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Abstract The biguanide drug metformin is a first-line blood glucose-lowering medication for type 2 diabetes, leading to its presence in the global environment. However, little is known about the fate of metformin by microbial catabolism. Here, we characterize a Ni2+-dependent heterohexameric enzyme (MetCaCb) from the ureohydrolase superfamily, catalyzing the hydrolysis of metformin into guanylurea and dimethylamine. Either subunit alone is catalytically inactive, but together they work as an active enzyme highly specific for metformin. The crystal structure of the MetCaCb complex shows the coordination of the binuclear metal cluster only in MetCa, with MetCb as a protein binder of its active cognate. An in-silico search and functional assay discover a group of MetCaCb-like protein pairs exhibiting metformin hydrolase activity in the environment. Our findings not only establish the genetic and biochemical foundation for metformin catabolism but also provide additional insights into the adaption of the ancient enzymes toward newly occurred substrate.

Abstract Alkaline hydrogen evolution reaction (HER) for scalable hydrogen production largely hinges on addressing the sluggish bubble‐involved kinetics on the traditional Ni‐based electrode, especially for ampere‐level current densities and beyond. Herein, 3D‐printed Ni‐based sulfide (3DPNS) electrodes with varying scaffolds are designed and fabricated. In situ observations at microscopic levels demonstrate that the bubble escape velocity increases with the number of hole sides (HS) in the scaffolds. Subsequently, we conduct multiphysics field simulations to illustrate that as the hole shapes transition from square, pentagon, and hexagon to circle, where a noticeable reduction in the bubble‐attached HS length and the pressure balance time around the bubbles results in a decrease in bubble size and an acceleration in the rate of bubble escape. Ultimately, the 3DPNS electrode with circular hole configurations exhibits the most favorable HER performance with an overpotential of 297 mV at the current density of up to 1000 mA cm−2 for 120 h. The present study highlights a scalable and effective electrode scaffold design that promotes low‐cost and low‐energy green hydrogen production through the ampere‐level alkaline HER.

Abstract Patulin (PAT) is a common mycotoxin in moldy fruits that causes gastrointestinal injury if accidentally ingested. Some studies have reported the symptoms of intestinal injury caused by PAT. However, the effects of PAT on the gut microbiota and gut metabolism remain to be investigated, which is important for clarifying the toxicological mechanisms. Thus, C57/BL6J mice were gavaged once with 0, 1, 4, and 16 mg/kg body weight PAT, and the small intestinal and colonic contents were collected. The 16S rRNA sequencing and targeted and untargeted metabolomics were applied to assess the alterations in microbiota and metabolism, respectively. The results showed that Mycoplasma, Dubosiella, and Enterorhabdus were jointly affected by acute PAT exposure in the small intestinal and colonic contents. Some inflammation‐related bacteria, such as Mycoplasma in the small intestine and Mycoplasma, Alistipes, Eubacterium_coprostanoligenes_group, and Candidatus_saccharimona in the colon, increased with increasing doses of PAT. In metabolic results, amino acids decreased and bile acids elevated in both intestinal contents; lipids increased in the small intestinal contents but decreased in the colonic contents. PAT mainly affected host amino acid and lipid metabolism; it also downregulated microbial tryptophan metabolism and short‐chain fatty acid levels (mainly in the colon), which could be explained by the decrease of Bacteroides and Lactobacillus. These influences in microbial abundances and metabolic levels persisted after PAT and its products were cleared. These results fill a gap in the effects of PAT on the gut microbiota and provide a theoretical basis for elucidating the toxic mechanism of mycotoxins.

Abstract The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell–cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.

Abstract Background Tuberculosis (TB) is a major cause of death worldwide, and Chinese TB burden ranked the second globally. Chinese primary healthcare (PHC) sectors implement the TB Control Program (TCP) to improve active case finding, referral, treatment adherence, and health education. This study aimed to identify barriers and enablers of TCP implementation in high TB burden regions of West China. Methods We conducted a representative study using mixed-methods in 28 counties or districts in Chongqing Municipality and Guizhou Province of West China from October 2021 to May 2022. Questionnaire surveys and semi-structured in-depth interviews were conducted with 2720 TB healthcare workers (HCWs) and 20 interviewees in PHC sectors. Descriptive statistical analysis was used to investigate TB HCWs’ characteristics, and path analysis model was utilized to analyze the impact of associated factors on TCP implementation. Thematic framework analysis was developed with the guide of the adapted Consolidated Framework for Implementation Research (CFIR) on factors of TCP implementation. Results This study found that 84.6% and 94.1% of community and village HCWs had low professional titles. Based on the results of multiple regression analysis and correlation analysis, lower TB core knowledge scores (-0.09) were identified as barriers for TCP implementation in community PHC sectors, and low working satisfaction (-0.17) and low working willingness (-0.10) are barriers for TPC implementation in village PHC sectors. The results of in-depth interviews reported barriers in all domains and enablers in four domains of CFIR. There were identified 19 CFIR constructs associated with TCP implementation, including 22 barriers such as HCWs’ heavy workload, and 12 enablers such as HCWs’ passion towards TCP planning. Conclusions With the guide of the CFIR framework, complex factors (barriers and enablers) of TCP implementation in PHC sectors of West China were explored, which provided important evidences to promote TB program in high TB burden regions. Further implementation studies to translate those factors into implementation strategies are urgent needed. Graphical Abstract

Abstract G protein-coupled receptors (GPCRs) widely exist in vivo and participate in many physiological processes, thus emerging as important targets for drug development. Approximately 30% of the Food and Drug Administration (FDA)-approved drugs target GPCRs. To date, the ‘one disease, one target, one molecule’ strategy no longer meets the demands of drug development. Meanwhile, small-molecule drugs account for 60% of FDA-approved drugs. Traditional Chinese medicine (TCM) has garnered widespread attention for its unique theoretical system and treatment methods. TCM involves multiple components, targets and pathways. Centered on GPCRs and TCM, this paper discusses the similarities and differences between TCM and GPCRs from the perspectives of syndrome of TCM, the consistency of TCM’s multi-component and multi-target approaches and the potential of GPCRs and TCM in the development of novel drugs. A novel strategy, ‘simultaneous screening of drugs and targets’, was proposed and applied to the study of GPCRs. We combine GPCRs with TCM to facilitate the modernisation of TCM, provide valuable insights into the rational application of TCM and facilitate the research and development of novel drugs. This study offers theoretical support for the modernisation of TCM and introduces novel ideas for development of safe and effective drugs.

