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Hepatitis B virus (HBV) is the most common chronic viral infection globally, affecting ∼360 million people and causing about 1 million deaths annually due to end-stage liver disease or hepatocellular carcinoma. Current antiviral treatments rarely achieve a functional cure for chronic hepatitis B, highlighting the need for improved monitoring and intervention strategies. This study explores the role of the sphingosine kinase 1 (SphK1)-sphingosine-1-phosphate (S1P) axis in HBV-related liver injury. We investigated the association between serum S1P concentration and HBV DNA levels in chronic hepatitis B patients, finding a significant positive correlation. Additionally, SphK1 was elevated in liver tissues of HBV-positive hepatocellular carcinoma patients, particularly in HBsAg-positive regions. HBV infection models in HepG2-sodium taurocholate cotransporting polypeptide cells confirmed that HBV enhances SphK1 expression and S1P production. Inhibition of HBV replication through antiviral agents and the CRISPR-Cas9 system reduced SphK1 and S1P levels. Further, we identified the transcription factor USF1 as a key regulator of SphK1 expression during HBV infection. USF1 binds to the SphK1 promoter, increasing its transcriptional activity, and is upregulated in response to HBV infection. In vivo studies in mice demonstrated that HBV exposure promotes the expression of USF1 and SphK1-S1P. These findings suggest that the SphK1-S1P axis, regulated by HBV-induced USF1, could serve as a potential biomarker and therapeutic target for HBV-related liver injury., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Ethnopharmacological Relevance: The people of the Pan-Himalayan region are among the most isolated and economically disadvantaged populations worldwide. The Sherpa people, located along the China and Nepal border, rely largely on the natural environment to access essential healthcare services. The region's ongoing economic and social developments threaten indigenous medicinal practices and biodiversity. However, there has been limited comprehensive investigation and documentation of traditional medicine and its associated knowledge in this region., Aim of the Study: The aims are to document the traditional medicinal knowledge of the Sherpa community, assess the conservation status of medicinal plants, and explore the historical factors that have influenced their traditional medicine practices., Material and Methods: Semi-structured interviews with 78 Sherpa people were conducted in Chenthang Town, Xizang, China. Use reports (URs) was used to determine the most frequently mentioned medicinal plants or a specific ailment or disease category. The International Classification of Primary Care-2nd edition (ICPC-2) was used to transform the original records into an internationally unified classification., Results: A total of 51 plant species, one fungus (Ophiocordyceps sinensis (Berk.) G.H.Sung, J.M.Sung, Hywel-Jones & Spatafora), two lichens (Flavopunctelia soredica (Nyl.) Hale and Parmotrema cetratum (Ach.) Hale), and four minerals were documented, resulting in 824 URs. Ranunculaceae had the most species (5 spp.). The most commonly used method for preparing medicinal substances was decoction (23 species, 40%). Oral application was the preferred route of administration for 81% (41 medicinal substances). Forty-four ailments across 14 ICPC-2 disease categories were documented. Respiratory (320 URs) and digestive (122 URs) categories are among the most common diseases. The top-five ailments were influenza (18 substances; URs = 227), injury blood/lymph/spleen other (11 substances; URs = 66), cough (10 substances; URs = 62), headache (7 substances; URs = 63), and abdominal pain/cramps general (6 substances; URs = 37). The most frequently reported medicinal substances were Panax pseudoginseng Wall. (URs = 128) and Neopicrorhiza scrophulariiflora (Pennell) D. Y. Hong (URs = 79). Two special therapies (hot spring therapy and dietary therapy) were described. In-depth ethnographic information on the livelihood and exchange history of Sherpa people were documented. A total of 25 species were sold, of which four species were listed as VU in the IUCN Red List (2023-1), six species were listed as VU, four species were NT, and one species was EN in the China Biodiversity Red list 2021., Conclusion: This study provides the first comprehensive documentation of the 58 traditional medicine substances and two special therapies (hot spring therapy and dietary therapy) used by the Sherpa people in Chenthang. Sherpa's medicinal knowledge has been shaped by historical interactions and contemporary trade practices. To better protect the biocultural diversity of the Himalayan region, priority should be given to the rapid assessment of medicinal plants, knowledge, and use status in this area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Plasma-activated water (PAW) contains multiple active species that alter the structure of myofibrillar protein (MP) to enhance their gel properties. This work investigated the impact of PAW on the oxidation of cysteine in MP by label-free quantitative proteomics. PAW treatment caused the oxidation of 8241 cysteine sites on 2815 proteins, and structural proteins such as nebulin, myosin XVIIIB, myosin XVIIIA, and myosin heavy chain were susceptible to oxidation by PAW. Bioinformatics analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, subcellular localization, and STRING analysis, indicated that these proteins with differential oxidation sites were mainly derived from the cytoplasm and membrane, and were involved in multiple GO terms and KEGG pathways. This is one of the first reports of the redox proteomic changes induced by PAW treatment, and the results are useful for understanding the possible mechanism of PAW-induced oxidation of MP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The controllable fabrication of patterned p-type and n-type channels with precise doping control presents a significant challenge, impeding the realization of complementary metal-oxide-semiconductor (CMOS) logic using a single van der Waals material. However, such an achievement could offer substantial benefits by enabling continued transistor scaling and unprecedented interlayer interconnect technologies. In this study, we devise a precise method for two-dimensional (2D) semiconductor substitutional doping, which allows for the production of wafer-scale 2H-MoTe 2 thin films with specific p-type or n-type doping. Notably, we extend this approach to the synthesis of spatially selective doped 2H-MoTe 2 thin films via a one-step growth method, facilitating the monolithic integration of p-type and n-type semiconductor channels. Leveraging this advancement, we successfully fabricate a chip-sized 2D CMOS inverter array that demonstrates excellent device performance and yield. Collectively, these findings represent a significant stride towards the practical incorporation of 2D semiconductors in very large-scale integration technology., (© 2024. The Author(s).)

The downscaling of complementary metal-oxide-semiconductor technology has produced breakthroughs in electronics, but more extreme scaling has hit a wall of device performance degradation. One key challenge is the development of insulators with high dielectric constant, wide bandgap and high tunnel masses. Here, we show that two-dimensional monocrystalline gadolinium pentoxide, which is devised through combining particle swarm optimization algorithm and theoretical calculations and synthesized via van der Waals epitaxy, could exhibit a high dielectric constant of ~25.5 and a wide bandgap simultaneously. A desirable equivalent oxide thickness down to 1 nm with an ultralow leakage current of ~10 -4  A cm -2 even at 5 MV cm -1 is achieved. The molybdenum disulfide transistors gated by gadolinium pentoxide exhibit high on/off ratios over 10 8 and near-Boltzmann-limit subthreshold swing at an operation voltage of 0.5 V. We also constructed inverter circuits with high gain and nanowatt power consumption. This reliable approach to integrating ultrathin monocrystalline insulators paves the way to future nanoelectronics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The atomic substitution in two-dimensional (2D) materials is propitious to achieving compositionally engineered semiconductor heterostructures. However, elucidating the mechanism and developing methods to synthesize 2D heterostructures with atomic-scale precision are crucial. Here, we demonstrate the synthesis of monolayer WSe 2 -WS 2 heterostructures with a relatively sharp interface from monolayer WSe 2 using a chalcogen atom-exchange synthesis route at high temperatures for short periods. The substitution was initiated at the edges of monolayer WSe 2 and the lateral diffuse along the heterointerface, and the reaction can be controlled by the precise reaction time and temperature. The lateral heterostructure and substitution process are studied by Raman and photoluminescence (PL) spectroscopies, electron microscopy, and device characterization, revealing a possible mechanism of strain-induced transformation. Our findings demonstrate a highly controllable synthesis of 2D layered materials through atom substitutional chemistry and provide a simple route to control the atomic structure.

