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The concept of orbital angular momentum (OAM) of light has not only advanced fundamental physics research but also yielded a plethora of practical applications, benefitting from the abundant methods for OAM generation based on linear, nonlinear and combined schemes. The combined scheme could generate octave-separating OAM beams, potentially increasing the channels for optical communication and data storage. However, this scheme faces a challenge in achieving high conversion efficiency. In this work, we have demonstrated the generation of multiple OAM beams at both fundamental frequency and second harmonic (SH) wavelengths using a three-dimensional forked grating array with both spatial χ (1) and χ (2) distributions in a lithium niobate nonlinear photonic crystal platform. The enhancements of the fundamental and SH OAM beams have been achieved by employing linear Bragg diffraction and nonlinear Bragg diffraction, respectively, i.e., quasi-phase matching. The experimental results show that OAM beams with variable topological charges can be enhanced at different diffraction orders via wavelength or angle tuning, achieving conversion efficiencies of 60.45 % for the linear OAM beams and 1.08 × 10−4 W−1 for the nonlinear ones. This work provides a promising approach for parallel detection of OAM states in optical communications, and extends beyond OAM towards the control of structured light via cascaded linear and nonlinear processes.

Abstract Background Currently, the treatment outcomes for complex congenital arteriovenous malformations (AVMs) remain unsatisfactory. This article reports on the utilization of an abdominal aortic stent graft, in conjunction with embolization techniques, for managing acute heart failure triggered by complex congenital arteriovenous malformations in the lower limb. Case Presentation We present a case involving a patient with congenital AVMs in the lower limb, who had suffered from prolonged swelling in the left lower limb and recently developed symptoms of heart failure. At the age of 67, the patient was definitively diagnosed with a complex congenital AVMs in the lower limb. This article delves into the practical experiences and limitations encountered in employing an abdominal aortic stent graft, coupled with embolization, to address acute heart failure caused by complex congenital AVMs in the lower limb. Conclusions Our article presents the initial report on the challenges and limitations encountered in treating acute heart failure triggered by complex congenital AVMs in the lower limb, utilizing a combination of abdominal aortic stent graft placement and embolization techniques.

Abstract Soybean seeds are susceptible to damage from the Riptortus pedestris, which is a significant factor affecting the quality of soybean seeds. Currently, manual screening methods for soybean seeds are limited to visual inspection, making it difficult to identify seeds that are phenotypically defect-free but have been punctured by stink bugs on the sub-surface. To facilitate the convenient and efficient identification of healthy soybean seeds, this paper proposes a soybean seed pest detection method based on spatial frequency domain imaging combined with RL-SVM. Firstly, soybean optical data is obtained using single integration sphere technique, and the vigor index of soybean seeds is obtained through germination experiments. Then, based on the above two data items using feature extraction algorithms (the successive projections algorithm and the competitive adaptive reweighted sampling algorithm), the characteristic wavelengths of soybeans are identified. Subsequently, the spatial frequency domain imaging technique is used to obtain the sub-surface images of soybean seeds in a forward manner, and the optical coefficients such as the reduced scattering coefficient $${{\mu }{\prime}}_{s}$$ μ ′ s and absorption coefficient $${\mu }_{a}$$ μ a of soybean seeds are inverted. Finally, RL-MLR, RL-GRNN, and RL-SVM prediction models are established based on the ratio of the area of insect-damaged sub-surface to the entire seed, soybean varieties, and $${\mu }_{a}$$ μ a at three wavelengths (502 nm, 813 nm, and 712 nm) for predicting and identifying soybean the stinging and sucking pest damage levels of soybean seeds. The experimental results show that the spatial frequency domain imaging technique yields small errors in the optical coefficients of soybean seeds, with errors of less than 15% for $${\mu }_{a}$$ μ a and less than 10% for $${{\mu }{\prime}}_{s}$$ μ ′ s . After parameter adjustment through reinforcement learning, the Macro-Recall metrics of each model have improved by 10%-15%, and the RL-SVM model achieves a high Macro-Recall value of 0.9635 for classifying the pest damage levels of soybean seeds.

Abstract Functionalized mesoporous materials have become a promising carrier for enzyme immobilization. In this study, Santa Barbara Amorphous 15 (SBA-15) was modified by N-aminoethyl-γ-aminopropyl trimethoxy (R). R-SBA-15 was employed to purify and immobilize recombinant β-glucosidase from Terrabacter ginsenosidimutans (BgpA) in one step for the first time. Optimum pH of the constructed R-SBA-15@BgpA were 7.0, and it has 20 ℃ higher optimal temperature than free enzyme. Relative activity of R-SBA-15@BgpA still retained > 70% at 42 ℃ after 8-h incubation. The investigation on organic reagent resistance revealed that the immobilized enzyme can maintain strong stability in 15% DMSO. In leaching test and evaluation of storage stability, only trace amount of protein was detected in buffer of the immobilized enzyme after storage at 4 ℃ for 33 days, and the immobilized BgpA still maintained > 50% relative activity. It also demonstrated good reusability, with 76.1% relative activity remaining after fourteen successive enzymatic hydrolyses of epimedin A to sagittatoside A. The newly proposed strategy is an effective approach for the purification and immobilization of BgpA concurrently. In addition, R-SBA-15@BgpA was demonstrated to have high efficiency and stability in this application, suggesting its great feasibility and potential to produce bioactive compounds such as secondary glycosides or aglycones from natural products. Graphical Abstract

This is an article in the field of mineral processing engineering. The study objects are a spodumene waste rock in Sichuan. According to the mineral characteristics of thisspodumene waste rock, heavy medium separation tests were carried out at three different feed particle sizes (-15+0.5 mm, -10+0.5 mm, -5+0.5 mm) of the spodumene waste rock in laboratory. The test results show that the application of heavy medium separation in beneficiation of spodumene waste rock is very effective, and when -10+0.5 mm is used as the feed particle size range of the subsequent waste rock in heavy medium separation, and 2.70 g/cm3 is selected as the separation density, the results of heavy medium separation effect is relatively good. However, according to the actual production of heavy medium separation test results, the separation index is relatively good when the selected particle size is -15+0.5 mm and the medium density is 2.0 g/cm3.