Abstract Background Limited research has explored the associations of gestational age (GA) and breastfeeding practices with growth and nutrition in term infants. Methods This multicenter cross-sectional study recruited 7299 singleton term infants from well-child visits in Shandong, China, between March 2021 and November 2022. Data on GA, gender, ethnicity, birth weight, parental heights, gestational diabetes and hypertension, age at visit, breastfeeding practices (point-in-time data at visit for infants 4. Linear regression models adjused for covariates explored the impact of GA and breastfeeding practices on LAZ and WLZ, while logistic regression models evaluated their effect on the likelihood of moderate and severe stunting (MSS, LAZ 2). Sensitivity analysis was conducted on normal birth weight infants (2.5–4.0 kg). Results Infants born early-term and exclusively breastfed accounted for 31.1% and 66.4% of the sample, respectively. Early-term birth related to higher WLZ (

This study aimed to optimize the formula of plant-based almond yogurt to improve its quality and storage stability. Using sweet almonds as the main ingredient and adding conventional yogurt stabilizers such as emulsifiers and thickeners, plant-based almond yogurt was produced through lactic acid fermentation. The optimal stabilizer formula for yogurt was determined using principal component synthesis evaluation analysis and response surface optimization methodology, and the physical properties were characterized. The results showed that the optimal formula for plant-based almond yogurt was 0.4% tartaric acid mono-diglyceride, 2.0% hydroxypropyl distarch phosphate, and 0.1% glutamine transaminase, with a comprehensive score of 0.990. The predicted and verified comprehensive scores of plant-based yogurt were close. The quality and acceptability of the plant-based yogurt significantly improved after adjustment, and the micro-particles of the mixed plant-based almond yogurt (MPBAY) were fuller, the distribution of milk fat was more uniform, and the texture was richer. This study provides a certain research idea and scientific theoretical value reference for the development of plant-based yogurt and the study of plant protein gel aggregation systems.

Abstract Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity 83 member A (FAM83A) emerges as a notable focus due to its frequent overexpression in LUAD. Despite this, the precise role of FAM83A remains elusive. This study addresses this gap by unveiling the crucial involvement of FAM83A in maintaining the cancer stem cell-like (CSC-like) phenotype of LUAD. Through a global proteomics analysis, the study identifies human epidermal growth factor receptor 2 (HER2 or ErbB2) as a crucial target of FAM83A. Mechanistically, FAM83A facilitated ErbB2 expression at the posttranslational modification level via the E3 ubiquitin ligase STUB1 (STIP1-homologous U-Box containing protein 1). More importantly, the interaction between FAM83A and ErbB2 at Arg241 promotes calcineurin (CALN)-mediated dephosphorylation of ErbB2, followed by inhibition of STUB1-mediated ubiquitin-proteasomal ErbB2 degradation. The maintenance of the CSC-like phenotype by FAM83A, achieved through the posttranslational regulation of ErbB2, offers valuable insights for identifying potential therapeutic targets for LUAD.

Abstract China, is characterized by its remarkable ethnical diversity, which necessitates whole genome variation data from multiple populations as crucial tools for advancing population genetics and precision medical research. However, there has been a scarcity of research concentrating on the whole genome of ethnic minority groups. To fill this gap, we developed the Guizhou Multi-ethnic Genome Database (GMGD). It comprises whole genome sequencing data from 476 healthy unrelated individuals spanning 11 ethnic minorities groups in Guizhou Province, Southwest China, including Bouyei, Dong, Miao, Yi, Bai, Gelo, Zhuang, Tujia, Yao, Hui, and Sui. The GMGD database comprises more than 16.33 million variants in GRCh38 and 16.20 million variants in GRCh37. Among these, approximately 11.9% (1,956,322) of the variants in GRCh38 and 18.5% (3,009,431) of the variants in GRCh37 are entirely new and do not exist in the dbSNP database. These novel variants shed light on the genetic diversity landscape across these populations, providing valuable insights with an average coverage of 5.5 ×. This makes GMGD the largest genome-wide database encompassing the most diverse ethnic groups to date. The GMGD interactive interface facilitates researchers with multi-dimensional mutation search methods and displays population frequency differences among global populations. Furthermore, GMGD is equipped with a genotype-imputation function, enabling enhanced capabilities for low-depth genomic research or targeted region capture studies. GMGD offers unique insights into the genomic variation landscape of different ethnic groups, which are freely accessible at https://db.cngb.org/pop/gmgd/ .

The matrix protein 2 (M2) is a preferred target for developing a universal vaccine against the influenza A virus (IAV). This study aimed to develop a method for assessing antibody-dependent cell-mediated cytotoxicity (ADCC) associated with M2-based immunization in mice. We first established a stable cell line derived from mouse lymphoma cells (YAC-1) expressing M2 of H3N2. This cell line, designated as YAC-1-M2, was generated using a second-generation lentiviral tricistronic plasmid system to transduce the M2 gene into YAC-1 cells. The ADCC effect induced by polyclonal antibodies targeting matrix protein 2 ectodomain (M2e) was demonstrated by YAC-1-M2 cell lysis by natural killer cells (NK) derived from mice, in the presence of anti-M2 antibodies obtained from mice immunized with an mRNA vaccine based on M2e. This ADCC effect was found to be stronger compared to the effect induced by monoclonal antibodies (14C2) against M2. Moreover, the ADCC effect was enhanced as the effector-to-target ratio of NK to YAC-1-M2 cells increased. In conclusion, we established a novel method to detect ADCC of M2 of IAV, which paves the way for the development of an M2-based universal vaccine against IAV and an in-depth analysis of its mechanism of broad-spectrum immune protection in mice.

Abstract Entanglement and coherence are fundamental properties of quantum systems, promising to power near-future quantum technologies, such as quantum computation, quantum communication, and quantum metrology. Yet, their quantification, rather than mere detection, generally requires reconstructing the spectrum of quantum states, i.e., experimentally challenging measurement sets that increase exponentially with the system size. Here, we demonstrate quantitative bounds to operationally useful entanglement and coherence that are universally valid, analytically computable, and experimentally friendly. Specifically, our main theoretical results are lower and upper bounds to the coherent information and the relative entropy of coherence in terms of local and global purities of quantum states. To validate our proposal, we experimentally implement two purity detection methods in an optical system: shadow estimation with random measurements and collective measurements on pairs of state copies. The experiment shows that both the coherent information and the relative entropy of coherence of pure and mixed unknown quantum states can be bounded by purity functions. Our research offers an efficient means of verifying large-scale quantum information processing.

Abstract The herd immunity against SARS-CoV-2 is continuously consolidated across the world during the ongoing pandemic. However, the potential function of the nonconserved epitopes in the reverse preexisting cross-reactivity induced by SARS-CoV-2 to other human coronaviruses is not well explored. In our research, we assessed T cell responses to both conserved and nonconserved peptides shared by SARS-CoV-2 and SARS-CoV, identifying cross-reactive CD8+ T cell epitopes using enzyme-linked immunospot and intracellular cytokine staining assays. Then, in vitro refolding and circular dichroism were performed to evaluate the thermal stability of the HLA/peptide complexes. Lastly, single-cell T cell receptor reservoir was analyzed based on tetramer staining. Here, we discovered that cross-reactive T cells targeting SARS-CoV were present in individuals who had recovered from COVID-19, and identified SARS-CoV-2 CD8+ T cell epitopes spanning the major structural antigens. T cell responses induced by the nonconserved peptides between SARS-CoV-2 and SARS-CoV were higher and played a dominant role in the cross-reactivity in COVID-19 convalescents. Cross-T cell reactivity was also observed within the identified series of CD8+ T cell epitopes. For representative immunodominant peptide pairs, although the HLA binding capacities for peptides from SARS-CoV-2 and SARS-CoV were similar, the TCR repertoires recognizing these peptides were distinct. Our results could provide beneficial information for the development of peptide-based universal vaccines against coronaviruses.

