performance is attributed to the formation of a defect-free PIM-1 active layer (<1 μm) and the hydrophobic nature of the ZG fillers.Patricia Gorgojo is grateful to the Spanish Ministerio de Economía y Competitividad and the European Social Fund for her Ramon y Cajal Fellowship (RYC2019-027060-I/AEI/10.13039/501100011033). Boya Qiu would like to acknowledge the China Scholarship Council (CSC, file no. 202006240076)and the University of Manchester for the joint PhD studentship to support her research.Peer reviewe

A Robust Deep Learning Method with Uncertainty Estimation for the Pathological Classification of Renal Cell Carcinoma based on CT Images

Objectives To develop and validate a deep learning-based diagnostic model incorporating uncertainty estimation so as to facilitate radiologists in the preoperative differentiation of the pathological subtypes of renal cell carcinoma (RCC) based on CT images. Methods Data from 668 consecutive patients, pathologically proven RCC, were retrospectively collected from Center 1. By using five-fold cross-validation, a deep learning model incorporating uncertainty estimation was developed to classify RCC subtypes into clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). An external validation set of 78 patients from Center 2 further evaluated the model's performance. Results In the five-fold cross-validation, the model's area under the receiver operating characteristic curve (AUC) for the classification of ccRCC, pRCC, and chRCC was 0.868 (95% CI: 0.826-0.923), 0.846 (95% CI: 0.812-0.886), and 0.839 (95% CI: 0.802-0.88), respectively. In the external validation set, the AUCs were 0.856 (95% CI: 0.838-0.882), 0.787 (95% CI: 0.757-0.818), and 0.793 (95% CI: 0.758-0.831) for ccRCC, pRCC, and chRCC, respectively. Conclusions The developed deep learning model demonstrated robust performance in predicting the pathological subtypes of RCC, while the incorporated uncertainty emphasized the importance of understanding model confidence, which is crucial for assisting clinical decision-making for patients with renal tumors. Clinical relevance statement Our deep learning approach, integrated with uncertainty estimation, offers clinicians a dual advantage: accurate RCC subtype predictions complemented by diagnostic confidence references, promoting informed decision-making for patients with RCC.Comment: 16 pages, 6 figure

Deacetylation of HSD17B10 by SIRT3 regulates cell growth and cell resistance under oxidative and starvation stresses.

17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) plays an important role in mitochondrial fatty acid metabolism and is also involved in mitochondrial tRNA maturation. HSD17B10 missense mutations cause HSD10 mitochondrial disease (HSD10MD). HSD17B10 with mutations identified from cases of HSD10MD show loss of function in dehydrogenase activity and mitochondrial tRNA maturation, resulting in mitochondrial dysfunction. It has also been implicated to play roles in the development of Alzheimer disease (AD) and tumorigenesis. Here, we found that HSD17B10 is a new substrate of NAD-dependent deacetylase Sirtuin 3 (SIRT3). HSD17B10 is acetylated at lysine residues K79, K99 and K105 by the acetyltransferase CBP, and the acetylation is reversed by SIRT3. HSD17B10 acetylation regulates its enzymatic activity and the formation of mitochondrial RNase P. Furthermore, HSD17B10 acetylation regulates the intracellular functions, affecting cell growth and cell resistance in response to stresses. Our results demonstrated that acetylation is an important regulation mechanism for HSD17B10 and may provide insight into interrupting the development of AD

No causal association between plasma cystatin C and cardiovascular diseases: Mendelian randomization analyses in UK biobank