Abstract Dracaena cambodiana Pierre ex Gagn. (Asparagaceae) is the source plant of Dragon’s blood and has high ornamental values in gardening. Currently, this species is classified as the second-class state-protected species in the National Key Protected Wild Plants (NKPWP) of China. However, limited genomic data has hindered a more comprehensive scientific understanding of the processes involved in the production of Dragon’s blood and the related conservation genomics research. In this study, we assembled a haplotype-resolved genome of D. cambodiana. The haploid genomes, haplotype A and haplotype B, are 1,015.22 Mb and 1,003.13 Mb in size, respectively. The completeness of haplotype A and haplotype B genomes was 98.60% and 98.20%, respectively, using the “embryophyta_10” dataset. Haplotype A and haplotype B genomes contained 27,361 and 27,066 protein-coding genes, respectively, with nearly all being functionally annotated. These findings provide new insights into the genomic characteristics of D. cambodiana and will offer additional genomic resources for studying the biosynthesis mechanism of Dragon’s blood and the horticultural application of Dragon trees.

Abstract Background Cardiovascular disease (CVD) remains the foremost cause of mortality globally. Taurine, an amino acid, holds promise for cardiovascular health through mechanisms such as calcium regulation, blood pressure reduction, and antioxidant and anti-inflammatory effects. Despite these potential benefits, previous studies have yielded inconsistent results. This meta-analysis of randomized controlled trials (RCTs) aims to evaluate the existing evidence on the quantitative effects of taurine on hemodynamic parameters and cardiac function grading, which are indicative of overall cardiovascular health and performance. Methods We conducted an electronic search across multiple databases, including Embase, PubMed, Web of Science, Cochrane CENTRAL, and ClinicalTrials.gov, from their inception to January 2, 2024. Our analysis focused on key cardiovascular outcomes, such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) Functional Classification. Meta-regression was applied to explore dose-dependent relationships based on the total taurine dose administered during the treatment period. A subgroup analysis, stratified according to the baseline disease status of patients, was also conducted. Results The analysis included a pooled sample of 808 participants from 20 randomized controlled trials. Taurine demonstrated a significant reduction in HR (weighted mean difference [WMD] = -3.579 bpm, 95% confidence interval [CI] = -6.044 to -1.114, p = 0.004), SBP (WMD = -3.999 mm Hg, 95% CI = -7.293 to -0.706, p = 0.017), DBP (WMD: -1.435 mm Hg, 95% CI: -2.484 to -0.386, p = 0.007), NYHA (WMD: -0.403, 95% CI: -0.522 to -0.283, p

Abstract Glycyl-tRNA synthetase (GARS1) is differentially expressed across cancers. In this study, the value of GARS1 in the diagnosis and prognosis of various cancers was comprehensively evaluated by multiple omics integrative pan-cancer analysis and experimental verification. Through Kaplan–Meier, ROC and multiple databases, we explored GARS1 expression and prognostic and diagnostic patterns across cancers. The GARS1 relative reaction network was identified in PPI, GO, KEGG, methylation models and the genetic mutation atlas. Further research on the GARS1 value in bladder urothelial carcinoma (BLCA) was conducted by regression and nomogram models. We further analyzed the correlation between GARS1 and immune markers and cells in BLCA. Finally, in vitro experiments were used to validate GARS1 the oncogenic function of GARS1 in BLCA. We found that GARS1 was highly expressed across cancers, especially in BLCA. GARS1 expression was correlated with poor survival and had high diagnostic value in most tumor types. GARS1 is significantly associated with tRNA-related pathways whose mutation sites are mainly located on tRNA synthetase. In addition, Upregulation of GARS1 was connected with immune cell infiltration and five key MMR genes. M2 macrophages, TAMs, Th1 and T-cell exhaustion, and marker sets associated with GARS1 expression indicated specific immune infiltration in BLCA. Finally, in vitro experiments validated that GARS1 expression promotes BLCA cell proliferation and metastasis and inhibits apoptosis. Overall, GARS1 can be a novel prognostic and immunological biomarker through multiple omics integrative pan-cancer analysis. The expression of GARS1 in BLCA was positively correlated with specific immune infiltration, indicating that GARS1 might be related to the tumor immune microenvironment.

Abstract TP53 mutation (TP53-mut) correlates with inferior survival in many cancers, whereas its prognostic role in diffuse large B-cell lymphoma (DLBCL) is still in controversy. Therefore, more precise risk stratification needs to be further explored for TP53-mut DLBCL patients. A set of 2637 DLBCL cases from multiple cohorts, was enrolled in our analysis. Among the 2637 DLBCL patients, 14.0% patients (370/2637) had TP53-mut. Since missense mutations account for the vast majority of TP53-mut DLBCL patients, and most non-missense mutations affect the function of the P53 protein, leading to worse survival rates, we distinguished patients with missense mutations. A TP53 missense mutation risk model was constructed based on a 150-combination machine learning computational framework, demonstrating excellent performance in predicting prognosis. Further analysis revealed that patients with high-risk missense mutations are significantly associated with early progression and exhibit dysregulation of multiple immune and metabolic pathways at the transcriptional level. Additionally, the high-risk group showed an absolutely suppressed immune microenvironment. To stratify the entire cohort of TP53-mut DLBCL, we combined clinical characteristics and ultimately constructed the TP53 Prognostic Index (TP53PI) model. In summary, we identified the truly high-risk TP53-mut DLBCL patients and explained this difference at the mutation and transcriptional levels.