With Polygonatum cyrtonema tender buds as subjects, Polygonatum cyrtonema tender bud tea was prepared using the technology for processing flat green tea after fixation by microwave, pan frying and steaming, respectively. The effects of different fixation methods on the quality of Polygonatum cyrtonema tender bud tea was then explored through physicochemical composition, color and gloss of tea broth, volatile aroma component analysis and organoleptic evaluation. The results showed that the Polygonatum cyrtonema tender bud tea prepared by microwave fixation not only presented good organoleptic properties, but also had the highest contents of water extract, soluble sugar, tea polyphenols and total flavonoids, 48.04%, 14.49%, 1.32% and 1.66%, respectively. A total of 84 volatile olfactory compounds were detected in Polygonatum cyrtonema tender bud tea prepared by the three different fixation methods, mainly consisting of aldehydes (12 types), ketones (11 types), olefins (10 types), alcohols (8 types) and esters (8 types). There were 10, 12 and 7 key aroma components in Polygonatum cyrtonema tender bud tea with microwave, pan frying and steaming fixation, respectively. Among them, ethyl butyrate was a unique key aroma component to microwave fixation, while heptanal, pentanal, hexanal and 1-pentanol were the key aroma components unique to pan frying fixation. Overall, there are differences in the quality of Polygonatum cyrtonema tender bud tea prepared by different fixation methods, among which microwave fixation is more suitable for the preparation of Polygonatum cyrtonema tender bud tea.

Abstract Background Ruminant gut microbiota are critical in ecological adaptation, evolution, and nutrition utilization because it regulates energy metabolism, promotes nutrient absorption, and improves immune function. To study the functional roles of key gut microbiota in sheep and goats, it is essential to construct reference microbial gene catalogs and high-quality microbial genomes database. Results A total of 320 fecal samples were collected from 21 different sheep and goat breeds, originating from 32 distinct farms. Metagenomic deep sequencing and binning assembly were utilized to construct a comprehensive microbial genome information database for the gut microbiota. We successfully generated the largest reference gene catalogs for gut microbiota in sheep and goats, containing over 162 million and 82 million nonredundant predicted genes, respectively, with 49 million shared nonredundant predicted genes and 1138 shared species. We found that the rearing environment has a greater impact on microbial composition and function than the host’s species effect. Through subsequent assembly, we obtained 5810 medium- and high-quality metagenome-assembled genomes (MAGs), out of which 2661 were yet unidentified species. Among these MAGs, we identified 91 bacterial taxa that specifically colonize the sheep gut, which encode polysaccharide utilization loci for glycan and mucin degradation. Conclusions By shedding light on the co-symbiotic microbial communities in the gut of small ruminants, our study significantly enhances the understanding of their nutrient degradation and disease susceptibility. Our findings emphasize the vast potential of untapped resources in functional bacterial species within ruminants, further expanding our knowledge of how the ruminant gut microbiota recognizes and processes glycan and mucins. Video Abstract

Abstract Background Previous studies have implicated inherited mutations in mitochondrial DNA (mtDNA) in sensorineural hearing loss (SNHL). However, the definitive association between mitochondrial 12S rRNA (MT-RNR1) variants and hearing loss in the population has not been well established, particularly in Asia. The objective of this retrospective cohort study was to assess the association between MT-RNR1 variants and the risk of SNHL in patients in Taiwan. Methods The cohort included 306,068 participants from Taiwan between January 2003 and December 2020. Participants were classified based on genetic variants, particularly mitochondrial mutations (rs267606618, rs267606619, rs267606617). MT-RNR1 variant cases were matched 1:10 with non-mutant patients by age, gender, and visit year, excluding those with pre-existing hearing loss. The primary endpoint was SNHL, identified using specific ICD-TM codes with a 90% positive predictive value. Medication exposure history was determined via self-report or electronic medical records in the hospital. Cox proportional hazard regression models were used to assess the association between MT-RNR1 variants and hearing loss, adjusting for various covariates. Kaplan-Meier survival curves and log-rank tests compared hearing loss incidence between groups. Results The mean age of the mtDNA variants group is 32.4 years, with a standard deviation of 19.2 years. The incidence density of hearing loss for the mutation group was 36.42 per 10,000 person-years (95% Confidence Interval [CI], 27.21–47.73), which was higher than the 23.77per 10,000 person-years (95% CI, 21.32–26.42) in the wild-type group (p = 0.0036). Additionally, diabetes mellitus was associated with an increased risk of developing SNHL in individuals with MT-RNR1 variants (adjusted hazard ratio = 1.76 [95% CI, 1.00-3.09], p

BackgroundHypoglycemic episodes cause varying degrees of damage in the functional system of elderly inpatients with type 2 diabetes mellitus (T2DM). The purpose of the study is to construct a nomogram prediction model for the risk of hypoglycemia in elderly inpatients with T2DM and to evaluate the predictive performance of the model.MethodsFrom August 2022 to April 2023, 546 elderly inpatients with T2DM were recruited in seven tertiary-level general hospitals in Beijing and Inner Mongolia province, China. Medical history and clinical data of the inpatients were collected with a self-designed questionnaire, with follow up on the occurrence of hypoglycemia within one week. Factors related to the occurrence of hypoglycemia were screened using regularized logistic analysis(r-LR), and a nomogram prediction visual model of hypoglycemia was constructed. AUROC, Hosmer-Lemeshow, and DCA were used to analyze the prediction performance of the model.ResultsThe incidence of hypoglycemia of elderly inpatients with T2DM was 41.21% (225/546). The risk prediction model included 8 predictors as follows(named ADOCHBIU): duration of diabetes (OR=2.276, 95%CI 2.097˜2.469), urinary microalbumin(OR=0.864, 95%CI 0.798˜0.935), oral hypoglycemic agents (OR=1.345, 95%CI 1.243˜1.452), cognitive impairment (OR=1.226, 95%CI 1.178˜1.276), insulin usage (OR=1.002, 95%CI 0.948˜1.060), hypertension (OR=1.113, 95%CI 1.103˜1.124), blood glucose monitoring (OR=1.909, 95%CI 1.791˜2.036), and abdominal circumference (OR=2.998, 95%CI 2.972˜3.024). The AUROC of the prediction model was 0.871, with sensitivity of 0.889 and specificity of 0.737, which indicated that the nomogram model has good discrimination. The Hosmer-Lemeshow was χ2 = 2.147 (P=0.75), which meant that the prediction model is well calibrated. DCA curve is consistently higher than all the positive line and all the negative line, which indicated that the nomogram prediction model has good clinical utility.ConclusionsThe nomogram hypoglycemia prediction model constructed in this study had good prediction effect. It is used for early detection of high-risk individuals with hypoglycemia in elderly inpatients with T2DM, so as to take targeted measures to prevent hypoglycemia.Trial registrationChiCTR2200062277. Registered on 31 July 2022.

