Alterations of contralesional hippocampal subfield volumes and relations to cognitive functions in patients with unilateral stroke.

BACKGROUND: The volumes of the hippocampal subfields are related to poststroke cognitive dysfunctions. However, it remains unclear whether contralesional hippocampal subfield volume contributes to cognitive impairment. This study aimed to investigate the volumetric differences in the contralesional hippocampal subfields between patients with left and right hemisphere strokes (LHS/RHS). Additionally, correlations between contralesional hippocampal subfield volumes and clinical outcomes were explored. METHODS: Fourteen LHS (13 males, 52.57 ± 7.10 years), 13 RHS (11 males, 51.23 ± 15.23 years), and 18 healthy controls (11 males, 46.94 ± 12.74 years) were enrolled. Contralesional global and regional hippocampal volumes were obtained with T1-weighted images. Correlations between contralesional hippocampal subfield volumes and clinical outcomes, including the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), were analyzed. Bonferroni correction was applied for multiple comparisons. RESULTS: Significant reductions were found in contralesional hippocampal as a whole (adjusted p = .011) and its subfield volumes, including the hippocampal tail (adjusted p = .005), cornu ammonis 1 (CA1) (adjusted p = .002), molecular layer (ML) (adjusted p = .004), granule cell and ML of the dentate gyrus (GC-ML-DG) (adjusted p = .015), CA3 (adjusted p = .009), and CA4 (adjusted p = .014) in the RHS group compared to the LHS group. MoCA and MMSE had positive correlations with volumes of contralesional hippocampal tail (p = .015, r = .771; p = .017, r = .763) and fimbria (p = .020, r = .750; p = .019, r = .753) in the LHS group, and CA3 (p = .007, r = .857; p = .009, r = .838) in the RHS group, respectively. CONCLUSION: Unilateral stroke caused volumetric differences in different hippocampal subfields contralesionally, which correlated to cognitive impairment. RHS leads to greater volumetric reduction in the whole contralesional hippocampus and specific subfields (hippocampal tail, CA1, ML, GC-ML-DG, CA3, and CA4) compared to LHS. These changes are correlated with cognitive impairments, potentially due to disrupted neural pathways and interhemispheric communication.

Comparison of Cox regression and generalized Cox regression models to machine learning in predicting survival of children with diffuse large B-cell lymphoma.

Background: The incidence of diffuse large B-cell lymphoma (DLBCL) in children is increasing globally. Due to the immature immune system in children, the prognosis of DLBCL is quite different from that of adults. We aim to use the multicenter large retrospective analysis for prognosis study of the disease. Methods: For our retrospective analysis, we retrieved data from the Surveillance, Epidemiology and End Results (SEER) database that included 836 DLBCL patients under 18 years old who were treated at 22 central institutions between 2000 and 2019. The patients were randomly divided into a modeling group and a validation group based on the ratio of 7:3. Cox stepwise regression, generalized Cox regression and eXtreme Gradient Boosting (XGBoost) were used to screen all variables. The selected prognostic variables were used to construct a nomogram through Cox stepwise regression. The importance of variables was ranked using XGBoost. The predictive performance of the model was assessed by using C-index, area under the curve (AUC) of receiver operating characteristic (ROC) curve, sensitivity and specificity. The consistency of the model was evaluated by using a calibration curve. The clinical practicality of the model was verified through decision curve analysis (DCA). Results: ROC curve demonstrated that all models except the non-proportional hazards and non-log linearity (NPHNLL) model, achieved AUC values above 0.7, indicating high accuracy. The calibration curve and DCA further confirmed strong predictive performance and clinical practicability. Conclusions: In this study, we successfully constructed a machine learning model by combining XGBoost with Cox and generalized Cox regression models. This integrated approach accurately predicts the prognosis of children with DLBCL from multiple dimensions. These findings provide a scientific basis for accurate clinical prognosis prediction.

Single-cell transcriptomics reveals writers of RNA modification-mediated immune microenvironment and cardiac resident Macro-MYL2 macrophages in heart failure.

BACKGROUND: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown. METHODS: We comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored. RESULTS: Single-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics. CONCLUSION: Our study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.

Natriuretic peptide receptor-C perturbs mitochondrial respiration in white adipose tissue.