This study aimed to explore the effect of cyclosporine (CsA) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in systemic lupus erythematosus (SLE) patients to provide a valuable reference for clinical treatment strategies in the context of the long-term risk of SARS-CoV-2 infection. SLE patients who visited the Rheumatology Outpatient Department of Fujian Medical University Union Hospital between 1 May and 31 October 2022 were included. Data on SARS-CoV-2 infection in patients between 1 November 2022 and 31 July 2023 were obtained by telephone follow-up. Patients were divided into two groups according to whether CsA was used during the observation period: the glucocorticoid or hydroxychloroquine group and the CsA group. To assess the robustness of the results, Data sets 1 and 2 were established to be analyzed independently. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for symptomatic coronavirus disease (COVID-19). A total of 184 patients were included, among whom 129 were definite symptomatic COVID-19 patients; 29 were presumptive symptomatic COVID-19 patients; and 4 had signs and symptoms of COVID-19, but tested negative for SARS-CoV-2 in a virological test. According to the multivariable-adjusted models, CsA was associated with lower odds of symptomatic COVID-19 ( P = 0.042, OR = 0.316, 95% CI: 0.104-0.959 in Data set 1 and P = 0.021, OR = 0.257, 95% CI: 0.081-0.812 in Data set 2). CsA is associated with lower odds of contracting symptomatic COVID-19. The use of CsA may be considered an appropriate therapeutic option for disease management in patients with rheumatic diseases who have severe disease activity and persistent SARS-CoV-2 infection., Importance: Our study indicated that cyclosporine may reduce the risk of symptomatic COVID-19 in systemic lupus erythematosus patients in spite of its immunosuppressive effects. This study provides a reference for clinical treatment strategies for AIIRD patients in the context of the long-term risk of SARS-CoV-2 infection., Competing Interests: The authors declare no conflict of interest.

Nanotechnology has emerged as a promising innovative avenue for therapeutic intervention in cancer research. However, achieving satisfactory accumulation of nanoparticles in the tumor and fabricating optimized nanoparticles remain challenging. In this work, we developed a novel polymeric micelle system to actively target integrin receptors, which are usually overexpressed in breast cancer. We first synthesized a targeted peptide-modified cyclic (Arg-Gly-Asp-D-Phe-Cys) (c(RGDfc))-polyethylene glycol-acitretin amphipathic conjugate (RPA) and prepared doxorubicin (DOX)-loaded RPADm (RPA@DOX) micelles with a high drug loading content of more than 11 %. Compared with unmodified DOX-containing micelles, RPADm demonstrated increased cytotoxicity and cellular uptake by MCF-7 cells. Importantly, competitive binding experiments confirmed that the observed enhancement effect was attributed to the modification of c(RGDfc) on the surface of the micelles. Furthermore, due to its active tumor-targeting ability, compared with the other DOX-based formulations, the RPADm exhibited the highest tumor distribution and strongest therapeutic efficacy in MCF-7 tumor-bearing nude mice. Additionally, the safety evaluation experiments revealed that the DOX-loaded micelles had no obvious systemic toxicity. These results suggest that the developed micelles modified with c(RGDfc) are promising candidates for tumor-active targeting therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Escherichia coli and Staphylococcus aureus are the most prevalent pathogenic bacteria, often resulting in the foodborne disease outbreaks through food spoilage and foodborne infections. To prevent and control food spoilage and foodborne infections induced by Escherichia coli and Staphylococcus aureus, the antibacterial hydrogels were fabricated using fibrinogen hydrolysate-carrageenan (AHs-C) and flavonoids (apigenin and quercetin), and the antibacterial effect of the composite hydrogels against Escherichia coli and Staphylococcus aureus was further investigated. The results of mechanical property exhibited that the composite hydrogels with 0.2 % of apigenin and quercetin (AHs-C-Ap/Que) showed the highest hardness and swelling property compared with the separate addition of apigenin or quercetin. Scanning electron microscopy and atomic force microscopy showed that the dense networks were formed in the hydrogels of AHs-C-Ap/Que., and the average roughness of AHs-C-Ap/Que. significantly increased to 30.70 nm compared with AHs-C. 1 H NMR and FTIR spectra demonstrated that apigenin and quercetin were bound to AHs-C by hydrogen bond, hydrophobic interaction and Schiff base, where the interactions between Ap/Que. and AHs-C was stronger compared with the separate addition of apigenin or quercetin. The hydrogels of AHs-C-Ap/Que. showed the highest antibacterial capacity and antibacterial adhesion against Escherichia coli and Staphylococcus aureus. The antibacterial adhesion assay showed that 99 % removal ratios for E. coli and S. aureus were observed in AHs-C-Ap/Que. hydrogels, which showed a great potential to prevent food spoilage and foodborne infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite the challenges associated with the synthesis of flexible metal-covalent organic frameworks (MCOFs), these offer the unique advantage of maximizing the atomic utilization efficiency. However, the construction of flexible MCOFs with flexible building units or linkages has rarely been reported. In this study, novel flexible MCOFs are constructed using flexible building blocks and copper clusters with hydrazone linkages. The heterometallic frameworks (Cu, Co) are prepared through the hydrazone linkage coordination method and evaluated as catalysts for the oxygen evolution reaction (OER). Owing to the spatial separation and functional cooperation of the heterometallic MCOF catalysts, the as-synthesized MCOFs exhibited outstanding catalytic activities with an overpotential of 268.8 mV at 10 mA cm -2 for the OER in 1 M KOH, which is superior to those of the reported covalent organic frameworks (COFs)-based OER catalysts. Theoretical calculations further elucidated the synergistic effect of heterometallic active sites within the linkages and frameworks, contributing to the enhanced OER activity. This study thus introduces a novel approach to the fundamental design of flexible MCOF catalysts for the OER, emphasizing their enhanced atomic utilization efficiency., (© 2024 Wiley‐VCH GmbH.)