Liming Qin,1,2,&ast; Moqin Qiu,3,&ast; Jingmei Tang,2 Shuyan Liu,4 Qiuling Lin,5 Qiongguang Huang,2 Xiaoxia Wei,5 Qiuping Wen,1 Peiqin Chen,6 Zihan Zhou,7 Ji Cao,7 Xiumei Liang,8 Qian Guo,9 Cunli Nong,9 Yizhen Gong,5 Yuying Wei,1 Yanji Jiang,10 Hongping Yu,1,2,11– 13 Yingchun Liu1 1Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2School of Public Health, Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 4Key Laboratory of Biological Molecular Medicine Research, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, People’s Republic of China; 5Department of Clinical Research, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 6Editorial Department of Chinese Journal of Oncology Prevention and Treatment, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 7Department of Cancer Prevention and Control, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 8Department of Disease Process Management, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 9Liuzhou Worker’s Hospital, Liuzhou, People’s Republic of China; 10Department of Scientific Research, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 11Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People’s Republic of China; 12Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, People’s Republic of China; 13Key Cultivated Laboratory of Cancer Molecular Medicine of Guangxi Health Commission, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingchun Liu; Hongping Yu, Department of Experimental Research, Guangxi Medical University Cancer Hospital, 71&num; Hedi Road, Qingxiu District, Nanning, People’s Republic of China, Tel +86-15877191237 ; +86-771-5330850, Fax +86-771-5312000, Email liuyingchun@stu.gxmu.edu.cn; yuhongping@stu.gxmu.edu.cnPurpose: P53 is a suppressor gene closely related to carcinogenesis. However, the associations between genetic variants in the p53 signaling pathway and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unknown. The current study aims to analyze associations between the single nucleotide polymorphisms (SNPs) in p53 pathway-related genes and survival of patients with HBV-HCC.Methods: We evaluated the associations between 4698 SNPs in 70 genes of the p53 pathway and overall survival (OS) of 866 patients in additive genetic models by using Cox proportional hazards regression analysis. Stepwise multivariable Cox regression analysis was conducted to determine the independent effects of identified SNPs in single-locus analyses. The expression of quantitative trait loci (eQTL) was also analyzed using data from GTEx and 1000 Genomes Project, and functional prediction of SNPs was performed by using RegulomeDB v2.2, 3DSNP v2.0, HaploReg v4.2 and VannoPortal.Results: We found that two novel SNPs of CD82 rs7925603 A > G and PMAIP1 rs4396625 A > T, were significantly and independently associated with OS [adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were 1.27 (1.10– 1.48) and 0.77 (0.66– 0.91), respectively; P = 0.001 and = 0.002, respectively] and that the combined risk genotypes of these SNPs showed a significant association with OS in patients with HBV-HCC (Ptrend < 0.001). Further eQTL analysis in the GTEx dataset showed that the rs7925603 G allele was associated with lower CD82 mRNA expression levels, while the rs4396625 T allele was associated with higher PMAIP1 mRNA expression levels in whole blood cells.Conclusion: We identified two observed survival-associated SNPs in CD82 and PMAIP1 in the p53 pathway, which influenced HBV-HCC survival possibly through a mechanism of altering mRNA expression. Large studies are warranted to validate our findings.Keywords: hepatocellular carcinoma, hepatitis B virus, p53 signaling pathway, genetic variants, survival

Abstract Shrews being insectivores, serve as natural reservoirs for a wide array of zoonotic viruses, including the recently discovered Langya henipavirus (LayV) in China in 2018. It is crucial to understand the shrew-associated virome, viral diversity, and new viruses. In the current study, we conducted high-throughput sequencing on lung samples obtained from 398 shrews captured along the eastern coast of China, and characterized the high-depth virome of 6 common shrew species (Anourosorex squamipes, Crocidura lasiura, Crocidura shantungensis, Crocidura tanakae, Sorex caecutiens, and Suncus murinus). Our analysis revealed numerous shrew-associated viruses comprising 54 known viruses and 72 new viruses that significantly enhance our understanding of mammalian viruses. Notably, 34 identified viruses possess spillover-risk potential and six were human pathogenic viruses: LayV, influenza A virus (H5N6), rotavirus A, rabies virus, avian paramyxovirus 1, and rat hepatitis E virus. Moreover, ten previously unreported viruses in China were discovered, six among them have spillover-risk potential. Additionally, all 54 known viruses and 12 new viruses had the ability to cross species boundaries. Our data underscore the diversity of shrew-associated viruses and provide a foundation for further studies into tracing and predicting emerging infectious diseases originated from shrews.