Natriuretic peptide receptor-C (NPR-C) is highly expressed in adipose tissues, and regulates obesity related diseases, however the detailed mechanism remains unknown. In this research, we aimed to explore the potential role of NPR-C in cold exposure and high-fat/high-sugar (HF/HS) diet induced metabolic changes, especially in regulating white adipose tissue (WAT) mitochondrial function. Our findings showed that NPR-C expression, especially in epididymal WAT (eWAT), was reduced after cold exposure. Global Npr3 (gene encoding NPR-C protein) deficiency led to reduced body weight, increased WAT browning, thermogenesis, and enhanced expression of genes related to mitochondrial biogenesis. RNA-sequencing of eWAT showed that Npr3 deficiency enhanced expression of mitochondrial respiratory chain complex genes and promoted mitochondrial oxidative phosphorylation in response to cold exposure. In addition, Npr3 KO mice were able to resist obesity induced by HF/HS diet. Npr3 knockdown in stromal vascular fraction (SVF)-induced white adipocytes promoted the expression of proliferator-activated receptor gamma coactivator 1α (PGC1α), uncoupling protein 1 (UCP1) and mitochondrial respiratory chain complexes. Mechanistically, NPR-C inhibited cGMP and calcium signaling in an NPR-B-dependent manner but suppressed cAMP signaling in an NPR-B-independent manner. Moreover, Npr3 knockdown induced browning via AKT and p38 pathway activation, which were attenuated by Npr2 knockdown. Importantly, treatment with the NPR-C specific antagonist, AP-811, decreased WAT mass and increased PGC-1α, UCP1 and mitochondrial complex expression. These findings demonstrate that NPR-C deficiency enhances metabolic health by boosting energy expenditure in WAT, emphasizing the potential of NPR-C inhibition for treating obesity and related metabolic disorders.

Current investigation of the high prevalence of sexual dysfunction in female patients with systemic lupus erythematosus: a cross-sectional study.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects women of childbearing age and has been reported to cause sexual dysfunction in women. Although there are articles on sexual function in women with SLE, the number of articles is small, and the factors affecting sexual function in women with SLE are controversial. Based on this, this study aimed to investigate the prevalence of sexual dysfunction in Chinese female SLE patients and to explore the factors that influence it. The study design was a cross-sectional study conducted from December 2023 to April 2024 in the Department of Rheumatology and Immunology of a tertiary hospital in Hefei, Anhui Province. A total of 293 female patients diagnosed with SLE were enrolled using face-to-face questionnaires and online questionnaires. The questionnaire consisted of four parts: general information questionnaire, fatigue severity scale (FSS), depression-anxiety-stress scale (DASS-21), and female sexual functioning index (FSFI) scale. A total of 173 (59.04%) patients had sexual dysfunction, including 251 (85.67%) with decreased libido and 186 (63.46%) with difficulty in sexual arousal. There was a correlation between the patients' total FSFI scores and age (p = 0.028), marital satisfaction (p < 0.001), own education level (p = 0.008), partner's education level (p = 0.003), place of residence (p = 0.039), monthly household income (p < 0.001), family financial satisfaction(p < 0.001), menstrual status (p = 0.003), hormone use (p = 0.021),immunosuppressant use (p = 0.042), disease activity (p = 0.016), FSS score (p < 0.001), stress score (p < 0.001), anxiety score (p < 0.001) and depression score (p < 0.001)were correlated. The results of stepwise regression analysis showed that marital satisfaction (b = 2.011, t = 3.797, p < 0.001), monthly household income (b = 0.854, t = 2.316, p = 0.021), menstrual status (b = 1.218, t = 2.350, p = 0.019), fatigue scale score (b = - 0.069, t = - 2.302, p = 0.022), and depression score (b = - 0.117, t = - 2.910, p = 0.004) were the influencing factors of FSFI total score, and the difference was statistically significant. The incidence of sexual dysfunction in Chinese female SLE patients is high, and medical personnel should pay more attention to patients' sexual problems, to provide theoretical and practical bases for further prevention, treatment, and care of sexual dysfunction in female SLE patients.

Associations of neutrophil-percentage-to-albumin ratio level with all-cause mortality and cardiovascular disease-cause mortality among patients with hypertension: evidence from NHANES 1999-2010.