Objective: This study aimed to develop and validate a machine learning (ML) model to predict high-grade heterotopic ossification (HO) following Anterior cervical disc replacement (ACDR)., Methods: Retrospective review of prospectively collected data of patients undergoing ACDR or hybrid surgery (HS) at a quaternary referral medical center was performed. Patients diagnosed as C3-7 single- or multi-level cervical disc degeneration disease with > 2 years of follow-up and complete pre- and postoperative radiological imaging were included. An ML-based algorithm was developed to predict high grade HO based on perioperative demographic, clinical, and radiographic parameters. Furthermore, model performance was evaluated according to discrimination and overall performance., Results: In total, 339 ACDR segments were included (61.65% female, mean age 45.65 ± 8.03 years). Over 45.65 ± 8.03 months of follow-up, 48 (14.16%) segments developed high grade HO. The model demonstrated good discrimination and overall performance according to precision (High grade HO: 0.71 ± 0.01, none-low grade HO: 0.85 ± 0.02), recall (High grade HO: 0.68 ± 0.03, none-low grade HO: 0.87 ± 0.01), F1-score (High grade HO: 0.69 ± 0.02, none-low grade HO: 0.86 ± 0.01), and AUC (0.78 ± 0.08), with lower prosthesis‑endplate depth ratio, higher height change, male, and lower postoperative-shell ROM identified as the most important predictive features., Conclusion: Through an ML approach, the model identified risk factors and predicted development of high grade HO following ACDR with good discrimination and overall performance. By addressing the shortcomings of traditional statistics and adopting a new logical approach, ML techniques can support discovery, clinical decision-making, and intraoperative techniques better., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The interplay between influential factors and the incidence of subthreshold depression (SD) in young adults remains poorly understood., Objectives: This study sought to understand the dietary habits, gut microbiota composition, etc. among individuals with SD in young adults and to investigate their association with SD occurrence., Methods: Employing a cross-sectional approach, 178 individuals with SD, aged 18-32 years, were matched with 114 healthy counterparts. SD status was evaluated using the Zung Self-rating Depression Scale (SDS), Zung Self-rating Anxiety Scale (SAS), Beck Depression Inventory 2nd version (BDI-II), the 17-item Hamilton Rating Scales of Depression (HAMD-17), and Pittsburgh Sleep Quality Index (PSQI). Metagenomic sequencing was utilized to identify fecal microbial profiles. Dietary patterns were discerned via factor analysis of a 25-item food frequency questionnaire (FFQ). Logistic regression analysis and mediation analysis were performed to explore the potential links between gut microbiota, dietary patterns, and incident SD., Results: Data on dietary habits were available for 292 participants (mean [SD] age, 22.1 [2.9] years; 216 [73.9 %] female). Logistic regression analysis revealed that dietary patterns Ⅰ (odds ratio [OR], 0.34; 95 % CI, 0.15-0.75) and IV (OR, 0.39; 95 % CI, 0.17-0.86 and OR, 0.39; 95 % CI, 0.18-0.84) were associated with reduced risk of SD. Distinct microbial profiles were observed in young adults with SD, marked by increased microbial diversity and taxonomic alterations. Moreover, mediation analysis suggested Veillonella atypica as a potential mediator linking SDS or BDI-II scores with a healthy dietary pattern rich in bean products, coarse grains, nuts, fruits, mushrooms, and potatoes (β = 0.25, 95 % CI: 0.02-0.78 and β = 0.18, 95 % CI: 0.01-0.54)., Conclusions: Our findings highlight the complex interplay between dietary patterns, gut microbiota, and the risk of developing SD in young adults, underscoring the potential for dietary interventions and microbiome modulation in mental health promotion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Cyclodipeptide synthases (CDPSs) catalyze the synthesis of diverse cyclodipeptides (CDPs) by utilizing two aminoacyl-tRNA (aa-tRNA) substrates in a sequential ping-pong reaction mechanism. Numerous CDPSs have been characterized to provide precursors for diketopiperazines (DKPs) with diverse structural characteristics and biological activities. BcmA, belonging to the XYP subfamily, is a cyclo(l-Ile-l-Leu)-synthesizing CDPS involved in the biosynthesis of the antibiotic bicyclomycin. The structural basis and determinants influencing BcmA enzyme activity and substrate selectivity are not well understood. Here, we report the crystal structure of Ss BcmA from Streptomyces sapporonensis . Through structural comparison and systematic site-directed mutagenesis, we highlight the significance of key residues located in the aminoacyl-binding pocket for enzyme activity and substrate specificity. In particular, the nonconserved residues D161 and K165 in pocket P2 are essential for the activity of Ss BcmA without significant alteration of the substrate specificity, while the conserved residues F158 as well as F210 and S211 in P2 are responsible for determining substrate selectivity. These findings facilitate the understanding of how CDPSs selectively accept hydrophobic substrates and provide additional clues for the engineering of these enzymes for synthetic biology applications.

Sir2-HerA is a widely distributed antiphage system composed of a RecA-like ATPase (HerA) and an effector with potential NADase activity (Sir2). Sir2-HerA is believed to provide defense against phage infection in Sir2-dependent NAD + depletion to arrest the growth of infected cells. However, the detailed mechanism underlying its antiphage activity remains largely unknown. Here, we report functional investigations of Sir2-HerA from Staphylococcus aureus (SaSir2-HerA), unveiling that the NADase function of SaSir2 can be allosterically activated by the binding of SaHerA, which then assembles into a supramolecular complex with NADase activity. By combining the cryo-EM structure of SaSir2-HerA in complex with the NAD + cleavage product, it is surprisingly observed that Sir2 protomers that interact with HerA are in the activated state, which is due to the opening of the α15-helix covering the active site, allowing NAD + to access the catalytic pocket for hydrolysis. In brief, our study provides a comprehensive view of an allosteric activation mechanism for Sir2 NADase activity in the Sir2-HerA immune system., (© 2024. The Author(s).)

Dihydromyricetin (DMY), a natural flavonoid compound, are believed to prevent inflammatory response, dealing with pathogens and repairing the intestinal barrier. The objective of this study was to investigate whether DMY supplementation could attenuate intestinal damage in the context of enterotoxigenic Escherichia coli K88 (ETEC F4 + ) infection. After weaning, different litters of pigs were randomly assigned to one of the following treatments: (1) non-challenged control (CON, fed with basal diet); (2) ETEC-challenged control (ECON, fed with basal diet); and (3) ETEC challenge + DMY treatment (EDMY, fed with basal diet plus 300 mg kg -1 DMY). We observed a significant reduction in fecal Escherichia coli shedding and diarrhea incidence, but an increase in ADG in pigs of EDMY group compared to the pigs of ECON group. Relative to the pigs of ECON group, dietary DMY treatment decreased (P < 0.05) concentrations of the serum D-xylose, D-lactate and diamine oxidase (DAO), but increased the abundance of zonula occludens-1 (ZO-1) in the jejunum of pigs. In addition, DMY also decreased (P < 0.05) the number of S-phase cells and the percentage of total apoptotic epithelial cells of jejunal epithelium in pigs of the EDMY group compared to the pigs of the ECON group. Furthermore, DMY decreased the mRNA expression levels of critical immune-associated genes TLR4, NFκB, Caspase3, Caspase9, IL-1β, IL-6, TNF-α and the protein p-NFκB and p-IκBα expressions of intestinal epithelium in pigs of the EDMY group compared to the pigs of the ECON group. Compared to the ECON group, DMY elevated (P < 0.05) the expression levels of β-defensins PBD1, PBD2, PBD3, PBD129, as well as the abundance of secreted IgA in intestinal mucosae of the EDMY group. Thus, our results indicate that DMY may relieve intestinal integrity damage due to Escherichia coli F4., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases hair cell regeneration, however, these cells fail to fully mature. Here, we profiled mouse utricles at 14 time points, and defined transcriptomes of developing and mature vestibular hair cells. To mimic native hair cells which downregulate endogenous ATOH1 as they mature, we engineered viral vectors carrying the supporting cell promoters GFAP and RLBP1. In utricles damaged ex vivo, both CMV-ATOH1 and GFAP-ATOH1 increased regeneration more effectively than RLBP1-ATOH1, while GFAP-ATOH1 and RLBP1-ATOH1 induced hair cells with more mature transcriptomes. In utricles damaged in vivo, GFAP-ATOH1 induced regeneration of hair cells expressing genes indicative of maturing type II hair cells, and more hair cells with bundles and synapses than untreated organs. Together our results demonstrate the efficacy of spatiotemporal control of ATOH1 overexpression in inner ear hair cell regeneration., (© 2024. The Author(s).)