Abstract Lung adenocarcinoma is the most common primary lung cancer seen in the world, and identifying genetic markers is essential for predicting the prognosis of lung adenocarcinoma and improving treatment outcomes. It is well known that alterations in circadian rhythms are associated with a higher risk of cancer. Moreover, circadian rhythms play a regulatory role in the human body. Therefore, studying the changes in circadian rhythms in cancer patients is crucial for optimizing treatment. The gene expression data and clinical data were sourced from TCGA database, and we identified the circadian clock-related genes. We used the obtained TCGA-LUAD data set to build the model, and the other 647 lung adenocarcinoma patients’ data were collected from two GEO data sets for external verification. A risk score model for circadian clock-related genes was constructed, based on the identification of 8 genetically significant genes. Based on ROC analyses, the risk model demonstrated a high level of accuracy in predicting the overall survival times of lung adenocarcinoma patients in training folds, as well as external data sets. This study has successfully constructed a risk model for lung adenocarcinoma prognosis, utilizing circadian rhythm as its foundation. This model demonstrates a dependable capacity to forecast the outcome of the disease, which can further guide the relevant mechanism of lung adenocarcinoma and combine behavioral therapy with treatment to optimize treatment decision-making.

Abstract Aim To investigate the impact of preoperative cardiovascular disease on the perioperative period of rectal cancer patients over 75 years old. Methods The clinicopathological data of 625 elderly patients aged ≥ 75 years who underwent radical rectal cancer surgery in the Cancer Hospital of the Chinese Academy of Medical Sciences and affiliated Heji Hospital of Changzhi Medical College from January 2011 to December 2022 were retrospectively collected and analyzed. According to preoperative comorbidities, all patients were divided into cardiovascular disease group (n = 361) and non-cardiovascular disease group (n = 264). One hundred and ninety-two pairs were selected from each group through Propensity score-matched to further analysis. Perioperative indexes and postoperative complications were compared between the two groups. Results There were no significant differences in clinicopathological data between the two groups (P > 0.05). The proportion of elderly patients with cardiovascular disease who went to ICU after radical surgery was significantly higher than those without cardiovascular disease (19.3% vs. 10.4%, P = 0.015). There was no significant difference between the two groups in the time to first flatus (3.0 vs. 3.5 days, P = 0.332) and postoperative hospital stay (11.3 vs. 10.5 days, P = 0.297). One patient in the cardiovascular disease group died due to pulmonary embolism. A total of 100 patients (26.0%) developed postoperative complications, and the incidence of overall complications (30.7% vs. 21.4%, P = 0.036) and grade 3–5 complications (12.5% vs. 6.3%, P = 0.036) in the cardiovascular disease group was significantly higher than that in the non-cardiovascular disease group. In terms of gastrointestinal disorders, the incidence of anastomotic leakage (6.8% vs. 2.1%, P = 0.026) in elderly patients with cardiovascular diseases was significantly higher than that in patients without cardiovascular disease. In addition, the incidence of cardiac disorders (8.3% vs. 2.6%, P = 0.014) in elderly patients with cardiovascular disease was significantly higher. Conclusion Elderly rectal cancer patients over 75 years old with cardiovascular disease are more likely to develop severe complications after radical surgery, especially anastomotic leakage and cardiac disorders.

Abstract Organs-on-chips are microphysiological systems that allow to replicate the key functions of human organs and accelerate the innovation in life sciences including disease modeling, drug development, and precision medicine. However, due to the lack of standards in their definition, structural design, cell source, model construction, and functional validation, a wide range of translational application of organs-on-chips remains a challenging. “Organs-on-chips: Intestine” is the first group standard on human intestine-on-a-chip in China, jointly agreed and released by the experts from the Chinese Society of Biotechnology on 29th April 2024. This standard specifies the scope, terminology, definitions, technical requirements, detection methods, and quality control in building the human intestinal model on a chip. The publication of this group standard will guide the institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of intestine-on-a-chip for translational applications.

Abstract Background Extensive research has been conducted on embryonic developmental disorders linked to Polycystic Ovary Syndrome (PCOS), a pathological condition that affects 5−10% of women and is characterized by irregularities in the menstrual cycle and infertility. By employing RNA sequencing (RNA-seq), we performed an in-depth investigation of PCOS-related changes in gene expression patterns at the mouse blastocyst stage. Methods The zygotes of female B6D2 mice were obtained and then differentiated into blastocysts in K + Simplex Optimised Medium (KSOM) cultures containing exo-NC (negative control for exosomes) or exo-LIPE-AS1 (a novel exosomal marker of PCOS). Subsequently, blastocysts were collected for RNA-seq. The bioinformatics was performed to analyze and compare the differences of gene expression profile between blastocysts of control and PCOS group. Results There were 1150 differentially expressed genes (DEGs) between the two groups of mouse blastocysts; 243 genes were upregulated and 907 downregulated in the blastocysts of the exo-LIPE-AS1 group compared to those of the exo-NC group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the genes involved in amino acid synthesis and glutathione metabolic pathways were down-regulated in exo-LIPE-AS1 group. Conclusion This study has revealed that blastocyst developmental retardation may be associated with the downregulation of amino acid synthesis and glutathione metabolism, which may affect energy metabolism, biosynthesis, cellular osmotic pressure, antioxidant synthesis, ROS clearance or mitochondrial function, and ultimately cause blastocyst cell development abnormalities. Our research offers encouraging data on the mechanisms underlying aberrant embryonic development in patients with PCOS as well as potential treatment strategies.