Ecosystem services (ES) such as carbon storage (CS), soil conservation (SC), habitat quality (HQ), and water yield (WY) play a crucial role in maintaining ecological balance and supporting sustainable regional development. With increasing environmental changes, understanding the spatiotemporal dynamics of these services and their driving factors has become essential in environmental science. This study focuses on the Nanchang metropolitan area, quantifying CS, SC, HQ, and WY from 2000 to 2020. It explores the impacts of major factors, including climate, topography, and social aspects, on the spatial heterogeneity of ES. The results reveal that between 2000 and 2020, CS and HQ decreased by 0.1385×108 tons/ha and 0.0507, respectively, while SC and WY increased by 2.4754×109 tons/ha and 1.6668×1010 m3, respectively. Notable spatial heterogeneity exists in the correlation between driving factors and changes in ES. The spatial distribution of ESs is higher in mountainous regions compared to central plains. Among human factors, population (POP) and gross domestic product (GDP) predominantly influenced changes in CS and HQ, whereas climate and POP drove changes in SC. Changes in WY were primarily affected by climate and topography. These findings suggest a need to focus on key driving factors to formulate targeted land policies aimed at enhancing the ES value in the Nanchang metropolitan area.

Aims: To investigate the therapeutic effects and mechanisms of Semaglutide in Alzheimer's disease (AD), and identify its potential targets. Methods: We systematically evaluated the effect of Semaglutide on Alzheimer's disease (AD), using both mice and human organoid models. Results: Behavioral analyses on APP/PS1 mice demonstrated that Semaglutide improved the cognitive capabilities, particularly in the learning and memory domains. Biochemical investigations further highlighted its role in reducing amyloid plaque deposition and down-regulating the expression of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression in the mouse brain tissues. Meanwhile, oxytocin (OXT) was up-regulated after Semaglutide treatment. Subsequent studies using human AD-brain organoids (BOs) models revealed that, upon Semaglutide treatment, these AD-BO models also exhibited reduced levels of amyloid-beta (Aβ), phosphorylated Tau (p-Tau) and GFAP expression as well as increased OXT level. Conclusions: Semaglutide can ameliorate Alzheimer's disease in pre-clinical models, suggesting the promising therapeutic potential in AD patients.

IntroductionTo assess the prevailing trends in the incidence of ischemic heart disease (IHD) across 204 countries and territories from 1990 to 2019, and to elucidate their correlations with age, period, and birth cohort, a comprehensive analysis was conducted.MethodsFrom 1990 to 2019, we employed the Global Burden of Disease Study (GBD) Results Tool in conjunction with an age-period-cohort model. This approach facilitated the estimation of annual percentage changes in incidence, referred to as net drifts, encompassing the overall population. Additionally, we calculated annual percentage changes spanning ages 15 - 19 to 95 + years, denoted as local drifts. Furthermore, our analysis involved determining period and cohort relative risks, elucidating the effects associated with distinct periods and birth cohorts.ResultsGlobally, 21,203,479 [95% uncertainty interval (UI): 18,799,322 − 23,704,124] cases of IHD occurred in 2019. There were 33 countries with at least 100000 cases. Between 1990 and 2019, the net drift of IHD incidence exhibited a range from −1.7% per year [95% confidence interval (CI): −1.79, −1.61] in countries with a high socio-demographic index (SDI) to 0.08% per year (95% CI: 0.05, 0.11) in countries with a low SDI. Age effects across all countries and genders demonstrated an increasing trend over time, indicating age as a significant risk factor for IHD. Moreover, period and cohort effects in higher SDI countries exhibited a more rapid decline in both genders compared to lower SDI countries. The findings indicated that nations with a higher SDI manifested overall favorable trends in the relative risk of IHD incidence, both across time and in successive younger birth cohorts.DiscussionThe incidence of IHD serves as a valuable and accessible indicator for assessing trends in IHD provision, spanning from early youth through later life. Enhancements in IHD prevention have the potential to mitigate risks for successively younger cohorts and, over time, redistribute the risk across all age groups. Despite global declines in IHD incidence over the last three decades, decreasing trends in incidence have slowed and, in some countries, flattened. Many countries have experienced unfavorable period and cohort effects.

Our skin serves as the primary barrier against external environmental insults, the latter of which can cause oxidative stress within cells, while various bioactive peptides sourced from natural resources hold promise in protecting cells against such oxidative stress. In this study, we investigate the efficacy of a low molecular weight extract from the sea cucumber Apostichopus japonicus, denoted as Sample-P, in facilitating cell migration and wound healing under oxidative stress conditions in skin cells. The naturally derived compound is a highly complex mix of peptides exhibiting antioxidative properties, as highlighted through liquid chromatography-mass spectrometry peptide screening and an in vitro antioxidant assay. Our results demonstrate that Sample-P is capable of promoting cell migration while preventing severe stress responses such as visible through mTOR expression. To further identify the molecular pathways underpinning the overall protective mechanism of Sample-P, we have utilised a proteomics approach. Our data reveal that Sample-P regulates protein expression associated with ribosomal pathways, glycolysis/gluconeogenesis and protein processing in the endoplasmic reticulum (ER), which help in preserving DNA integrity and safeguarding cellular organelles, such as mitochondria and the ER, under oxidative stress conditions in skin cells. In summary, in the presence of H2O2, Sample-P exhibits antioxidative properties at both molecular and cellular levels, rendering it a promising candidate for topical skin treatment to wound healing and to address age-related skin conditions.

Staphylococcus aureus (S. aureus) infection is the most prevalent and resistant bacterial infection, posing a worldwide health risk. Compared with healthy people, diabetes patients with weak immune function and abnormal metabolism are more vulnerable to bacterial infection, which aggravates the intensity of infection and causes a series of common and dangerous complications, such as diabetes foot ulcer (DFU). Due to metabolic abnormalities of diabetic patients, S. aureus on the skin surface of DFU transitions from a commensal to an invasive infection. During this process, S. aureus resists a series of unfavorable conditions for bacterial growth by altering energy utilization and metabolic patterns, and secretes various virulence factors, causing persistent infection. With the emergence of multiple super-resistant bacteria, antibiotic treatment is no longer the only treatment option, and developing new drugs and therapies is urgent. Regulating the metabolic signaling pathway of S. aureus plays a decisive role in regulating its virulence factors and impacts adjuvant therapy for DFU. This article focuses on studying the impact of regulating metabolic signals on the virulence of S. aureus from a metabolism perspective. It provides an outlook on the future direction of the novel development of antimicrobial therapy.