Polycystic ovary syndrome (PCOS) is a metabolic disorder with clinical heterogeneity. PCOS women with non-hyperandrogenemia (NA) might be misdiagnosed due to a lack of diagnostic markers. This study aims to systematically analyze the differences in steroid hormones between PCOS women with hyperandrogenemia (HA) and NA, and to screen classification diagnosis models for PCOS. The serum samples from 54 HA-PCOS, 79 NA-PCOS and 60 control women (Non-PCOS) aged between 18 and 35 were measured by an integrated steroid hormone-targeted quantification assay using LC-MS/MS. The levels of serum androgens, corticosteroids, progestins and estrogens in the steroid hormone biosynthesis pathway were analyzed in PCOS and Non-PCOS women. Eight machine learning methods including Linear Discriminant Analysis (LDA), K-nearest Neighbors (KNN), Boosted Logistic Regression (LogitBoost), Naive Bayes (NB), C5.0 algorithm (C5), Random Forest (RF), Support Vector Machines (SVM), and Neural Network (NNET) were performed, evaluated and selected for classification diagnosis of PCOS. A 10-fold cross-validation on the training set was performed. The whole metabolic flux from cholesterol to downstream steroid hormones increased significantly in PCOS, especially in HA-POCS women. The RF model was chosen for the classification diagnosis of HA-PCOS, NA-PCOS, and Non-PCOS women due to the maximum average accuracy (0.938, p<0.001), AUC (0.989, p<0.001), and kappa (0.906, p<0.001), and the minimum logLoss (0.200, p<0.001). Five steroid hormones including testosterone, androstenedione, total 2-methoxyestradiol, total 4-methoxyestradiol, and free estrone were selected as the decision trees for the simplified RF model. A total of 37 women were included in the validation set. The diagnostic sensitivity for HA-PCOS, NA-PCOS, and Non-PCOS was 100 %, 93.3 % and 91.7 %, respectively. HA-PCOS, NA-PCOS, and Non-PCOS women showed obvious different steroid hormone profiles. The simplified RF model based on two androgens and three estrogens could be effectively applied to the classification diagnosis of PCOS, further reducing the missed diagnosis rate of NA-PCOS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tim-1 (T-cell immunoglobulin and mucin domain 1), also known as Kim-1 (kidney injury molecule 1) or hepatitis A virus cellular receptor 1 (HAVCR1), is a transmembrane protein expressed on various immune and epithelial cells. It plays a role in modulating inflammatory and immune responses. In this study, we find that Tim-1 is overexpressed in hepatocellular carcinoma (HCC) samples and that its expression is significantly correlated with postoperative survival. Bulk RNA sequencing reveals a general upregulation of extracellular matrix-related genes in HCC tissues with Tim-1 overexpression. The results of the cell and in vivo experiments reveal that Tim-1 in HCC not only affects biological processes such as the proliferation, migration, and invasion of HCC cells but also broadly promotes extracellular matrix processes by influencing cytokine secretion. Further studies demonstrate that Tim-1 mediates the activation of hepatic stellate cells and upregulates Th1 and Th2 cytokines, thereby promoting HCC progression. Thus, Tim-1 may represent a novel target for future interventions in HCC and liver fibrosis.

Background: Bilirubin (BIL) and creatinine (Cr) have been used as potential early predictors of the severity of many diseases. A recent study found that the Cr to BIL ratio (CTR) was more sensitive and specific than either serum Cr or BIL alone. Our research focused on the clinical significance of CTR in evaluating the severity and prognosticating outcomes of acute pancreatitis (AP) in patients., Methods: Patients diagnosed with AP at the First Affiliated Hospital of Guangdong Pharmaceutical University between July 1, 2016, and December 31, 2020 were included. The analysis then focused on examining the relationship between CTR levels and the severity of the illness, the occurrence of complications, and the prognosticating outcomes for individuals diagnosed with AP. A total of 286 AP patients were enrolled., Results: Multivariate regression analyses showed that patients with AP with increased CTR levels had a poorer disease (easier to develop severe AP); higher Ranson, and Acute Physiology and Chronic Health Evaluation (APACHE-II) scores; higher incidence of organ failure (acute heart failure, acute kidney injury and acute myocardial infarction ); and leading to a worse prognosis characterized more by frequent use of vasoactive and diuretic agents. When CTR &gt;14.05, AP patients had increased occurrence of AHF and AKI, higher 30-day all-cause mortality rates, more frequently using vasoactive agent and diuretic agent. Besides, the disease severity scores and hospital stays were markedly increased., Conclusion: Patients with AP who exhibit higher CTR levels tend to experience escalating disease severity, more complications, and a poorer outcome compared with those with lower CTR levels., (S. Karger AG, Basel.)

Background: Septic shock (SS) is a highly fatal and heterogeneous syndrome. Identifying distinct clinical phenotypes provides valuable insights into the underlying pathophysiological mechanisms and may help to propose precise clinical management strategies., Methods: Latent profile analysis (LPA), a model-based unsupervised method, was used for phenotyping in the MIMIC cohort, and the model was externally independently validated in the eICU and AUMC cohorts., Results: Three phenotypes, labeled phenotype I, II, and III, were derived. These phenotypes varied in demographics, clinical features, comorbidities, patterns of organ dysfunction, organ support, and prognosis. Phenotype I, characterized by the most severe organ dysfunction (especially liver), the youngest age, and the highest BMI, had the highest mortality (p < 0.001). Phenotype II, with moderate mortality, was characterized by severe renal injury. In contrast, phenotype III, associated with the oldest age and the fewest comorbidities, exhibited significantly lower mortality. Phenotype I patients had the steepest survival curves and demonstrated an ultra-high risk of death, particularly within the first few days after SS onset., Conclusions: The individualized identification of phenotypes is well suited to clinical practice. The three SS phenotypes differed significantly in pathophysiological and clinical outcomes, which are crucial for informing management decisions and prognosis., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary fibrosis (PF) is a lethal disease caused by inordinate repair of damaged lungs, for which limited strategies are available. Polyphyllin VI (PPVI), extracted and isolated from Paris polyphylla Smith var. chinensis (Franch.) Hara, has been regarded as an important traditional Chinese herbal medicine for the treatment of respiratory system diseases. This study evaluated effects of PPVI on PF and its underlying mechanism. Experimental procedure For evaluating the anti-PF effect of PPVI, we established an in vivo PF mouse model via intratracheal infusion of bleomycin (BLM) in mice and an in vitro PF model induced by TGF-β1 in NIH/3T3, HPF and A549, respectively. Subsequently, the mechanism of PPVI effects was further explored using RNA sequencing (RNA-Seq). The in vivo and in vitro results demonstrated that PPVI significantly inhibited inflammation, oxidative damage, and epithelial-mesenchymal transition. Furthermore, RNA sequencing indicated that PPVI ameliorated PF by modulating inflammation and oxidative stress responses. Furthermore, dual specificity phosphatase 6 (DUSP6), was the shared and most significant differentially expressed gene associated with inflammation and oxidative stress response after PPVI treatment. Mechanistically, silencing DUSP6 can eliminate the suppressive impact on PPVI for the activation of fibroblast and the phosphorylation of ERK and AKT. Summarily, our findings revealed the potential of PPVI in mitigating PF via upregulating DUSP6 and highlighted the regulatory function of DUSP6 in the pathogenesis of PF., (© 2024 John Wiley & Sons Ltd.)

Infectious gastroenteritis is the major cause for diarrhea in piglets. The protection of spray-dried plasma (SDP) on viral gastroenteritis during the progression of rotavirus (RV) infection remain unclear. In this study, 64 weanling piglets were randomly assigned to control diets ( n  = 40) and SDP diets ( n  = 24) for 14 days, and then pigs were challenged with RV on day 15. Pigs were sacrificed on day 14 (normal condition), day 18 (manifestation stage), and day 21 (convalescent stage) of the trial. Prior to RV infection, SDP increased ADG, M1 macrophages and CD4 + T cells in different organs without increasing proinflammatory cytokines, indicating a more robust immunity with less inflammation. During the manifestation of infection, SDP enhanced mucosal immunity by increasing M1 macrophages, M1/M2 ratio and cytokines in mucosa and increasing intraepithelial CD8 + T cells for RV clearance. During the convalescence, SDP promoted M2 macrophage polarization and reduced pro-inflammatory cytokines to facilitate intestinal repair and prevent prolonged inflammation. Collectively, SDP enhanced mucosal immunity to promote viral clearance and maintained immune homeostasis to prevent long-lasting inflammation as a therapeutically approach for infectious gastroenteritis., Competing Interests: JC and YS were employed by APC LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yan, Dong, Li, He, Yu, Mao, Yu, Luo, Luo, Wu, Pu, Wang, Wang, Crenshaw, Shen and Chen.)