BackgroundWe aimed to determine whether the plasma cystatin C is a causal risk factor for cardiovascular events, stroke, myocardial infarction (MI), and cardiovascular disease (CVD) mortality by conducting Mendelian randomization (MR) designs.MethodsOur study included 277,057 individuals free of CVDs or cancer at baseline in the UK Biobank. The genetic scores of plasma cystatin C comprising 67 single-nucleotide polymorphisms were calculated on the basis of data from a large genome-wide association study. By stratifying the genetic score, we conducted cox regression to assess the relationship between plasma cystatin C and CVDs. In this study, linear MR analysis was used to estimate the causal association between plasma cystatin C and CVDs.ResultsObservational analyses showed that plasma cystatin C concentrations were associated with the risk of CVDs [hazard ratios (HR) per standard deviation (SD) 1.09, 95% confidence interval (CI); 1.07–1.10] and CVD mortality (1.14, 1.11–1.17). Among CVDs, plasma cystatin C were associated with stroke (1.10, 1.08–1.11) and MI (1.08, 1.07–1.10). Linear MR analysis did not provide evidence of a causal association between plasma cystatin C and the risk of CVDs [odds ratio (OR) per SD 0.96, 95% CI;0.90–1.03], stroke (0.96, 0.93–1.01), MI (0.97, 0.91–1.03), and CVD mortality (0.98, 0.96–1.01), with consistent estimates from sensitivity analyses.ConclusionObservational findings indicated that higher plasma cystatin C is associated with a higher risk of CVDs; According to MR studies, there is no causal association between plasma cystatin C and the risk of CVDs and CVD mortality

Underlying beneficial effects of Rhubarb on constipation-induced inflammation, disorder of gut microbiome and metabolism

Background: Constipation is a common syndrome and a worldwide healthy problem. Constipation patients are becoming younger, with a 29.6% overall prevalence in children, which has captured significant attention because of its epigenetic rejuvenation and recurrent episodes. Despite the usage of rhubarb extract to relieve constipation, novel targets and genes implicated in target-relevant pathways with remarkable functionalities should still be sought for.Materials and methods: We established a reliable constipation model in C57B/6N male mice using intragastric administration diphenoxylate, and the eligible subjects received 600 mg/25 g rhubarb extract to alleviate constipation. Resultant constipation was morphological and genetically compared with the specimen from different groups.Results: Constipation mice exhibited thicker muscle layers, higher levels of cytokines, including IL-17 and IL-23, and lower content of IL-22. Bacterial abundance and diversity varied tremendously. Notably, the alterations were reversed following rhubarb extract treatment. Additionally, Constipation also had a substantial impact on short-chain fatty acids (SCFAs), medium- and long-chain fatty acids (MLCFAs), and the expression of SCFA receptors, GPR41 and GPR43.Conclusion: This thesis has provided insight that rhubarb extract promoted the flexibility of collagen fiber, reduced pro-inflammatory cytokines, enhanced anti-inflammatory cytokines, and maintained gut microflora balance with potential impacts on the fatty acid and polyamine metabolism

Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis

BACKGROUND: The odds ratio (OR) comparing pathogen presence in diarrhoeal cases versus asymptomatic controls is a measure for diarrhoeal disease cause that has been integrated into burden of disease estimates across diverse populations. This study aimed to estimate the OR describing the association between pathogen detection in stool and diarrhoea for 15 common enteropathogens by age group and child mortality setting. METHODS: We did a systematic review to identify case-control and cohort studies published from Jan 1, 1990, to July 9, 2019, which examined at least one enteropathogen of interest and the outcome diarrhoea. The analytical dataset included data extracted from published articles and supplemented with data from the Global Enteric Multicenter Study and the Malnutrition and Enteric Disease study. Random effects meta-analysis models were fit for each enteropathogen, stratified by age group and child mortality level, and adjusted for pathogen detection method and study design to produce summary ORs describing the association between pathogen detection in stool and diarrhoea. FINDINGS: 1964 records were screened and 130 studies (over 88 079 cases or diarrhoea samples and 135 755 controls or non-diarrhoea samples) were available for analysis. Heterogeneity (I2) in unadjusted models was substantial, ranging from 27·6% to 86·6% across pathogens. In stratified and adjusted models, summary ORs varied by age group and setting, ranging from 0·4 (95% CI 0·2-0·6) for Giardia lamblia to 54·1 (95% CI 7·4-393·5) for Vibrio cholerae. INTERPRETATION: Incorporating effect estimates from diverse data sources into diarrhoeal disease cause and burden of disease models is needed to produce more representative estimates. FUNDING: WHO, Bill & Melinda Gates Foundation, and National Institutes of Health

Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells

The genome of the severe acute respiratory syndrome coronavirus encodes for eight accessory viral proteins with no known homologues in other coronaviruses. One of these is the 3b protein, which is encoded by the second open reading frame in subgenomic RNA 3 and contains 154 amino acids. Here, a detailed time-course study was performed to compare the apoptosis and necrosis profiles induced by full-length 3b, a 3b mutant that was deleted by 30 amino acids from the C terminus (3b 124-154) and the classical apoptosis inducer, Bax. Our results showed that Vero E6 cells transfected with a construct for expressing 3b underwent necrosis as early as 6 h after transfection and underwent simultaneous necrosis and apoptosis at later time-points. At all the time-points analysed, the apoptosis induced by the expression of 3b was less than the level induced by Bax but the level of necrosis was comparable. The 3b 124-154 mutant behaves in a similar manner indicating that the localization of the 3b protein does not seems to be important for the cell-death pathways since full-length 3b is localized predominantly to the nucleolus, while the mutant is found to be concentrated in the peri-nuclear regions. To our knowledge, this is the first report of the induction of necrosis by a SARS-CoV protein.IS

Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide

Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many autophagy genes. Here, we show that, in contrast to Fip200 deletion, inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 does not impair the maintenance and differentiation of postnatal neural stem cells (NSCs). Only Fip200 deletion, but not Atg5, Atg16L1, or Atg7 deletion, caused p62/sequestome1 aggregates to accumulate in NSCs. Fip200 and p62 double conditional knockout mice demonstrated that p62 aggregate formation triggers aberrant superoxide increases by impairing superoxide dismutase functions. By comparing the inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 with Fip200 deletion, we revealed a critical role of increased p62 in determining the fate of autophagy-deficient NSCs through intracellular superoxide control

Sexual behaviour change following HIV testing services: a systematic review and meta-analysis.

INTRODUCTION: Learning one's HIV status through HIV testing services (HTS) is an essential step toward accessing treatment and linking to preventive services for those at high HIV risk. HTS may impact subsequent sexual behaviour, but the degree to which this varies by population or is true in the setting of contemporary HIV prevention activities is largely unknown. As part of the 2019 World Health Organization Consolidated Guidelines on HTS, we undertook a systematic review and meta-analysis to determine the effect of HTS on sexual behaviour. METHODS: We searched nine electronic databases for studies published between July 2010 and December 2019. We included studies that reported on at least one outcome (condom use [defined as the frequency of condom use or condom-protected sex], number of sex partners, HIV incidence, STI incidence/prevalence). We included studies that prospectively assessed outcomes and that fit into one of three categories: (1) those evaluating more versus less-intensive HTS, (2) those of populations receiving HTS versus not and (3) those evaluating outcomes after versus before HTS. We conducted meta-analyses using random-effects models. RESULTS AND DISCUSSION: Of 29 980 studies screened, 76 studies were included. Thirty-eight studies were randomized controlled trials, 36 were cohort studies, one was quasi-experimental and one was a serial cross-sectional study. There was no significant difference in condom use among individuals receiving more-intensive HTS compared to less-intensive HTS (relative risk [RR]=1.03; 95% CI: 0.99 to 1.07). Condom use was significantly higher after receiving HTS compared to before HTS for individuals newly diagnosed with HIV (RR = 1.65; 95% CI: 1.36 to 1.99) and marginally significantly higher for individuals receiving an HIV-negative diagnosis (RR = 1.63; 95% CI: 1.01 to 2.62). Individuals receiving more-intensive HTS reported fewer sex partners at follow-up than those receiving less-intensive HTS, but the finding was not statistically significant (mean difference = -0.28; 95% CI: -3.66, 3.10). CONCLUSIONS: Our findings highlight the importance of using limited resources towards HTS strategies that focus on early HIV diagnosis, treatment and prevention services rather than resources dedicated to supplementing or enhancing HTS with additional counselling or other interventions