Objectives This study aimed to examine the relationship between measures of kidney function and impaired lung function in individuals with diabetes and to assess all-cause mortality risk associated with having chronic kidney disease (CKD) and or impaired lung function.Design Cross-sectional and retrospective cohort study.Setting The National Health and Nutrition Examination Survey 2007–2012.Participants A total of 10 809 participants aged over 20 years were included in this study: 9503 with normal spirometry, 951 with preserved ratio impaired spirometry (PRISm) and 355 with variable obstruction (VO).Exposure and outcome measures Kidney function measures, including estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR), were considered exposure variables. PRISm and VO were outcome variables. PRISm was defined as a forced expiratory volume in 1 s (FEV1)60. After adjustments, an increase in UACR was associated with higher odds of PRISm in individuals with diabetes (OR (95% CI)=1.21 (1.08, 1.36), p=0.002), and UACR ≥300 mg/g significantly increased odds of having PRISm in idividuals with diabetes (OR (95% CI)=2.34 (1.23, 4.47), p=0.01). During a mean follow-up of 12.3 years, 10 500 deaths occurred. In the diabetic group, compared with normal spirometry without CKD, those with both PRISm and CKD had a significantly increased risk of all-cause mortality (HR (95% CI)=3.46 (1.94, 6.16), p

Abstract Clusterization‐triggered emissive (CTE) materials have attracted great attention in recent years. The regulation of the emission property of materials with CTE property through supramolecular interactions is an excellent strategy for the construction of smart fluorescent materials. In this work, we have prepared a regulatable supramolecular polymer network with CTE properties through pillararene‐based host−guest interactions. The pillar[5]arene‐grafted poly(methyl methacrylate) (PMMA) showed a classic CTE character. After adding Brooker's merocyanine‐grafted polymer to the solution of the pillar[5]arene‐containing PMMA, the supramolecular polymer network gel formed by the host−guest interactions between pillararene and Brooker's merocyanine guest. This supramolecular network showed brighter fluorescence than the pillar[5]arene‐grafted PMMA in the solid state. In addition, the fluorescence emission of the supramolecular network can be further regulated by pH conditions. After adding an acid, the Brooker's merocyanine‐containing guest polymer was protonated, and the supramolecular network changed to a protonated network through host−guest interactions between protonated Brooker's merocyanine guest and pillararene. Interestingly, the fluorescence was quenched when the supramolecular network turned into the protonated network. After adding a base, the protonated network can convert back to the original network, along with recovery of the fluorescence. Therefore, the regulation of the fluorescence of the supramolecular polymer materials with CTE was successfully realized by pillararene‐based host−guest interactions. Furthermore, this tailorable fluorescent supramolecular polymer network system was applied as an information encryption material.

BackgroundIncreased oxidative stress due to aging can lead to increased bone loss. The most abundant form of vitamin E, namely α-tocopherol, has high antioxidant properties and biological activity; however, its effect on osteoporosis has not been well studied in humans. We aimed to investigate the association between dietary vitamin E (α-tocopherol) and osteoporosis among older adults in the United States.MethodsThis cross-sectional study analyzed data on older adults in the United States aged ≥50 years from the 2007–2010, 2013–2014 and 2017–2020 pre-pandemic cycles of the National Health and Nutrition Examination Survey. Sample-weighted multivariate regression models were used, with adjustments for relevant confounders.ResultsThis study comprised 5,800 individuals with available data on dietary intake and bone mineral density of hip and spine. The mean participant age was 61.4 (standard deviation, 8.7) years, and approximately 9.9% had osteoporosis. High vitamin E intake was significantly associated with a reduced risk of osteoporosis (odds ratio, 0.96, 95% confidence interval, 0.93–0.98). In addition, there was evidence of interaction between dietary vitamin E and prior fracture on preventing osteoporosis.ConclusionsOur study indicated a linear association between dietary vitamin E levels and osteoporosis in an older population in the United States. Further research is required to explore the potential effects of different forms of vitamin E on osteoporosis.

Abstract To address the variable initial state and trail length this paper first presents a robust PD‐type open‐closed‐loop iterative learning control (ILC) law for a multiple‐input‐multiple‐output (MIMO) linear discrete‐time system. It is demonstrated that the convergence condition is dependent on the PD‐type feed‐forward learning gains, while an appropriate feedback learning gain can improve the ILC convergence performance. As a special case of PD‐type open‐closed‐loop ILC law, P‐type and D‐type open‐closed‐loop ILC laws are deduced. The three developed ILC laws ensure that as the number of iterations approaches infinity, the expectation of ILC tracking error will be constrained within a limited range, where the boundary is proportional to the initial state variation. Through a numerical simulation, the effectiveness of the proposed ILC laws is illustrated.

ObjectiveMultiple system atrophy (MSA) is commonly associated with rapid eye movement sleep behavior disorder (RBD). Research on the prevalence of RBD in MSA and its effects on MSA patients has yielded inconsistent results. Currently, there is only one meta-analysis discussing the prevalence of RBD in MSA, but no meta-analysis discussing the impact of RBD on MSA.MethodsA systematic review and meta-analysis was conducted by searching studies related to MSA and RBD in PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled as necessary to calculate prevalence of RBD, odds ratio (OR), weighted mean differences (WMD) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic.ResultsThe prevalence of polysomnography confirmed-RBD in MSA was 79.9% (95% CI, 68.8–89.3%) in a pooled sample of 598 subjects. Patients with MSA who had RBD were notably younger at examination than those without RBD (WMD −3.26 years, 95% CI −4.99 to −1.53), and the age of disease onset in MSA patients with RBD was significantly lower than in those without RBD (WMD −3.27, 95% CI −5.06 to −1.48). Additionally, RBD was more common among male patients with MSA compared to female patients (OR 2.11, 95% CI 1.31 to 3.39). MSA patients with RBD also exhibited significantly higher Unified Multiple System Atrophy Rating Scale (UMSARS) I and IV scores than those without RBD (WMD 2.99, 95% CI 0.10 to 4.88, and WMD 0.23, 95% CI 0.03 to 0.43).ConclusionThe prevalence of polysomnography-confirmed RBD in MSA is 79.9%. The prevalence in Asian population was lower than in Europe and America, which might be related to an underestimation in Asian populations. Additionally, patients with MSA and RBD tend to be younger at examination, have an earlier age of onset, and exhibit more severe disease manifestations compared to MSA patients without RBD.

BackgroundPatients with locally advanced non-small cell lung cancer (LA-NSCLC) usually bear high tumor burden and are not tolerated well to concurrent chemoradiation therapy (CRT) followed by consolidation immunotherapy. We investigated the feasibility of chemoimmunotherapy as induction therapy before CRT for LA-NSCLC.MethodsWe retrospectively analyzed data from 91 patients with unresectable stage III NSCLC treated with either induction chemoimmunotherapy or chemotherapy before CRT. Tumor responses, survival statistics, and toxic effects were compared. The dosimetric parameters of the RT protocol were evaluated. The primary endpoint was progression-free survival (PFS). The overall response (ORR), the depth of response (DpR) were accessed at the end of CRT (ORRinduc+CRT, DpRinduc+CRT) and induction therapy (ORRinduc, DpRinduc).ResultsThe median PFS (mPFS) were significantly longer in the chemoimmunotherapy induction group (13.5 months vs. 11.2 months; HR, 0.56; 95% CI, 0.32–0.97; p=0.036). The ORRinduc+CRT, median DpRinduc+CRT (mDpRinduc+CRT) and mDpRinduc were significantly higher in the chemoimmunotherapy induction group (ORRinduc+CRT, 84.0% vs. 65.9%, p=0.044; mDpRinduc+CRT, 49.5% vs. 39.0%, p = 0.012; mDpRinduc, 38.5% vs. 28.0%, p=0.044). Incidence of treatment-related adverse events (AE) was similar between groups, with myelosuppression being the most common grade ≥ 3 AE. Regarding radiotherapy, adopting a mapping strategy with a 5–8 mm margin for clinical tumor volume resulted in decreased radiation doses to critical organs in the chemoimmunotherapy induction group.ConclusionsChemoimmunotherapy induction therapy before CRT improves efficacy with comparable incidence of AEs compared to chemotherapy induction in LA-NSCLC patients. Further studies are warranted to validate these findings.