Background: The associations of neutrophil-percentage-to-albumin ratio (NPAR) level with all-cause and cardiovascular disease (CVD)-cause mortality among patients with hypertension remain unclear. This study aims to investigate the associations of NPAR level with all-cause and CVD-cause mortality among patients with hypertension. Methods: This prospective cohort study included 8,990 patients with hypertension who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010. Multivariable Cox proportional hazards regression models were used to compute hazard ratios and 95% CIs for the associations of NPAR level with all-cause mortality and CVD-cause mortality. Restricted cubic spline analyses were used to examine the nonlinear association of NPAR level with all-cause mortality and CVD-cause mortality. Results: This cohort study included data from 8,990 participants in analysis. During 104,474 person-years of follow-up, 3,069 all-cause deaths and 1,449 CVD-cause deaths were documented. Nonlinear associations were observed for NPAR levels with risk of all-cause mortality and CVD-cause mortality among patients with hypertension. Compared with participants in T1 of NPAR, there was a significantly increased risk of all-cause mortality and CVD-cause mortality for participants in both T2 and T3 in the fully adjusted model (model 3). The corresponding HRs for all-cause mortality were 1.10 (95% CI, 0.98-1.22) and 1.63 (95% CI, 1.45-1.82). The corresponding HRs for CVD-cause mortality were 1.10 (95% CI, 0.99-1.23) and 1.63 (95% CI, 1.46-1.81). Conclusions: Elevated NPAR level was significantly associated with an increased risk of all-cause and CVD-cause mortality in adults with hypertension. NPAR may be clinically useful for predicting long-term health outcomes and mortality in hypertensive population.

Altered Brain Functional and Effective Connectivity Induced by Electroacupuncture in Rats Following Anterior Cruciate Ligament Transection.

Background: The chronic pain arising from knee osteoarthritis (KOA) is a prevalent clinical manifestation. As a traditional Chinese approach, electroacupuncture (EA) has a positive influence in relieving chronic pain from KOA. The study aims to explore functional connectivity (FC) and effective connectivity (EC) alterations induced by EA in anterior cruciate ligament transection (ACLT) rat model of KOA using resting-state functional magnetic resonance imaging (fMRI). Methods: After the establishment of ACLT, rats were randomly divided into the EA group and the sham-EA group. The EA group received EA intervention while the sham-EA group received sham-intervention for 3 weeks. Mechanical pain threshold (MPT) assessment was performed before and after intervention, and fMRI was conducted after intervention. Results: EA intervention effectively relieved pain in post-ACLT rats. Results of rest-state functional connectivity (rs-FC) analysis revealed that compared with the sham-EA group, the EA group had higher FC between the right raphe and the left auditory cortex, the left caudate_ putamen and the left internal capsule (IC), as well as the right zona incerta (ZI) and the left piriform cortex, but lower FC between the right raphe and the left hippocampus ventral, as well as the right septum and the left septum. Furthermore, Granger causality analysis (GCA) found the altered EC between the right septum and the left septum, as well as the left IC and the right septum. Conclusion: The results confirmed the effect of EA on analgesia in post- ACLT rats. The alterations of FC and EC, mainly involving basal ganglia and limbic system neural connections, might be one of the neural mechanisms underlying the effect of EA, providing novel information about connectomics plasticity of EA following ACLT.

Evaluating perceived technology self-efficacy and telehealth acceptance in optometry students.

CLINICAL RELEVANCE: Constant technological improvements require practitioners to be open to adopting technologies such as telehealth for enhanced patient care. Understanding the barriers and facilitators of telehealth adoption will guide stakeholders in making decisions for safe and effective implementation of telehealth. BACKGROUND: Effective use of telehealth improves patient outcomes. It is unclear if optometry students feel supported in using and/or are accepting of telehealth. This study evaluated telehealth acceptance of optometry students, its association with their technology self-efficacy, and whether telehealth training alters this relationship. METHODS: Final-year optometry students at the University of Melbourne were invited to participate in a telehealth course. A 22-item online survey adapted from the Technology Proficiency Self-Assessment for twenty-first Century Learning was used to evaluate technology self-efficacy pre- and post-learning. Telehealth acceptance was evaluated using a 34-item survey according to the Unified Theory of Acceptance and Use of Technology-2. A 5-point Likert scale was used for each item, yielding two total scores. Respondent demographics, frequency of usage and number of devices were recorded. Descriptive statistics, ANOVA and Pearson correlation were used to analyse demographic variables and relationship between technology self-efficacy and telehealth acceptance. RESULTS: 58 (68%) and 49 (58%) students participated in the pre- and post-learning surveys. Majority were 20-29-year-old females. Students used between two and four devices for online activities, with 62% being online at least hourly. Technology self-efficacy scores (average ± SD) pre- and post-learning were 83.8% ± 8.2 and 87.8% ± 7.1. Telehealth acceptance scores pre- and post-learning were 66.1% ± 9.6 and 73.98% ± 9.9. There was no association with gender, number of devices and frequency of online use for all scores. Correlation between technology self-efficacy and telehealth acceptance was insignificant pre-learning (p = 0.3) but was significant post-learning (p = 0.04). CONCLUSION: Optometry students demonstrated high technology self-efficacy compared to telehealth acceptance. Telehealth training resulted in marked improvement in telehealth acceptance.