Abstract Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Bladder cancer poses a significant challenge to chemotherapy due to its resistance to cisplatin, especially at advanced stages. Understanding the mechanisms behind cisplatin resistance is crucial for improving cancer therapy. The enzyme glutathione S‐transferase omega class 1 (GSTO1) is known to be involved in cisplatin resistance in colon cancer. This study focused on its role in cisplatin resistance in bladder cancer. Our analysis of protein expression in bladder cancer cells stimulated by secretions from tumor‐associated macrophages (TAMs) showed a significant increase in GSTO1. This prompted further investigation into the role of GSTO1 in bladder cancer. We found a strong correlation between GSTO1 expression and cisplatin resistance. Mechanistically, GSTO1 triggered the release of large extracellular vesicles (EVs) that promoted cisplatin efflux, thereby reducing cisplatin–DNA adduct formation and enhancing cisplatin resistance. Inhibition of EV release effectively counteracted the cisplatin resistance associated with GSTO1. In conclusion, GSTO1‐mediated EV release may contribute to cisplatin resistance caused by TAMs in bladder cancer. Strategies to target GSTO1 could potentially improve the efficacy of cisplatin in treating bladder cancer.

Abstract Sleep disturbances, including rapid eye movement sleep behavior disorder (RBD), excessive daytime sleepiness, and insomnia, are common non-motor manifestations of Parkinson’s disease (PD). Little is known about the underlying mechanisms, partly due to the inability of current rodent models to adequately mimic the human PD sleep phenotype. Clinically, increasing studies have reported that variants of the glucocerebrosidase gene (GBA) increase the risk of PD. Here, we developed a mouse model characterized by sleep–wakefulness by injecting α-synuclein preformed fibronectin (PFF) into the sublaterodorsal tegmental nucleus (SLD) of GBA L444P mutant mice and investigated the role of the GBA L444P variant in the transition from rapid eye movement sleep behavior disorder to PD. Initially, we analyzed spectral correlates of REM and NREM sleep in GBA L444P mutant mice. Importantly, EEG power spectral analysis revealed that GBA L444P mutation mice exhibited reduced delta power during non-rapid eye movement (NREM) sleep and increased theta power (8.2–10 Hz) in active rapid eye movement (REM) sleep phases. Our study revealed that GBA L444P-mutant mice, after receiving PFF injections, exhibited increased sleep fragmentation, significant motor and cognitive dysfunctions, and loss of dopaminergic neurons in the substantia nigra. Furthermore, the over-expression of GBA-AAV partially improved these sleep disturbances and motor and cognitive impairments. In conclusion, we present the initial evidence that the GBA L444P mutant mouse serves as an essential tool in understanding the complex sleep disturbances associated with PD. This model further provides insights into potential therapeutic approaches, particularly concerning α-synuclein accumulation and its subsequent pathological consequences.

Abstract Nanosizing confers unique functions in materials such as graphene and quantum dots. Here, we present two nanoscale-covalent organic frameworks (nano-COFs) that exhibit exceptionally high activity for photocatalytic hydrogen production that results from their size and morphology. Compared to bulk analogues, the downsizing of COFs crystals using surfactants provides greatly improved water dispersibility and light-harvesting properties. One of these nano-COFs shows a hydrogen evolution rate of 392.0 mmol g−1 h−1 (33.3 μmol h−1), which is one of the highest mass-normalized rates reported for a COF or any other organic photocatalysts. A reverse concentration-dependent photocatalytic phenomenon is observed, whereby a higher photocatalytic activity is found at a lower catalyst concentration. These materials also show a molecule-like excitonic nature, as studied by photoluminescence and transient absorption spectroscopy, which is again a function of their nanoscale dimensions. This charts a new path to highly efficient organic photocatalysts for solar fuel production.

Abstract The escalating atmospheric CO2 concentration has become a global concern due to its substantial influence on climate change, emphasizing the necessity of carbon capture to achieve carbon neutrality. Adsorption-based CO2 separation is a promising approach for carbon capture, highlighting the importance of developing solid porous materials as effective adsorbents. Among these porous materials, zeolites stand out as promising adsorbents due to their extensively tunable adsorption/separation properties, superior structural stability, non-toxicity, and cost-effectiveness. This review provides a comprehensive overview of the mechanisms, strategies, and prospects for zeolite development in separating CO2 from critical scenarios, encompassing flue gas (CO2/N2), natural/bio/landfill gases (CO2/CH4), and air, respectively. This review outlines general mechanisms for CO2 separation using zeolites, discusses specific strategies for zeolite development, and concludes with a summary of current findings and an outlook for future research.

Abstract Background Previous studies have reported reduced acute exacerbation rates and improved symptom control in asthma patients treated using inhaled corticosteroids plus formoterol maintenance and reliever therapy (MART). Fluticasone furoate (FF) and vilanterol (VIL) also provide rapid bronchodilation and sustained anti-inflammatory effects, however no studies have investigated FF/VIL as MART for asthma control. Methods From October 1, 2021 to September 30, 2023, this retrospective study included asthma patients classified as step 3 or 4 according to the Global Initiative for Asthma guidelines, who were then divided into two groups. One group received BUD/FOR as MART, while the other received FF/VIL as MART. Pulmonary function tests, exacerbation rates, Asthma Control Test (ACT), fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts were measured before and after 12 months of treatment. Results A total of 161 patients were included, of whom 36 received BUD/FOR twice daily as MART, and 125 received FF/VIL once daily as MART. After 12 months of treatment, the FF/VIL group showed a significant increase in ACT scores by 1.57 (p