BackgroundWWOX-related epileptic encephalopathy is an autosomal recessive disorder caused by mutations in the WW-containing oxidoreductase gene, characterized by the onset of refractory seizures in infants. Early-onset epilepsy, electroencephalography abnormalities, and developmental delay or degeneration are the main clinical manifestations. Early death can occur in severe cases. In the present study, a novel variant in WWOX was detected in a patient with epilepsy and his healthy parents.Case presentationA 5-month-old boy presented with epilepsy. The main manifestations were intractable seizures, mental and motor retardation and hearing impairment. Subsequent genetic testing revealed the presence of an epilepsy-associated novel mutation: c.991C>A (amino acid change: p.Ser304Tyr) in the WWOX gene. Variants were inherited from parents with healthy phenotypes. Finally, a patient died at 6 months of age.ConclusionThe discovery of novel variants has enriched the existing database of WWOX gene variants and may expand the range of clinical options for treating WWOX-related disorders.

Age-related hearing loss (ARHL) is a prevalent sensory organ disorder among elderly individuals that significantly impacts their cognitive function, psychological well-being, and ability to perform activities of daily living. As the population ages, the number of ARHL patients is increasing. However, the Audiological rehabilitation (AR) status of patients is not promising. In recent years, there has been an increasing focus on the health and rehabilitation of elderly individuals, and significant progress has been made in researching various age-related disorders. However, a unified definition of ARHL in terms of etiology and rehabilitation treatment is still lacking. This study aims to provide a reference for future research on ARHL and the development of AR strategies by reviewing the classification, etiology, and rehabilitation of ARHL.

Summary: Background: Biliary atresia (BA) is a devastating neonatal cholangiopathy with an unclear pathogenesis, and prompt diagnosis of BA is currently challenging. Methods: Proteomic and immunoassay analyses were performed with serum samples from 250 patients to find potential BA biomarkers. The expression features of polymeric immunoglobulin receptor (PIGR) were investigated using human biopsy samples, three different experimental mouse models, and cultured human biliary epithelial cells (BECs). Chemically modified small interfering RNA and adenovirus expression vector were applied for in vivo silencing and overexpressing PIGR in a rotavirus-induced BA mouse model. Luminex-based multiplex cytokine assays and RNA sequencing were used to explore the molecular mechanism of PIGR involvement in the BA pathogenesis. Findings: Serum levels of PIGR, poliovirus receptor (PVR), and aldolase B (ALDOB) were increased in BA patients and accurately distinguished BA from infantile hepatitis syndrome (IHS). Combined PIGR and PVR analysis distinguished BA from IHS with an area under the receiver operating characteristic curve of 0.968 and an accuracy of 0.935. PIGR expression was upregulated in the biliary epithelium of BA patients; Th1 cytokines TNF-α and IFN-γ induced PIGR expression in BECs via activating NF-κB pathway. Silencing PIGR alleviated symptoms, reduced IL-33 expression, and restrained hepatic Th2 inflammation in BA mouse model; while overexpressing PIGR increased liver fibrosis and IL-33 expression, and boosted hepatic Th2 inflammation in BA mouse model. PIGR expression promotes the proliferation and epithelial–mesenchymal transition, and reduced the apoptosis of BECs. Interpretation: PIGR participated in BA pathogenesis by promoting hepatic Th2 inflammation via increasing cholangiocytes derived IL-33; PIGR has the value as a diagnostic and therapeutic biomarker of BA. Funding: This study was financially supported by the National Natural Science Foundation of China (82170529), the National Key R&D Program (2021YFC2701003), and the National Natural Science Foundation of China (82272022).

Superior soft-magnetic materials are necessary for the development of modern magnetic devices with energy-saving and high-power density requirements. However, improving the magnetism by nanocrystallization always brings about the sacrifice of resistivity, presenting a common trade-off in Fe-based amorphous-nanocrystalline alloys. Here, the comprehensive merits of both superior soft-magnetic properties (high saturation magnetization of 1.81 T and low coercivity of 3.8 A/m) and high resistivity of 117.2 μΩ·cm were obtained by precisely tailoring amorphous-nanocrystalline microstructure close to electrical percolation threshold for a Fe82.5B12P2C1Cu0.5Co2 amorphous alloy. The soft-magnetic properties are attributed to the low magnetic anisotropy stemming from high nuclei number density and ultrafine nanocrystalline grains of 9.2 nm. The high resistivity is associated with the electrical percolation behavior with a nanocrystalline volume threshold of 14.8 % in the composite alloy. The results provide an effective strategy to overcome the trade-off in traditional amorphous-nanocrystalline alloys, significant for applications in high-frequency, high-power, and energy-saving devices.

Instructional image editing has received a significant surge of attention recently. In this work, we are interested in the challenging problem of instructional image editing within the particular fashion realm, a domain with significant potential demand in both commercial and personal contexts. This specific domain presents heightened challenges owing to the stringent quality requirements. It necessitates not only the creation of vivid details in alignment with instructions, but also the preservation of precise attributes unrelated to the text guidance. Naive extensions of existing image editing methods produce noticeable artifacts. In order to achieve high-fidelity fashion editing, we propose a novel framework, leveraging the generative prior of a pre-trained human generator and performing edit in the latent space. In addition, we introduce a novel CLIP-based loss to better align the generated target with the instruction. Extensive experiments demonstrate that our approach outperforms prior works including GAN-based editing as well as diffusion-based editing by a large margin, showing impressive visual quality.

Effective species management and conservation require an understanding of geographical distribution patterns and reasons for species dispersal in a larger environment. The Xisha Islands are currently the largest green sea turtle nesting grounds in China, and green sea turtles breeding there belong to an independent geographic population with irreplaceable conservation value. In this study, field surveys and remote sensing satellite image mapping were used to investigate the use of green sea turtle nesting sites on 15 islands in the Xisha Islands and to analyze the effects of island morphology and human disturbances on nesting ground selection. The results revealed that green sea turtle nesting grounds were distributed throughout 10 islands with a total area of 0.1062 km2. The average beaches utilization rate by green sea turtle for nesting was 32.46 %, with the North Island of Qilianyu having the biggest nesting ground area (0.0436 km2) and the highest beach utilization rate (70.75 %). The next highest utilization rates were found on Ganquan Island, South Island, Jinqing Island, and South Sand. Generalized linear model (GLM) indicated that the effect of beach width on nest density was significant, building density and sand particle size affected nest density. Therefore, green sea turtles prefer to nest in islands with wider beaches, higher proportion of coarse and medium sand, and lower human activity. These areas should be prioritized for protection and management.