Revealing and reconstructing the 3D Li-ion transportation network for superionic poly(ethylene) oxide conductor.

Understanding the Li-ions conduction network and transport dynamics in polymer electrolyte is crucial for developing reliable all-solid-state batteries. In this work, advanced nano- X-ray computed tomography combined with Raman spectroscopy and solid state nuclear magnetic resonance are used to multi-scale qualitatively and quantitatively reveal ion conduction network of poly(ethylene) oxide (PEO)-based electrolyte (from atomic, nano to macroscopic level). With the clear mapping of the microstructural heterogeneities of the polymer segments, aluminium-oxo molecular clusters (AlOC) are used to reconstruct a high-efficient conducting network with high available Li-ions (76.7%) and continuous amorphous domains via the strong supramolecular interactions. Such superionic PEO conductor (PEO-LiTFSI-AlOC) exhibites a molten-like Li-ion conduction behaviour among the whole temperature range and delivers an ionic conductivity of 1.87 × 10-4 S cm-1 at 35 °Ï¹. This further endows Li electrochemical plating/stripping stability under 50 µA cm-2 and 50 µAh cm-2 over 2000 h. The as-built Li|PEO-LiTFSI-AlOC|LiFePO4 full batteries show a high rate performance and a capacity retention more than 90% over 200 cycling at 250 µA cm-2, even enabling a high-loading LiFePO4 cathode of 16.8 mg cm-2 with a specific capacity of 150 mAh g-1 at 50 °Ï¹.

Radiological Features of Primary Pulmonary Invasive Mucinous Adenocarcinoma Based on 312 Consecutive Patients.

BACKGROUND: The aim of this study is to investigate the radiological features of primary pulmonary invasive mucinous adenocarcinoma (IMA) in a relatively large population to help improve its further understanding and its accuracy of initial diagnosis. METHODS: This retrospective study included consecutive patients with pathologically confirmed primary pulmonary IMA from January 2019 to December 2021. According to tumor morphology, IMAs were divided into regular nodule/mass, irregular, and large consolidative types. According to tumor density, IMAs were divided into solid, halo, part-solid, pure ground-glass, and cystic types. ANOVA, chi-square, or Fisher exact tests were used to analyze the differences in radiological and clinicopathological characteristics of IMA according to morphological and density subtypes. RESULTS: We analyzed 312 patients. Pulmonary IMA tended to occur in the elderly, with a slightly higher number of women than men. IMA showed a predominance in the lower lobe and adjacent to pleura. IMA of regular nodule/mass, irregular, and large consolidative types accounted for 80.8% (252/312), 13.8% (43/312), and 5.4% (17/312), respectively. Solid, halo, part-solid, pure ground-glass, and cystic IMAs accounted for 55.8% (174/312), 28.2% (88/312), 11.2% (35/312), 1.3% (4/312), and 3.5% (11/312), respectively. The lobulated (76.9%), spiculated (63.5%), and air bronchogram (56.7%) signs were common in IMA. Dead branch sign (88.2%), angiogram sign (88.2%), and satellite nodules/skipping lesions (47.1%) were common in large-consolidative-type IMA. Kirsten rat sarcoma viral oncogene mutations were common (56.1%), whereas epidermal growth factor receptor mutations were relatively rare (2.3%). CONCLUSIONS: Pulmonary IMA of regular nodule/mass type and solid type were the most common at the initial diagnosis. Detailed radiological features can aid in the differential diagnosis of IMA.