To clarify the mechanical characteristics of tight sandstone in the Cretaceous Bashijiqike Formation of Kuqa Depression in Tarim Basin, and address field issues in deep and ultra-deep oil and gas exploration and development, triaxial compression experiments were used to quantitatively study the patterns of changes in rock mechanical properties influenced by confining pressure, fluid, and loading rate, with a preliminary analysis of their causes. The results showed that the maximum principal stress difference and elastic modulus of the sandstone samples increased significantly with confining pressure. The micro-reason was that the increase in confining pressure reduced the distance between particles inside the rock, enhancing the rock's cohesion and making particle dispersion less likely. Sandstone samples exhibited a progression from brittleness under low confining pressure to brittle-ductile transformation, and to ductile deformation under high confining pressure. Compared with dry sandstone samples, the reduction in the elastic modulus of samples soaked in pure water, 150 g/L solution, 250 g/L solution, and 350 g/L solution were 67.71%, 61.45%, 64.69%, and 57.32%, respectively, with pure water soaking causing the greatest reduction. Increasing fluid salinity could mitigate the weakening trend in rock mechanical parameters. Crystallization on crystal surfaces and changes in the electric double layer thickness were important controlling factors for these patterns. At lower loading rates, the values for maximum principal stress difference, elastic modulus, and Poisson's ratio of the sandstone samples were smaller, but they increased faster with increasing loading rates. When the loading rate reached a certain critical value (around 0.05 mm/min in this experiment), the rate of increase in rock mechanical parameters slowed down.

Abstract Spin- and charge- stripe order has been extensively studied in the superconducting cuprates, among which underdoped La2−x Sr x CuO4 (LSCO) is an archetype with static spin stripes at low temperatures. An intriguing, but not completely understood, phenomenon in LSCO is that the stripes are tilted away from the high-symmetry Cu-Cu directions. Using high-resolution neutron scattering on LSCO with x = 0.12, we find two coexisting phases at low temperatures, one with static spin stripes and the other with fluctuating ones, both sharing the same tilt angle. Our numerical calculations using the doped Hubbard model elucidate the tilting’s origin, attributing it to anisotropic next-nearest neighbor hopping $${t}^{{\prime} }$$ t ′ , consistent with the material’s slight orthorhombicity. Our results underscore the model’s success in describing specific details of the ground state of this real material and highlight the role of $${t}^{{\prime} }$$ t ′ in the Hamiltonian, revealing the delicate interplay between stripes and superconductivity across theoretical and experimental contexts.

Abstract Online food delivery has become a popular mode of urban food consumption in China as its underlying business mechanism, Online To Offline (O2O), gaining popularity. However, the environmental impacts of a rapidly expanding online food delivery industry and its potential to mitigate environmental burdens remained unexplored in China. Our research found that Chinese cities generated 1.67 MtCO2-equivalent (CO2e) from 13.07 billion times of deliveries in 2019, including transport and packaging. The transportation-related GHG emissions were 745 KtCO2e in 2019, with an average of 0.057 kg CO2e per order and an average of 0.011 kg CO2e per capita. These emissions have surged from 0.31 MtCO2e in 2014 to 2.74 MtCO2e in 2021. We predict that this figure will increase further to 5.94 MtCO2e by 2035. However, with a range of policies such as replacing motorcycles with electric bikes and optimizing traffic routes, it is possible to mitigate such GHG emissions by 4.39–10.97 MtCO2e between 2023 and 2035. These findings highlight the need for further research into the environmental impact of online food delivery and the potential for mitigating it.

Abstract Background B-cell CLL/lymphoma 6 member B (BCL6B) operates as a sequence-specific transcriptional repressor within the nucleus, playing crucial roles in various biological functions, including tumor suppression, immune response, stem cell self-renew, and vascular angiogenesis. However, whether BCL6B is involved in endothelial cell (EC) development has remained largely unknown. ETS variant transcription factor 2 (ETV2) is well known to facilitate EC differentiation. This study aims to determine the important role of BCL6B in EC differentiation and its potential mechanisms. Methods Doxycycline-inducible human induced pluripotent stem cell (hiPSC) lines with BCL6B overexpression or BCL6B knockdown were established and subjected to differentiate into ECs and vessel organoids (VOs). RNA sequencing analysis was performed to identify potential signal pathways regulated by BCL6B during EC differentiation from hiPSCs. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of pluripotency and vascular-specific marker genes expression. EC differentiation efficiency was determined by Flow cytometry analysis. The performance of EC was evaluated by in vitro Tube formation assay. The protein expression and the vessel-like structures were assessed using immunofluorescence analysis or western blot. Luciferase reporter gene assay and chromatin immunoprecipitation (ChIP)-PCR analysis were used to determine the regulatory relationship between BCL6B and ETV2. Results Functional ECs and VOs were successfully generated from hiPSCs. Notably, overexpression of BCL6B suppressed while knockdown of BCL6B improved EC differentiation from hiPSCs. Additionally, the overexpression of BCL6B attenuated the capacity of derived hiPSC-ECs to form a tubular structure. Furthermore, compared to the control VOs, BCL6B overexpression repressed the growth of VOs, whereas BCL6B knockdown had little effect on the size of VOs. RNA sequencing analysis confirmed that our differentiation protocol induced landscape changes for cell/tissue/system developmental process, particularly vascular development and tube morphogenesis, which were significantly modulated by BCL6B. Subsequent experiments confirmed the inhibitory effect of BCL6B is facilitated by the binding of BCL6B to the promoter region of ETV2, led to the suppression of ETV2's transcriptional activity. Importantly, the inhibitory effect of BCL6B overexpression on EC differentiation from hiPSCs could be rescued by ETV2 overexpression. Conclusions BCL6B inhibits EC differentiation and hinders VO development by repressing the transcriptional activity of ETV2.