Abstract BackgroundPulmonary tuberculosis (PTB), as a respiratory infectious disease, poses significant risks of covert transmission and dissemination. The high aggregation and close contact among students in Chinese schools exacerbate the transmission risk of PTB outbreaks. ObjectiveThis study investigated the epidemiological characteristics, geographic distribution, and spatiotemporal evolution of student PTB in Chongqing, Southwest China, aiming to delineate the incidence risks and clustering patterns of PTB among students. MethodsPTB case data from students monitored and reported in the Tuberculosis Information Management System within the China Information System for Disease Control and Prevention were used for this study. Descriptive analyses were conducted to characterize the epidemiological features of student PTB. Spatial trend surface analysis, global and local spatial autocorrelation analyses, and disease rate mapping were performed using ArcGIS 10.3. SaTScan 9.6 software was used to identify spatiotemporal clusters of PTB cases. ResultsFrom 2016 to 2022, a total of 9920 student TB cases were reported in Chongqing, Southwest China, with an average incidence rate of 24.89/100,000. The incidence of student TB showed an initial increase followed by a decline, yet it remained relatively high. High school students (age: 13‐18 years; 6649/9920, 67.03%) and college students (age: ≥19 years; 2921/9920, 29.45%) accounted for the majority of student PTB cases. Patient identification primarily relied on passive detection, with a high proportion of delayed diagnosis and positive etiological results. COVID-19 prevention measures have had some impact on reducing incidence levels, but the primary factor appears to be the implementation of screening measures, which facilitated earlier case detection. Global spatial autocorrelation analysis indicated Moran IPPP ConclusionsFuture efforts should comprehensively enhance prevention and control measures in high-risk areas of PTB in Chongqing to mitigate the incidence risk among students. Additionally, implementing proactive screening strategies and enhancing screening measures are crucial for early identification of student patients to prevent PTB outbreaks in schools.

The plant-specific INDETERMINATE DOMAIN (IDD) gene family is important for plant growth and development. However, a comprehensive analysis of the IDD family in orchids is limited. Based on the genome data of Phalaenopsis equestris, the IDD gene family was identified and analyzed by bioinformatics methods in this study. Ten putative P. equestris IDD genes (PeIDDs) were characterized and phylogenetically classified into two groups according to their full amino acid sequences. Protein motifs analysis revealed that overall structures of PeIDDs in the same group were relatively conserved. Its promoter regions harbored a large number of responsive elements, including light responsive, abiotic stress responsive elements, and plant hormone cis-acting elements. The transcript level of PeIDD genes under cold and drought conditions, and by exogenous auxin (NAA) and abscisic acid (ABA) treatments further confirmed that most PeIDDs responded to various conditions and might play essential roles under abiotic stresses and hormone responses. In addition, distinct expression profiles in different tissues/organs suggested that PeIDDs might be involved in various development processes. Furthermore, the prediction of protein-protein interactions (PPIs) revealed some PeIDDs (PeIDD3 or PeIDD5) might function via cooperating with chromatin remodeling factors. The results of this study provided a reference for further understanding the function of PeIDDs.

Abstract Quasi‐2D perovskites light‐emitting diodes (PeLEDs) have achieved significant progress due to their superior optical and electronic properties. However, the blue PeLEDs still exist inefficient energy transfer and electroluminescence performance caused by mixed multidimensional phase distribution. In this work, transition metal salt (zinc bromide, ZnBr2) is introduced to modulate phase distributions by suppressing the nucleation of high n phase perovskites, which effectively shortens the energy transfer path for blue emission. Moreover, ZnBr2 also facilitates energy level matching and reduces non‐radiative recombination, thus improving electroluminescence (EL) efficiency. Benefiting from these combined improvements, an efficient blue PeLEDs is obtained with a maximum external quantum efficiency (EQE) of 16.2% peaking located at 486 nm. This work provides a promising approach to tune phase distribution of quasi‐2D perovskites and achieving highly efficient blue PeLEDs.

Summary: FOXA1 serves as a crucial pioneer transcription factor during developmental processes and plays a pivotal role as a mitotic bookmarking factor to perpetuate gene expression profiles and maintain cellular identity. During mitosis, the majority of FOXA1 dissociates from specific DNA binding sites and redistributes to non-specific binding sites; however, the regulatory mechanisms governing molecular dynamics and activity of FOXA1 remain elusive. Here, we show that mitotic kinase Aurora B specifies the different DNA binding modes of FOXA1 and guides FOXA1 biomolecular condensation in mitosis. Mechanistically, Aurora B kinase phosphorylates FOXA1 at Serine 221 (S221) to liberate the specific, but not the non-specific, DNA binding. Interestingly, the phosphorylation of S221 attenuates the FOXA1 condensation that requires specific DNA binding. Importantly, perturbation of the dynamic phosphorylation impairs accurate gene reactivation and cell proliferation, suggesting that reversible mitotic protein phosphorylation emerges as a fundamental mechanism for the spatiotemporal control of mitotic bookmarking.

ObjectivesTo investigate the safety and cost analysis of oral propranolol treatment for high-risk infantile hemangiomas starting from the outpatient setting.MethodsA total of 41 high-risk infantile hemangioma patients from outpatient settings and 43 from inpatient settings were selected for the study. After routine pre-treatment examinations, patients were administered propranolol in a stepwise incremental dosing regimen over three consecutive days in the outpatient clinic. Changes in heart rate, blood pressure and PR interval before and after medication were compared. On the 10th day post-medication, liver and kidney functions, fasting blood glucose, tumor ultrasonography, and electrocardiogram were re-evaluated. The costs of treatment starting from the outpatient clinic (including pre-treatment examinations and the first three days of treatment) were calculated and compared with those of similarly managed inpatient cases.ResultsThe majority of patients exhibited a reduction in heart rate and blood pressure, as well as an extended PR interval after treatment of medication (P < 0.05), which remained within normal limits without clinical symptoms. On the 10th day post-medication, statistical differences in blood biochemistry and electrocardiograms were observed when compared to pre-treatment values (P < 0.05), but all values remained within normal ranges. No severe adverse reactions such as hypoglycemia occurred. Additionally, the cost of treatment from the outpatient clinic was significantly lower than that of inpatient care.ConclusionOral propranolol treatment for high-risk infantile hemangiomas starting from the outpatient setting is associated with few adverse reactions and significantly reduced treatment costs. It is worthy of broader application in hospitals without dermatology wards.