Whole-genome sequencing identifies novel genes for autism in Chinese trios.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (P<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (SCN2A, NF1, SHANK3, CHD8 etc.), several high confidence genes were highlighted by a series of functional analyses, including CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1, and MRPL12, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of de novo variants found in patient was significantly associated with the parents' ages at the birth of the child, and gender with trend. We also identified small de novo structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.

Association between CYP3A5 Gene Polymorphism and Post-Transplant Acute Immune Rejection in Renal Transplant Recipients Receiving Tacrolimus Therapy: A Correlation Study.

BACKGROUND: Acute immune rejection remains a challenge in the post-transplant period, with approximately 7.8% of renal transplant recipients experiencing rejection episodes within the first year. Genetic polymorphisms in the CYP3A5 gene, which influences tacrolimus metabolism, have garnered interest regarding their association with clinical outcomes in renal transplantation. METHODS: This retrospective correlation study analysed clinical data from kidney transplant patients who received tacrolimus treatment at our hospital from June 2015 to June 2023. The presence of CYP3A5 gene polymorphisms, tacrolimus trough levels, and demographic and clinical data were collected and analysed. RESULTS: A total of 105 kidney transplant patients were included. Patients were divided into acute immune rejection (n = 56) and non-acute immune rejection (n = 49) groups. The distribution of CYP3A5 gene polymorphisms differed significantly between the acute rejection and non-acute rejection groups (p = 0.037). The acute rejection group exhibited a higher frequency of CYP3A5 *1/*1 or *1/*3 genotypes than the non-acute rejection group. No statistically significant differences were found in the tacrolimus trough levels between the two groups. Correlation analysis revealed a statistically significant correlation between CYP3A5 gene polymorphism and post-transplant acute immune rejection (r = 0.223, p < 0.05). CONCLUSIONS: This study demonstrated a significant association between CYP3A5 gene polymorphism and the risk of post-transplant acute immune rejection in renal transplant recipients receiving tacrolimus therapy. These findings highlighted the importance of genetic variability in tacrolimus metabolism when managing immunosuppressive therapy in transplant recipients.

Optimizing the standardized assays for determining the catalytic activity and kinetics of peroxidase-like nanozymes.

Nanozymes are nanomaterials with enzyme-like catalytic properties. They are attractive reagents because they do not have the same limitations of natural enzymes (e.g., high cost, low stability and difficult storage). To test, optimize and compare nanozymes, it is important to establish fundamental principles and systematic standards to fully characterize their catalytic performance. Our 2018 protocol describes how to characterize the catalytic activity and kinetics of peroxidase nanozymes, the most widely used type of nanozyme. This approach was based on Michaelis-Menten enzyme kinetics and is now updated to take into account the unique physicochemical properties of nanomaterials that determine the catalytic kinetics of nanozymes. The updated procedure describes how to determine the number of active sites as well as other physicochemical properties such as surface area, shape and size. It also outlines how to calculate the hydroxyl adsorption energy from the crystal structure using the density functional theory method. The calculations now incorporate these measurements and computations to better characterize the catalytic kinetics of peroxidase nanozymes that have different shapes, sizes and compositions. This updated protocol better describes the catalytic performance of nanozymes and benefits the development of nanozyme research since further nanozyme development requires precise control of activity by engineering the electronic, geometric structure and atomic configuration of the catalytic sites of nanozymes. The characterization of the catalytic activity of peroxidase nanozymes and the evaluation of their kinetics can be performed in 4 h. The procedure is suitable for users with expertise in nano- and materials technology.

Computer-aided nanodrug discovery: recent progress and future prospects.

Nanodrugs, which utilise nanomaterials in disease prevention and therapy, have attracted considerable interest since their initial conceptualisation in the 1990s. Substantial efforts have been made to develop nanodrugs for overcoming the limitations of conventional drugs, such as low targeting efficacy, high dosage and toxicity, and potential drug resistance. Despite the significant progress that has been made in nanodrug discovery, the precise design or screening of nanomaterials with desired biomedical functions prior to experimentation remains a significant challenge. This is particularly the case with regard to personalised precision nanodrugs, which require the simultaneous optimisation of the structures, compositions, and surface functionalities of nanodrugs. The development of powerful computer clusters and algorithms has made it possible to overcome this challenge through in silico methods, which provide a comprehensive understanding of the medical functions of nanodrugs in relation to their physicochemical properties. In addition, machine learning techniques have been widely employed in nanodrug research, significantly accelerating the understanding of bio-nano interactions and the development of nanodrugs. This review will present a summary of the computational advances in nanodrug discovery, focusing on the understanding of how the key interfacial interactions, namely, surface adsorption, supramolecular recognition, surface catalysis, and chemical conversion, affect the therapeutic efficacy of nanodrugs. Furthermore, this review will discuss the challenges and opportunities in computer-aided nanodrug discovery, with particular emphasis on the integrated "computation + machine learning + experimentation" strategy that can potentially accelerate the discovery of precision nanodrugs.