Catastrophe theory was used to establish a safety assessment model to reduce the reliance on subjective judgments in evaluation of timber-framed heritage buildings. This study was conducted in three phases. Initially, a comprehensive evaluation index system was established from the perspective of foundation. It consisted of eight aspects and 25 safety evaluation indicators using superstructure load-bearing elements, maintenance structures, and their interconnections in timber-framed heritage buildings. The 25 safety evaluation indicators included foundation, base, stone piers, columns, beams, lintels (beams, pads, and other bending components), bracket sets, arches, maintenance walls, beam-brace connections, and roof structures. The bottom-level indicators in the index system were dimensionless. The second phase employed typical catastrophe models (cusp, swallowtail, and butterfly) for normalization, resulting in calculated catastrophe scales and evaluation levels. The case study of the Buddha Hall of Zhihua Temple, Beijing, was applied in the final phase. It was found that the catastrophe scales method solved the subjectivity issues in determining weights. Additionally, the calculations were found to be concise and reliable, providing accurate results. The model can be used as a theoretical reference for the future safety assessment of timber-framed heritage buildings.

T-shaped mortise and tenon members are the main structure of traditional Chinese furniture. In this paper, the double-dovetail joint used for face-to-face joint of rubber wood (Hevea brasiliensis Muell. Arg) is transformed into a new type of double-dovetail joint and rounded double-dovetail joint for T-shaped members of point joint structure. The ultimate pull-out test and bending strength test were carried out on the two structures and three structures of oval mortise, round rod mortise and right angle mortise. The results show that the ultimate pull-out force of the round double-dovetail joint is 39% higher than that of the double-dovetail joint, and the bending resistance capacity is 8.9% higher, and the strength and stability are better than those of other split mortises and tenons, which proves that this structure can be used in actual production, and also proves that the mortise and tenon connected by the surface has the possibility of transforming into a point connection structure. The concave structure of the rounded double-dovetail joint makes the mortise and tenon fit well, the tenon squeezed tight, and a good bonding effect was achieved. This structure can also provide greater friction and resistance, delay rubber adhesive failure and improve the stability.

Abstract Anion exchange membrane fuel cells (AEMFCs) have been hailed as a promising hydrogen energy technology due to high energy conversion efficiency, zero carbon emission and the potential independence on scare and expensive noble metal electrocatalysts. A variety of platinum group metal (PGM)‐free catalysts has been developed with superior catalytic performance to noble metal benchmarks toward cathodic oxygen reduction reactions (ORR). However, PGM electrocatalysts still dominate the anodic catalyst research because the kinetics of hydrogen oxidation reaction (HOR) are two or three orders of magnitude slower than in that acidic media. Therefore, it is urgently desirable to improve noble metal utilization efficiency and/or develop high‐performance PGM‐free electrocatalysts for HOR, thus promoting the real‐world implementation of AEMFCs. In this review, the current research progress of electrocatalysts for HOR in alkaline media is summarized. We start with the discussion on the current HOR reaction mechanisms and existing controversies. Then, methodologies to improve the HOR performance are reviewed. Following these principles, the recently developed HOR electrocatalysts including PGM and PGM‐free HOR electrocatalysts in alkaline media are systematically introduced. Finally, we put forward the challenges and prospects in the field of HOR catalysis.

Abstract Background Cervical spondylosis (CS), including myelopathy and radiculopathy, is the most common degenerative cervical spine disease. This study aims to evaluate the clinical outcomes of unilateral biportal endoscopy (UBE) compared to those of conventional anterior cervical decompression and fusion (ACDF) for treating unilateral cervical radiculopathy or coexisting cervical myelopathy induced by unilateral cervical herniated discs. Methods A prospective, randomized, controlled, noninferiority trial was conducted. The sample consisted of 131 patients who underwent UBE or ACDF was conducted between September 2021 and September 2022. Patients with cervical nerve roots or coexisting spinal cord compression symptoms and imaging-defined unilateral cervical radiculopathy or coexisting cervical myelopathy induced by unilateral cervical herniated discs were randomized into two groups: a UBE group (n = 63) and an ACDF group (n = 68). The operative time, blood loss, length of hospital stay after surgery, and perioperative complications were recorded. Preoperative and postoperative modified Japanese Orthopaedic Association (mJOA) scale scores, visual analog scale (VAS) scores, neck disability index (NDI) scores, and recovery rate (RR) of the mJOA were utilized to evaluate clinical outcomes. Results The hospital stay after surgery was significantly shorter in patients treated with UBE than in those treated with ACDF (p

Abstract Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I–III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p

Abstract Evolution of SARS-CoV-2 variants emphasizes the need for multivalent vaccines capable of simultaneously targeting multiple strains. SCTV01E is a tetravalent COVID-19 vaccine derived from the spike protein of SARS-CoV-2 variants Alpha, Beta, Delta, and Omicron BA.1. In this double-blinded placebo-controlled pivotal efficacy trial (NCT05308576), the primary endpoint was vaccine efficacy (VE) against COVID-19 seven days post-vaccination in individuals without recent infection. Other endpoints included evaluating safety, immunogenicity, and the VE against all SARS-CoV-2 infections in individuals meeting the study criteria. Between December 26, 2022, and January 15, 2023, 9,223 individuals were randomized at a 1:1 ratio to receive SCTV01E or a placebo. SCTV01E showed a VE of 69.4% (95% CI: 50.6, 81.0) 7 days post-vaccination, with 75 cases in the placebo group and 23 in the SCTV01E group for the primary endpoint. VEs were 79.7% (95% CI: 51.0, 91.6) and 82.4% (95% CI: 57.9, 92.6), respectively, for preventing symptomatic infection and all SARS-CoV-2 infections 14 days post-vaccination. SCTV01E elicited a 25.0-fold higher neutralizing antibody response against Omicron BA.5 28 days post-vaccination compared to placebo. Reactogenicity was generally mild and transient, with no reported vaccine-related SAE, adverse events of special interest (AESI), or deaths. The trial aligned with the shift from dominant variants BA.5 and BF.7 to XBB, suggesting SCTV01E as a potential vaccine alternative effective against present and future variants.