Study Design: Machine learning model., Objectives: This study aimed to develop and validate a machine learning (ML) model to predict moderate-severe anterior bone loss (ABL) following anterior cervical disc replacement (ACDR)., Methods: A retrospective review of patients undergoing ACDR or Hybrid surgery (HS) at a single center was performed. Patients diagnosed as C3-7 single- or multi-level cervical disc degenerative diseases (CDDD) with more than 2 years of follow-up and complete pre- and postoperative radiological imaging were included. An ML-based algorithm was developed to predict moderate-severe ABL based on perioperative demographic, clinical, and radiographic parameters. Model performance was evaluated in terms of discrimination and overall performance., Results: A total of 339 ACDR segments were included (61.65% female, mean age 45.65 ± 8.03 years). During a follow-up period of 45.65 ± 8.03 months, 103 (30.38%) segments developed moderate-severe ABL. The model demonstrated good discrimination and overall performance according to precision (moderate-severe ABL: 0.71 ± 0.07, none-mild ABL: 0.73 ± 0.08), recall (moderate-severe ABL: 0.69 ± 0.08, none-mild ABL: 0.75 ± 0.07), F1-score (moderate-severe ABL: 0.70 ± 0.08, none-mild ABL: 0.74 ± 0.07), and area under the curve (AUC) (0.74 ± 0.10). The most important predictive features were higher height change, higher post-segmental angle, and longer operation time., Conclusions: Utilizing a ML approach, this study successfully identified risk factors and accurately predicted the development of moderate-severe ABL following ACDR, demonstrating robust discrimination and overall performance. By overcoming the limitations of traditional statistical methods, ML can enhance discovery, clinical decision-making, and intraoperative techniques., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pancreatic cancer is among the most immune-resistant tumor types due to its unique tumor microenvironment and low cancer immunogenicity. Single-agent immune modulators have thus far proven clinically ineffective. However, a growing body of evidence suggests that combination of these modulators with other strategies could unlock the potential of immunotherapy in pancreatic cancer. Herein, we describe the case of a 59-year-old male with metastatic pancreatic ductal adenocarcinoma, referred to our center to receive immunotherapy (serplulimab, a novel anti-PD-1 antibody) combined with chemotherapy (gemcitabine/nab-paclitaxel). During the initial three treatment cycles, the patient was assessed as having stable disease (SD) according to RECIST 1.1 criteria. However, following two additional cycles of combination therapy, the primary tumor mass increased from 4.9 cm to 13.2 cm, accompanied by the development of new lung lesions, ascites, and pelvic metastases. He succumbed to respiratory failure one month later. Retrospective analysis revealed that the patient had MDM4 amplification, identified as a high-risk factor for hyperprogressive disease (HPD). To our knowledge, this is the first reported case of HPD in pancreatic cancer with multiple metastases treated using combination therapy. We investigated the potential mechanisms and reviewed the latest literature on predictive factors for HPD. These findings suggest that while chemotherapy combined with immunotherapy may hold promise for treating pancreatic cancer, it is imperative to identify and closely monitor patients with high-risk factors for HPD when using immunotherapy., (© 2024. The Author(s).)

Photocatalytic reduction of diluted CO 2 from anthropogenic sources holds tremendous potential for achieving carbon neutrality, while the huge barrier to forming *COOH key intermediate considerably limits catalytic effectiveness. Herein, via coordination engineering of atomically scattered Ni sites in conductive metal-organic frameworks (CMOFs), we propose a facile strategy for tailoring the d-band center of metal active sites towards high-efficiency photoreduction of diluted CO 2 . Under visible-light irradiation in pure CO 2 , CMOFs with Ni-O 4 sites (Ni-O 4 CMOFs) exhibits an outstanding rate for CO generation of 13.3 μmol h -1 with a selectivity of 94.5 %, which is almost double that of its isostructural counterpart with traditional Ni-N 4 sites (Ni-N 4 CMOFs), outperforming most reported systems under comparable conditions. Interestingly, in simulated flue gas, the CO selectivity of Ni-N 4 CMOFs decreases significantly while that of Ni-O 4 CMOFs is mostly unchanged, signifying the supremacy for Ni-O 4 CMOFs in leveraging anthropogenic diluted CO 2 . In situ spectroscopy and density functional theory (DFT) investigations demonstrate that O coordination can move the center of the Ni sites' d-band closer to the Fermi level, benefiting the generation of *COOH key intermediate as well as the desorption of *CO and hence leading to significantly boosted activity and selectivity for CO 2 -to-CO photoreduction., (© 2024 Wiley-VCH GmbH.)

Background: Oxidative stress significantly impacts growth performance and liver function in piglets. Ferulic acid (FA) works as an antioxidant, however, the role and mechanism of FA in the regulation of diquat-induced oxidative stress in piglets are less known. This study was designed to investigate the effects of FA on growth performance and antioxidant capacity in piglets with diquat challenge., Methods: Thirty-two healthy DLY (Duroc × Landrace × Yorkshire) piglets (13.24 ± 0.19 kg) were randomly divided into one of two diets including 0 or 4 g/kg FA for 14 d. On d 15, all pigs were intraperitoneally injected diquat or sterile saline., Results: Dietary supplementation with ferulic acid (FA) significantly improved the average daily gain (ADG) and decreased feed-gain ratio (F/G) of piglets. Here, dietary FA supplementation reduced serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities in diquat challenged piglets. Furthermore, diquat infusion increased reactive oxygen radicals (ROS) level in liver, decreased the activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC) and increased malondialdehyde (MDA) content in the liver and serum. Supplementation with FA significantly increased T-AOC and T-SOD activities and decreased MDA and ROS levels. FA down-regulated gene and protein expression of Keap1, and up-regulated protein expression of Nrf2 and HO-1 in the liver of piglets with diquat challenge. Importantly, diquat challenge increased the ratio of late apoptosis, increased serum levels of IL-1β, IL-18 and lactate dehydrogenase (LDH), and up-regulated pyroptosis-related genes in the liver. FA supplementation reduced the ratio of late apoptosis and down-regulated mRNA expression of Caspase-1. Accordingly, FA addition reduced concentration of IL-1β, IL-18, and LDH under diquat challenge., Conclusions: Diquat-induced oxidative stress reduced growth performance and impaired liver function in piglets. Dietary FA supplementation enhanced the antioxidant capacity and reduced the degree of hepatocyte pyroptosis, thereby alleviating the oxidative damage in the liver and mitigating the impact of diquat on growth performance of piglets., (© 2024. The Author(s).)

Domain orientation modulation and controlled doping of two-dimensional (2D) transition-metal dichalcogenides (TMDCs) are two pivotal tasks for synthesizing wafer-scale single crystals and boosting device performances. However, realizing two such targets and uncovering internal physical mechanisms remain daunting challenges. We develop an accurate Fe doping strategy, which enables domain orientation control and electron mobility improvement of monolayer MoS 2 . By tuning of the Fe dopant dosages, parallel steps with different heights are formed, which induce edge-nucleation of unidirectionally aligned monolayer MoS 2 . In parallel, Fe doping induces the down shift of the conduction band minimum of monolayer MoS 2 and matches well with the work function of an electrode, which reduces Schottky barrier height and delivers ultralow contact resistance (561 Ω μm) and excellent electron mobility (37.5 cm 2 V -1 s -1 ). The modulation mechanism is clarified by combining theory calculations and electronic structure characterizations. This work hereby provides a new paradigm for synthesizing wafer-scale 2D TMDC single crystals and constructing high-performance devices.