An asymmetric nautilus-like HflK/C assembly controls FtsH proteolysis of membrane proteins.

FtsH, a AAA protease, associates with HflK/C subunits to form a megadalton complex that spans the inner membrane and extends into the periplasm of E. coli . How this complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following overproduction of protein components, recent cryo-EM structures reveal symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit degradation of membrane-embedded substrates. Here, we present structures of native complexes in which HflK/C instead forms an asymmetric nautilus-like assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. The membrane curvature in our FtsH·HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid-scramblase activity and possibly with FtsH's function in the degradation of membrane-embedded proteins.

Risk of hydrogen sulfide pollution from pressure release resulting from landfill mining.

Landfill mining (LFM) has gained widespread recognition due to its benefits in terms of resource utilization of landfill waste and reuse of landfill sites. However, it is important to thoroughly assess the associated environmental risks. This study simulated the pressure release induced from LFM in small-scale batch anaerobic reactors subject to different initial pressures (0.2-0.6 MPa). The potential risk of hydrogen sulfide (H2S) pollution resulting from pressure release caused by LFM was investigated. The results demonstrated that the concentration of H2S significantly increased following the simulated pressure treatments. At the low (25 °C) and high (50 °C) temperatures tested, the peak H2S concentration reached 19366 and 24794 mg·m-3, respectively. Both of these concentrations were observed under highest initial pressure condition (0.6 MPa). However, the duration of H2S release was remarkably longer (>90 days) at the low temperature tested. Microbial diversity analysis results revealed that, at tested low temperature, the sulfate-reducing bacteria (SRB) communities of various pressure-bearing environments became phylogenetically similar following the pressure releases. In contrast, at the high temperature tested, specific SRB genera (Desulfitibacter and Candidatus Desulforudis) showed further enrichment. Moreover, the intensified sulfate reduction activity following pressure release was attributed to the enrichment of specific SRBs, including Desulfovibrio (ASV585 and ASV1417), Desulfofarcimen (ASV343), Candidatus Desulforudis (ASV24), and Desulfohalotomaculum (ASV506 and ASV2530). These results indicate that the pressure release associated with LFM significantly increases the amount of H2S released from landfills, and the SRB communities have different response mechanisms to pressure release at different temperature conditions. This study highlights the importance of considering the potential secondary environmental risks associated with LFM.

SNX32 Regulates Sorting and Trafficking of Activated EGFR to the Lysosomal Degradation Pathway.

SNX32 is a member of the evolutionarily conserved Phox (PX) homology domain- and Bin/Amphiphysin/Rvs (BAR) domain- containing sorting nexin (SNX-BAR) family of proteins, which play important roles in sorting and membrane trafficking of endosomal cargoes. Although SNX32 shares the highest amino acid sequence homology with SNX6, and has been believed to function redundantly with SNX5 and SNX6 in retrieval of the cation-independent mannose-6-phosphate receptor (CI-MPR) from endosomes to the trans-Golgi network (TGN), its role(s) in intracellular protein trafficking remains largely unexplored. Here, we report that it functions in parallel with SNX1 in mediating epidermal growth factor (EGF)-stimulated postendocytic trafficking of the epidermal growth factor receptor (EGFR). Moreover, SNX32 interacts directly with EGFR, and recruits SNX5 to promote sorting of EGF-EGFR into multivesicular bodies (MVBs) for lysosomal degradation. Thus, SNX32 functions distinctively from other SNX-BAR proteins to mediate signaling-coupled endolysosomal trafficking of EGFR.