Non-alcoholic fatty liver disease (NAFLD) and its more advanced form, non-alcoholic steatohepatitis (NASH), have become global health challenges with significant morbidity and mortality rates. NAFLD encompasses several liver diseases, ranging from simple steatosis to more severe inflammatory and fibrotic forms. Ultimately, this can lead to liver cirrhosis and hepatocellular carcinoma. The intricate role of hepatic macrophages, particularly Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), in the pathogenesis of NAFLD and NASH, has received increasing attention. Hepatic macrophages can interact with hepatocytes, hepatic stellate cells, and endothelial cells, playing a crucial role in maintaining homeostasis. Paradoxically, they also participate in the pathogenesis of some liver diseases. This review highlights the fundamental role of hepatic macrophages in the pathogenesis of NAFLD and NASH, emphasizing their plasticity and contribution to inflammation and fibrosis, and hopes to provide ideas for subsequent experimental research and clinical treatment.

Background & Aims: The expression of HBsAg from integrated HBV DNA limits the achievement of functional cure for chronic hepatitis B. Thus, characterising the unique expression and secretion of HBsAg derived from integrated HBV DNA is of clinical significance. Methods: A total of 563 treatment-naive patients and 62 functionally cured patients were enrolled, and HBsAg and HBcAg immunohistochemistry of their liver biopsy tissues was conducted followed by semi-quantitative analysis. Then, based on stratified analysis of HBeAg-positive and -negative patients, long-read RNA sequencing analysis, as well as an in vitro HBV integration model, we explored the HBsAg secretion characteristics of integrated HBV DNA and underlying mechanisms. Results: In contrast to the significantly lower serum HBsAg levels, no significant decrease of intrahepatic HBsAg protein was observed in HBeAg-negative patients, as compared with HBeAg-positive patients. The results of long-read RNA sequencing of liver tissues from patients with chronic HBV infection and in vitro studies using integrated HBV DNA mimicking dslDNA plasmid revealed that, the lower HBsAg secretion efficiency seen in HBeAg-negative patients might be attributed to an increased proportion of preS1 mRNA derived from integrated HBV DNA instead of covalently closed circular DNA. The latter resulted in an increased L-HBsAg proportion and impaired HBsAg secretion. Enhancer 1 (EnhI) in integrated HBV DNA could retarget preS1 (SP1) and preS2 (SP2) promoters to disrupt their transcriptional activity balance. Conclusions: The secretion of HBsAg originating from integrated HBV DNA was impaired. Mechanistically, functional deficiency of core promoter leads to retargeting of EnhI and thus uneven activation of the SP1 over the SP2 promoter, resulting in an increase in the proportion of L-HBsAg. Impact and implications: Integrated hepatitis B virus (HBV) DNA can serve as an important reservoir for HBV surface antigen (HBsAg) expression, and this limits the achievement of a functional cure. This study revealed that secretion efficiency is lower for HBsAg derived from integrated HBV DNA than HBsAg derived from covalently closed circular DNA, as determined by the unique sequence features of integrated HBV DNA. This study can broaden our understanding of the role of HBV integration and shed new light on antiviral strategies to facilitate a functional cure. We believe our results are of great general interest to a broad audience, including patients and patient organisations, the medical community, academia, the life science industry and the public.

This study investigated the efficacy and mechanism of traditionally made kochujang(TMK) with different capsaicin levels to alleviate memory impairment in rats with scopolamine-induced amnesia. Sprague-Dawley male rats were administered scopolamine (2 mg/kg bw/day) intraperitoneally to suppress the parasympathetic nervous system(PNS) and induce memory impairment. The rats were divided into four experimental groups, each consuming a diet containing 1 % kochujang in a 43-energy% high-fat diet(HFD) for 8 weeks. The TMK samples used for the study were categorized according to their capsaicin(CPS) content as follows: Low-CPS(0.5 mg%), medium-CPS(1.2 mg%), and high-CPS(1.7 mg%). In addition, factory-made kochujang (FMK; 1.1 mg% capsaicin) was also tested. The effects of kochujang were compared with the Control group(scopolamine), Positive-control(scopolamine+donepezil), and Normal-control(saline) fed HFD. Kochujang consumption reduced body weight and fat mass compared to the Control group. Compared to the Control, memory function measured using passive avoidance, water maze, and novel object recognition tests was enhanced in kochujang-fed rats, especially in the Medium-CPS group, similar to Positive-control. The Medium-CPS and Positive-control groups also exhibited inhibition of hippocampal cell death and increased cholesterol and triglyceride contents and mRNA expression of TNF-α and IL-1β in the brain tissue compared to the Control group. Additionally, TMK elevated short-chain fatty acid, particularly, butyrate concentration in the portal vein. Scopolamine disturbed large intestine cell morphology and gut microbiota composition, and kochujang improved them. Kochujang in the medium-CPS (1.2 mg%) had a more significant impact on the gut microbiota in the interaction analysis between gut microbiota and memory function. In conclusion, kochujang, especially with medium-CPS (1.2 mg%), is a potential dietary intervention to mitigate memory impairment and promote overall cognitive health through improving eubiosis, potentially linked to the gut-brain axis in PNS-suppressed rats.

Alzheimer's disease (AD) is a neurodegenerative brain disorder that progressively impairs long-term and working memory. The function and mechanism of PA(Patchouli alcohol) in improving AD in the external treatment of encephalopathy remain unclear. This study aimed to investigate the therapeutic effect of PA on AD using an Aβ1–42 induced AD mouse model with LPS(Lipopolysaccharide) stimulation of BV2 microglial cells. Additionally, we aimed to explore the potential mechanism of PA in enhancing autophagy and reducing neuroinflammation through the AMPK (AMP-activated protein kinase)/mTOR (Mammaliam target of rapamycin) signaling pathway. The Morris water maze was used to assess cognitive function, and cortical and hippocampal tissues were collected for further analysis of the corresponding signaling pathways and inflammatory changes through biological experiments. Our research findings demonstrate that PA has a significant positive impact on cognitive and memory impairments in mice that have been induced with Aβ1–42-induced AD. Additionally, PA was also found to revert the activation of microglia induced by LPS. These effects may be attributed to the reduction of neuroinflammation and enhancement of the AMPK/mTOR autophagy pathway. Therefore, PA may serve as an effective therapeutic option to prevent or delay the progression of AD-associated memory dysfunction.

Purpose: To explore the utility of high frequency oscillations (HFO) and long-range temporal correlations (LRTCs) in preoperative assessment of epilepsy. Methods: MEG ripples were detected in 59 drug-resistant epilepsy patients, comprising 5 with parietal lobe epilepsy (PLE), 21 with frontal lobe epilepsy (FLE), 14 with lateral temporal lobe epilepsy (LTLE), and 19 with mesial temporal lobe epilepsy (MTLE) to identify the epileptogenic zone (EZ). The results were compared with clinical MEG reports and resection area. Subsequently, LRTCs were quantified at the source-level by detrended fluctuation analysis (DFA) and life/waiting -time at 5 bands for 90 cerebral cortex regions. The brain regions with larger DFA exponents and standardized life-waiting biomarkers were compared with the resection results. Results: Compared to MEG sensor-level data, ripple sources were more frequently localized within the resection area. Moreover, source-level analysis revealed a higher proportion of DFA exponents and life-waiting biomarkers with relatively higher rankings, primarily distributed within the resection area (p