With the increasing demand for high-performance passive nonlinear photonic devices, significant progress has been made in spatial self-phase modulation (SSPM) based on 2D nanomaterials in all-optical switches, logic gates, and information converters in recent years. However, there are still challenges in improving the responsiveness of photonic devices. In this work, we prepared a heterojunction of Ag nanoparticles deposited on the surface of violet phosphorus nanosheets (VP Ns), investigated their SSPM, and demonstrated their performance in all-optical switches. The SSPM experimental results show that compared with pure VP Ns at the same light intensity, both the maximum number and the formation time of self-diffraction rings in Ag/VP heterojunctions increase, and the nonlinear refractive index is approximately doubled. The main reason for optical nonlinearity enhancement is that the internal electric field in the heterojunction strengthens the mobility of the photogenerated carrier, thereby enhancing its optical nonlinearity. In particular, we demonstrate the performance of all-optical switches based on SSPM by utilizing the superior optical nonlinearity of Ag/VP heterojunctions. It is shown that with the increase of low-dose Ag content in heterojunctions, the switching time in the all-optical switch becomes shorter and the maximum number of self-diffraction rings of the signal light increases, although the quality of self-diffraction rings slightly decreases due to the scattering of Ag particles. The results contribute to the design and implementation of high-performance nonlinear photonic devices, based on the use of heterojunctions with low-cost preparation and a high nonlinear refractive index.

Hearing difficulty (HD) is a major health burden in older adults. While ageing-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analysed a large-scale HD genome-wide association study (GWAS; ntotal = 501 825, 56% females) and GWAS data related to 3935 brain imaging-derived phenotypes (IDPs) assessed in up to 33 224 individuals (52% females) using multiple MRI modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait co-localization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 in males and 171 in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven of them, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a co-localization signal for the rs13026575 variant between HD, primary visual cortex volume and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Heterostructure engineering provides versatile platforms for exploring exotic physics and enhancing the device performance through interface coupling. Despite the rich array of physical phenomena presented by heterostructures composed of semiconductor and metal van der Waals materials, significant gaps remain in understanding their optical, thermal, and electronic properties. Here, we demonstrate that the valley pseudospin and electron-phonon coupling in monolayer WSe 2 are significantly influenced by interface coupling with 1T-VSe 2 . The heterointerface alters the relaxation process of valley excitons, leading to a transition in magnetic-field-dependent valley polarization from a linear to a "V" shape. Furthermore, we uncover that enhanced electron-phonon coupling exacerbates variations in exciton and valley exciton behavior with temperature, involving higher phonon energies and a shift from acoustic to optical phonons. These findings highlight a promising pathway to manipulate valley excitons and investigate electron-phonon coupling through van der Waals interface interactions.

We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains. Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Visible-blind ultraviolet (UV) light detection has a wide application range in scenes like space environment monitoring and medical imaging. To realize miniaturized UV detectors with high performance and high integration ability, new device structures without bulky light filters need to be developed based on advanced mechanisms. Here the unipolar barrier van der Waals heterostructure (UB-vdWH) photodetector is reported that realizes filter-free visible-blind UV detection with good stability, robustness, selectivity, and high detection performance. The UB-vdWH shows a responsivity of 2452 A W -1 , a photo on-off ratio of 2.94 × 10 5 and a detectivity of 1.26 × 10 15  Jones as a UV detector, owing to the intentionally designed barrier height that suppresses dark current and photoresponse to visible light during the transport process. The good performance remains intact during 10 4 test cycles or even under high temperatures, which proves the stability, and robustness of the UB-vdWH, thus shows the huge potential for a wider application range., (© 2024 Wiley‐VCH GmbH.)

Euphorbiabietane F (1), a novel abietane diterpenoid with the unprecedented 6/6/5/6/5 carbon skeleton, one new strobane diterpenoid (2), together with one new pimarane diterpenoid (3) were isolated from the roots of Euphorbia fischeriana. The structures were elucidated by the extensive spectroscopic data, gauge-independent atomic orbital (GIAO) NMR calculations, the comparison of experimental and calculated ECD spectra, as well as single crystal X-ray diffraction. The cytotoxicity result suggested the moderate inhibition rate of 1 on the cell lines of HepG2 and A549., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are widely expressed in the brain and are associated with the development of neurological and neurodegenerative diseases. However, their roles and molecular mechanisms in major depressive disorder (MDD) remain largely unknown. This study aimed to identify lncRNAs and miRNAs involved in the development of MDD and elucidate their molecular mechanisms., Methods: Transcriptome and bioinformatic analyses were performed to identify miRNAs and lncRNAs related to MDD. C57 mice were subjected to chronic unpredictable mild stress (CUMS) to establish a depression model. Lentiviruses containing either lncRNA NPTN-IT1-201 or miR-142-5p were microinjected into the hippocampal region of these mice. Behavioral tests including the sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST) were conducted to evaluate depressive-like behaviors., Results: The results revealed that overexpression of lncRNA NPTN-IT1-201 or inhibition of miR-142-5p significantly ameliorated depressive-like behaviors in CUMS-treated mice. Dual-luciferase reporter assays confirmed interactions between miR-142-5p with both brain-derived neurotrophic factor (BDNF) and NPTN-IT1-201. ELISA analysis revealed significant alterations in relevant biomarkers in the blood samples of MDD patients compared to healthy controls. Histological analyses, including HE and Nissl staining, showed marked structural changes in brain tissues following CUMS treatment, which were partially reversed by lncRNA NPTN-IT1-201 overexpression or miR-142-5p inhibition. Immunofluorescence imaging demonstrated significant differences in the levels of BAX, Bcl2, p65, Iba1 among different treatment groups. TUNEL assays confirmed reduced apoptosis in brain tissues following these interventions. Western blotting showed the significant differences in BDNF, BAX, and Bcl2 protein levels among different treatment groups., Conclusion: NPTN-IT1-201 regulates inflammation and apoptosis in MDD by targeting BDNF via miR-142-5p, making it a potential therapeutic target for MDD., (© 2024. Huazhong University of Science and Technology.)

Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperidiones A-F (1-6), were obtained from Hypericum perforatum L. Their structures were characterized via extensive spectroscopic analyses, the circular dichroism data of the in situ formed [Mo 2 (OCOCH 3 ) 4 ] complexes, the nuclear magnetic resonance calculation with DP4 + probability analysis, and the calculated electronic circular dichroism (ECD) spectra. Compounds 1-6 are bicyclic polyprenylated acylphloroglucinols with a major bicyclo[3.3.1]nonane-2,4,9-trione skeleton. Notably, compound 1 is a rare PPAP with a hydroperoxy group, and a plausible biosynthetic pathway for 1 was proposed. Compounds 4 and 6 exhibited significant neuroprotective effects under 10 μM against corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, compound 4 demonstrated a noteworthy antidepressant effect at the dose of 5 mg/kg in the tail suspension test (TST) of mice, which was equivalent to 5 mg/kg of fluoxetine. And it potentially exerted an antidepressant effect through the hypothalamic-pituitary-adrenal (HPA) axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Radiation is a mainstay of lung cancer treatment; however, resistance frequently develops. Identifying novel therapeutic targets to increase radiation sensitivity is crucial. S6K1 is a serine/threonine kinase known to regulate protein translation which is associated with radioresistance, but the mechanisms involved are unknown. We proposed to determine whether S6K1 promotes radioresistance by regulating DNA repair in lung cancer. Colony formation, protein expression and proliferation were assessed. S6K1 was modulated pharmacologically by either PF-4708671 or genetically by Crispr-Cas9. Higher radioresistance levels in lung cancer cells were associated with lower phosphoactivation of MRN complex members, a key activator of radiation-induced DNA repair signaling. We also found lower levels of p-ATM, a target of the MRN complex, in more radioresistant cells, which was associated with a lower expression of γ-H2AX cafter radiation. Further, genetic and pharmacological S6K1 targeting sensitized lung cancer cells to low doses of radiation ( p ≤ 0.01). Additionally, S6K1 -/- deletion increased the phosphoactivation of MRN complex members, indicating that S6K1 itself can shut down DNA damage regulated by MRN signaling. This is the first report showing that S6K1 inhibition radiosensitizes lung cancer cells by decreasing MRN complex-regulated DNA repair signaling. Future studies should evaluate the role of S6K1 as a target to overcome radioresistance.