Viral shedding pattern of severe fever with thrombocytopenia syndrome virus in severely ill patients: A prospective, Multicenter cohort study.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is spreading rapidly in Asia. The pathway of SFTS virus shedding from patient and specific use of personal protective equipments (PPEs) against viral transmission have rarely been reported. The study was to determine SFTS virus (SFTSV) shedding pattern from the respiratory, digestive and urinary tract to outside in patients. Methods: Patients were divided into mild and severe groups in three sentinel hospitals for SFTS in Anhui province from April 2020 to October 2022. SFTSV level from blood, throat swabs, fecal/anal swabs, urine and bedside environment swabs of SFTS patients were detected by qRT-PCR. Specific PPEs were applied in healthcare workers contacting with the patients who had oropharyngeal virus shedding and hemorrhagic signs. Results: A total of 189 SFTSV-confirmed patients were included in the study, 54 patients died (case fatality rate, 28.57 %). Positive SFTSV in throat swabs (T-SFTSV), fecal/anal swabs (F-SFTSV) and urine (U-SFTSV) were detected in 121 (64.02 %), 91 (48.15 %) and 65 (34.4 %) severely ill patients, respectively. The levels of T-SFTSV, F-SFTSV and U-SFTSV were positively correlated with the load of SFTSV in blood. We firstly revealed that SFTSV positive rate of throat swabs were correlated with occurrence of pneumonia and case fatality rate of patients (P < 0.0001). Specific precaution measures were applied by healthcare workers in participating cardiopulmonary resuscitation and orotracheal intubation for severely ill patients with positive T-SFTSV, no event of SFTSV human-to-human transmission occurred after application of effective PPEs. Conclusions: Our research demonstrated SFTSV could shed out from blood, oropharynx, feces and urine in severely ill patients. The excretion of SFTSV from these parts was positively correlated with viral load in the blood. Effective prevention measures against SFTSV human-to-human transmission are needed.

Integrative rehabilitation in the treatment of lumbosacral muscle strain in elite trampoline athletes: a pilot study.

Background: Lumbosacral muscle strain (LMS) is common in Chinese elite trampoline athletes. Advanced lumbar muscle activation is necessary for postural control before upper extremity voluntary movements, called anticipatory postural adjustment to reduce internal postural interference (IPI). The potential of delayed lumbar muscle activation has been reported in patients with non-specific LBP (NLBP) in response to IPI. However, it remains unknown whether this effect exists in elite trampoline athletes. There is also limited literature reporting the rehabilitation of LMS in this population. This study first aimed to explore whether elite trampoline athletes with LMS experience delayed activation of lumbar muscles under IPI. The secondary aim was to preliminarily evaluate an integrative rehabilitation program's effectiveness. Materials and methods: Ten elite trampoline athletes with LMS were recruited and received 10 sessions of integrative rehabilitation, including extracorporeal shock wave therapy, acupuncture, Tui-na, and spine function exercises. At baseline and after all sessions, the relative activation time of the lumbar muscles under IPI in a modified rapid arm-rise test was used as a primary outcome measure. The secondary measures included a visual analog scale (VAS) and a questionnaire to assess low back pain (LBP) and athletic training performance. Results: The relative activation time of the lumbar muscles under IPI was delayed at baseline, but significantly decreased after the intervention (P < 0.05). The VAS was significantly decreased after the intervention (P < 0.05). There was no significant correlation between the difference in VAS and in activation time of the lumbar muscles before and after the intervention (P > 0.05). Conclusions: Elite trampoline athletes with LMS had delayed activation in their lumbar muscles under IPI. Integrative rehabilitation was effective in LBP relief and neuromuscular control of the lumbar muscles, and impacted positively on training performance. Future studies with a larger sample size, a control group, and long-term follow-ups are needed to further examine the efficacy of integrative rehabilitation in elite trampoline athletes with LMS. Additionally, the application of this approach in athletes with LMS or LBP in other sports, particularly those involving IPI, should be explored.

A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8.

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4+ T cell clones not only respond to proinsulin C-peptide (PI40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI40-47-IAPP74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognise self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4+ T cell clones reactive to native PI40-54 epitope and multiple HIPs fused at the same N-terminus (PI40-54) to the degradation products of two highly expressed pancreatic islet proteins, Neuropeptide Y (NPY68-74) and amyloid polypeptide (IAPP23-29 and IAPP74-80). We observed that five out of the selected SKW3 T cell lines expressing TCRs isolated from CD4+ T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI40-54 and HIP epitopes. Crystal structures of two TRAV26-1+-TRBV5-1+ T cell receptors (TCRs) in complex with PI40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI40-54 and HIPs determined that the P2, P7 and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8.