Wide bandgap (WBG) perovskite solar cells (PSCs) provide their merit of high voltage output but are faced with the overdeepened valence band and the notorious phase segregation. Herein, two alkylthiophene-substituted polythiophenes (PT4T-0F and PT4T-2F) are applied as the interfacial layer for the WBG (1.72 eV) PSCs. Compared with PT4T-0F, PT4T-2F with fluoride (F) on thiophene units in a conjugated backbone exhibits more planar configuration, higher hole mobility, and deeper highest occupied molecular orbital energy. By using PT4T-2F as an additive in antisolvent, crystal growth of FA 0.83 Cs 0.17 Pb(I 0.7 Br 0.3 ) 3 is successfully mediated, resulting in high ratio (100) plane exposure of the WBG perovskites, and defect passivation is simultaneously realized. The optimized device presents a high open-circuit voltage of 1.23 V and a power conversion efficiency of 19.20%. The long-term stabilities under moisture and thermal conditions are both improved. This work offers an ideal interlayer material for WBG PSC engineering and further provides a simple process to integrate simultaneous crystal mediation and interface optimization.

Alzheimer's disease (AD) is characterized by cognitive decline and the accumulation of amyloid-beta plaques and hyperphosphorylated tau protein. The role of tau lactylation at the K677 site in AD progression is not well understood. This study explores how tau K677 lactylation affects ferritinophagy, ferroptosis, and their functions in an AD mouse model. Results show that mutating the K677 site to R reduces tau lactylation and inhibits ferroptosis by regulating iron metabolism factors like NCOA4 and FTH1.Tau-mutant mice showed improved memory and learning skills compared to wild-type mice. The mutation also reduced neuronal damage and was associated with decreased tau lactylation at the K677 site, regardless of phosphorylated tau levels. Gene set enrichment analysis showed that lactylation at this site was linked to the MAPK pathway, which was important for ferritinophagy in AD mice. In summary, our research indicates that the K677 mutation in tau protein may protect against AD by influencing ferritinophagy and ferroptosis through MAPK signaling pathways. Understanding these modifications in tau could lead to new treatments for AD., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sedentary behavior (SB) has been linked in the past by observational studies to gastrointestinal illnesses, although the exact cause of the link is still unknown. To deal with this problem, we carried out a Mendelian randomization (MR) study to thoroughly examine the connection between SB and common gastrointestinal illnesses. We selected instrumental variables representing the SB from the UK Biobank study, including watching television viewing, playing computer, and driving. In addition, we obtained genetic associations of 21 common gastrointestinal disorders from the FinnGen research. After adjusting for common risk factors associated with gastrointestinal diseases, we analyzed the independent association between genetic. Furthermore, we used the inverse-variance weighted (IVW) method in conjunction with complementing techniques like MR-Egger (Mendelian randomization based on Egger Regression) and weighted median to assure the accuracy and dependability of the results. Our findings suggest that genetic susceptibility to prolonged television viewing is significantly associated with an increased risk of 9 out of 21 gastrointestinal disorders. Specifically, these disorders include gastroesophageal reflux disease, chronic gastritis, cholelithiasis, acute pancreatitis, chronic pancreatitis, gastroduodenal ulcer, fatty liver, irritable bowel syndrome, and acute appendicitis. These associations remained significant even after correcting for potential confounding factors. The replication analysis confirms the same conclusion. The results of this study demonstrate a causal relationship between cachexia and genetically predicted SB. To further understand the underlying pathogenic mechanisms at play, more study is required., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The susceptibility modules and characteristic genes of patients with osteoarthritis (OA) were determined by weighted gene co-expression network analysis (WGCNA), and the role of immune cells in OA related microenvironment was analyzed. GSE98918 and GSE117999 data sets are from GEO database. R language was used to conduct difference analysis for the new data set after merging. The formation of gene co-expression network, screening of susceptibility modules and screening of core genes are all through WGCNA. GO and KEGG enrichment analyses were used for Hub genes. The characteristic genes of the disease were obtained by Lasso regression screening. SSGSEA was used to estimate immune cell abundance in sample and a series of correlation analyses were performed. WGCNA was used to form 6 gene co-expression modules. The yellow-green module is identified as the susceptible module of OA. 202 genes were identified as core genes. Finally, RHOT2, FNBP4 and NARF were identified as the characteristic genes of OA. The results showed that the characteristic genes of OA were positively correlated with plasmacytoid dendritic cells, NKT cells and immature dendritic cells, but negatively correlated with active B cells. MDSC were the most abundant immune cells in cartilage. This study identified the Hippo signaling pathway, mTOR signaling pathway, and three characteristic genes (RHOT2, FNBP4, NARF) as being associated with osteoarthritis (OA). These three genes are downregulated in the cartilage of OA patients and may serve as biomarkers for early diagnosis and targeted therapy. Proper regulation of immune cells may aid in the treatment of OA. Future research should focus on developing tools to detect these genes and exploring their therapeutic applications.

Background: Marination is an important part of air-dried beef processing, and traditional methods are inefficient and produce inconsistent results. Ultrasound, as a novel technology, can be combined with traditional marination methods. The study aimed to investigate the improvement of beef flavor by ultrasound-assisted marination. At the same time, the potential relationship between the alteration of meat protein and flavor quality by ultrasound-assisted marinating was further investigated to enable better flavor modulation and research., Results: Headspace solid-phase microextraction-gas chromatography-mass spectrometry revealed that the spice flavor of beef was significantly enhanced by 500 W ultrasound-assisted marination. Meanwhile, the experimental results demonstrated that the ultrasound-assisted marination promoted the unfolding of beef myofibrillar protein structure, which increased the number of hydrophobic and hydrogen bonding sites, enhanced the electrostatic effect and improved the functional properties of the protein. Ultrasound-assisted marination significantly enhanced the binding ability of beef myofibrillar proteins to flavor compounds compared with conventional marination. An electronic nose confirmed that this resulted in a significant increase in the flavor of the marinated meat., Conclusion: Ultrasound-assisted marination effectively enhanced the flavor of marinated meat, which was closely related to the development of protein conformation. The results of this study have important implications for the food industry and the role of protein unfolding processes in flavor modulation. In particular, the findings can be practically applied to improving meat flavor under ultrasound-assisted marination. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Color vision relies on three cone photoreceptors that are sensitive to different wavelengths of light. The interaction of three incident light wavelengths over time creates a fascinating color coupling perception, termed chromamorphic computing. However, the realization of this fascinating characteristic in semiconductor devices remains a great challenge. Herein, a mixed-dimensional optoelectronic transistor based on a novel metal nanocluster Au 25 (SC 12 H 25 ) 18 and two-dimensional MoS 2 van der Waals (vdWaals) heterojunction is proposed for chromamorphic visual-afterimage emulation with red-green-blue three-color spatiotemporal coupling perception. This distinguished molecular-like electronic level of Au 25 nanoclusters allows the transistor to have visible light-sensitive properties, endowing it with the ability to perceive color information. Moreover, the chromamorphic functions are realized using a color spatiotemporal coupling approach. By utilizing the photogating effect of light stimulus, the device exhibits visual experience-dependent plasticity in accordance with the Bienenstock-Cooper-Munro (BCM) learning rule. Most importantly, for the first time, intriguing visual afterimages could be implemented using a color sensitization approach based on a close relationship between visual persistence and negative afterimages. These results represent an important step towards a new generation of intelligent visual color perception systems for human-computer interaction, bionic robots, etc .

Tumor cells invade normal surrounding tissues through continuous division. In this study, we hypothesized that cell cycle regulation changes the immune efficacy of ovarian cancer. To investigate this hypothesis, a Förster resonance energy transfer (FRET) sensor was constructed to characterize the cell activity in real time. Cell shrinkage caused by apoptosis induces the aggregation of proteins on the cell membrane, leading to variations in the fluorescence lifetime of FRET sensors. Moreover, we tracked cell activity across various cycles following co-culture with an immune checkpoint inhibitor. Consequently, we assessed how cell cycle regulation influences immunotherapy in a tumor mouse model. This approach, which involves inhibiting typical cell cycle processes, markedly enhances the effectiveness of immunotherapy. Our findings suggest that modulating the cycle progression of cancer cells may represent a promising approach to enhance the immune response of ovarian cancer cells and the efficacy of immunotherapy based on immune checkpoint inhibitors.

Introduction: Benzoic acid (BA) could be added to the diets of weaned pigs to prevent diarrhea due to its antibacterial function. However, BA may be absorbed or decomposed before it can reach the hindgut. This study was conducted to explore the effect of a novel coated benzoic acid (CBA) on growth performance, immunity, and intestinal barrier functions in weaned pigs upon enterotoxigenic Escherichia coli (ETEC) challenge., Methods: In a 21d experiment, 32 piglets were randomly assigned to 4 treatments: (1) a basal diet (CON), (2) CON added with CBA at 3  g/kg (CBA); (3) CON and challenged by ETEC (ECON); (4) CON added with CBA at 3 g/kg and challenged by ETEC (ECON). On d 22, all piglets were euthanised to obtain samples., Results: Dietary CBA supplementation elevated the average daily gain (ADG) of the ETEC-challenged pigs ( p < 0.05). CBA also improved the digestibility of dry matter, gross energy, and ash ( p < 0.05). Moreover, CBA elevated the ratio of blood basophil and the serum concentration of total cholesterol of the ETEC challenged pigs ( p < 0.05). Importantly, CBA increased the serum concentrations of immunoglobulin A (IgA), IgG, and IgM ( p < 0.05). CBA not only decreased the crypt depth but also increased the ratio of villus height to crypt depth (V:C) in the jejunum and ileum ( p < 0.05). Moreover, CBA increased the activities of jejunal and ileal sucrase, and the activities of duodenal and ileal maltase ( p < 0.05). Importantly, CBA elevated the expression levels of critical functional genes such as the claudin-1, occluding, glucose transporter-2 (GLUT2), and sodium/glucose cotransporter-1 (SGLT-1) in the jejunal epithelium upon ETEC challenge ( p < 0.05). Additionally, CBA increased the abundances of total bacteria and Bacillus , and increased the concentrations of volatile fatty acids (acetic acid, propanoic acid, and butyric acid) in cecum ( p < 0.05)., Discussion: These results suggested a beneficial role for CBA in alleviating intestinal injury in weaned pigs following ETEC challenge. Such effects may be tightly associated with elevated immunity and improved intestinal epithelium functions and microbiota., Competing Interests: YH, XZ, and TH were employed by the Nuacid Nutrition Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qi, Yu, Hu, Luo, Zheng, Mao, Yu, Zhao, He, Yan, Wu and He.)

Background: Recent developments in nanotechnology have provided efficient and promising methods for the treatment of diseases to achieve better therapeutic results and lower side effects. Titanium dioxide (TiO 2 ) nanomaterials are emerging inorganic nanomaterials with excellent properties such as low toxicity and easy functionalization. TiO 2 with special nanostructures can be used as delivery vehicles for drugs, genes and antigens for various therapeutic options. The exploration of TiO 2 -based drug delivery systems shows great promise for translating nanotechnology into clinical applications; Methods: Comprehensive data on titanium dioxide were collected from reputable online databases including PubMed, GreenMedical, Web of Science, Google Scholar, China National Knowledge Infrastructure Database, and National Intellectual Property Administration; Results: In this review, we discuss the synthesis pathways and functionalization strategies of TiO 2 . Recent advances of TiO 2 as a drug delivery system, including sustained and controlled drug release delivery systems were introduced. Rigorous long-term systematic toxicity assessment is an extremely critical step in application to the clinic, and toxicity is still a problem that needs to be closely monitored; Conclusions: Despite the great progress made in TiO 2 -based smart systems, there is still a great potential for development. Future research may focus on developing dual-reaction delivery systems and single-reaction delivery systems like redox and enzyme reactions. Undertaking thorough in vivo investigations is necessary prior to initiating human clinical trials. The high versatility of these smart drug delivery systems will drive the development of novel nanomedicines for personalized treatment and diagnosis of many diseases with poor prognosis.

Introduction: Yangxinshi tablet (YXST) is a effective traditional Chinese medicine in treating cardiovascular diseases such as heart failure and myocardial infarction., Objectives: This study aims to develop a method for screening thrombin inhibitors from YXST using an online immobilized enzyme microreactor (IMER) based on capillary electrophoresis (CE)., Materials and Methods: Thrombin (THR) was immobilized on the capillary's inner wall using polydopamine (PDA). The chromogenic substrate S-2238 was employed to assess thrombin (THR) activity and kinetic parameters. The stability and repeatability of the constructed thrombin-immobilized enzyme microreactor (THR-IMER) were evaluated over 40 runs, maintaining 85% of initial activity. The Michaelis-Menten constant (K m ) for THR was determined to be 11.98 mM. The half-maximal inhibitory concentration (IC 50 ) and inhibition constant (K i ) for argatroban on THR were calculated. Ten compounds in YXST were screened for THR inhibitory potency using the THR-IMER., Results: Salvianolic acid B and caffeic acid were identified as potential THR inhibitors in YXST, with inhibition rates at 200 μg/mL of 55.06 ± 6.70% and 31.88 ± 4.79%, respectively, aligning with microplate reader assay results. Molecular docking analysis confirmed their interactions with key THR residues, verifying their inhibitory activity., Conclusion: The CE-based THR-IMER method was successfully developed for screening thrombin inhibitors from YXST, offering a reliable approach for identifying potential therapeutic compounds., (© 2024 John Wiley & Sons Ltd.)

Global estimations suggest energy content within municipal solid waste (MSW) is underutilized, compromising efforts to reduce fossil CO 2 emissions and missing the opportunities for pursuing circular economy in energy consumption. The energy content of the MSW, represented by heating values (HVs), is a major determinant for the suitability of incinerating the waste for energy and managing waste flows. Literature reveals limitations in traditional statistical HV modelling approaches, which assume a linear and additive relationship between physiochemical properties of MSW samples and their HVs, as well as overlook the impact of non-combustible substances in MSW mixtures on energy harvest. Artificial intelligence (AI)-based models show promise but pose challenges in interpretation based on established combustion theories. From the variable selection perspectives, using MSW physical composition categories as explanatory variables neglects intra-category variations in energy contents while applying environmental or socio-economic factors emerges to address waste composition changes as society develops. The article contributes by showing to professionals and modellers that leveraging AI technology and incorporating societal and environmental factors are meaningful directions for advancing HV prediction in waste management. These approaches promise more precise evaluations of incinerating waste for energy and enhancing sustainable waste management practices., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.