Abstract Objective Self-rated health (SRH) has been documented as an important predictor of quality of life among the elderly and its risk factors are vision-specific among elderly males. The aim of this study was to clarify vision-specific risk factors to SRH among elderly females without dementia in Chinese urban areas. Methods From March to November 2012, 2147 elderly women in Liaoning Province of China were selected using a stratified sampling method. After cognitive screening, 1956 participants without dementia were finally enrolled. A questionnaire including SRH, visual ability and factors including demographic characteristics, physical conditions, lifestyle factors, social psychological status and social activities were analyzed. Multivariate logistic regression was used to clarify the association of SRH with risk factors, while stepwise multivariate logistic regression was used to examine the vision-specific associations with SRH. Results The mean age was 73.6 ± 5.82 (mean ± SD). The percentages of good SRH in good and impaired visual ability groups were 36.2% and 24.4%, respectively. Most characteristics between elderly females with different visual abilities were significantly different. Visual ability had interactions with physical conditions, lifestyle factors and social activities to affect SRH. Among elderly females with good visual ability, depressive symptoms, rather than chronic disease had the strongest association with good SRH followed by marital status, regular diet, going out alone to distant places, taking a walk, smoking and alcohol consumption. In the impaired visual ability group, going out alone to distant places had the strongest association with good SRH followed by chronic disease, filial piety, taking a walk, participating in entertainment, ethnicity, quality of sleep, worrying about falling and alcohol consumption. Conclusions Good SRH status was at a low level especially among elderly females with impaired visual ability and the risk factors differed between elderly females with different visual abilities. Social psychological status was crucial for SRH among elderly females with good visual ability whereas physical conditions were prominent for impaired visual ability group.

Titanium alloy is an important structural material with many advantages of high strength, excellent corrosion resistance, good biocompatibility, and good processing performance, which has been widely used in aerospace, medical devices, automobile manufacturing and various other fields. However, the presence of hydrogen in titanium alloys can lead to hydrogen embrittlement, which degrades the mechanical properties. Due to its high ionization energy, high reactivity, and high diffusivity, quantitative analysis of hydrogen in metal or alloy materials faces enormous challenge. Accurately and quickly detecting the hydrogen content in titanium alloys is of great significance for optimizing material design and controlling product quality. Traditional methods for determining the hydrogen in titanium alloys require complicated sample pretreatment, which greatly prolong the analysis time. The self-built high irradiance laser ablation and ionization time-of-flight mass spectrometry (LAI-TOF MS) has many advantages such as high sensitivity, high resolution, multi-element simultaneous detection, and simple sample pretreatment. It introduces helium into the ion source as a buffer gas to cool the high kinetic energy ions and reduce the multi-charged ion interferences, and has been successfully applied to the determination of metallic and nonmetallic elements in solid samples. In this study, a direct quantitative analysis method of LAI-TOF MS was established for detecting hydrogen in titanium alloys. The calibration curve of intensities and contents for hydrogen has a correlation coefficient of 0.991 3, the limit of detection (LOD) is calculated to be 0.000 4%, and the atomization and ionization efficiency of hydrogen can reach 13.4%. This method was applied to the analysis of hydrogen in other titanium alloy samples. The relative standard deviations (RSDs) of hydrogen signals are less than 14%. The relative errors of the quantitative results are less than 5% compared with values obtained by the pulsed heating-infrared method. The analysis time for a single titanium alloy sample is only a few minutes, significantly shorter than the 2-4 h required for the pulsed heating-infrared method. The spectrum obtained by LAI-TOF MS enables qualitative and semi-quantitative determination of trace elements of Be, C, Al, Si, P, Ca, Cr, Fe, Zr, Mo, Pd, In and Sn in the titanium alloy samples. Considering the advantages of less sample preparation, simplicity, rapidness, and high sensitivity, the method based on LAI-TOF MS can be used to the directly quantitative analysis of hydrogen in titanium alloys and can be further extended to the quantitative analysis of hydrogen in other materials, such as hydrogen storage materials, metal materials, ceramic materials and other related materials.

Abstract Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease. However, the relationship between the systemic immune-inflammation index (SII) and the prognosis of RA patients remains unclear. This study aimed to investigate the association between inflammatory biomarker SII and all-cause and cardiovascular mortality in RA patients. A retrospective analysis was conducted using data from the National Health and Nutrition Examination Survey database spanning from 1999 to March 2020. We assessed the association between the SII and all-cause as well as cardiovascular mortality in RA patients employing multivariable Cox proportional hazards regression analysis and restricted cubic spline plots. Receiver operating characteristic curves were employed to evaluate the prognostic capacity of SII in predicting outcomes in both the RA patients and the general population, alongside its predictive performance compared to other markers. This study comprised 2247 RA patients and a control cohort of 29,177 individuals from the general population. Over a 20-year follow-up period, 738 all-cause deaths and 215 deaths attributable to cardiovascular disease were documented in RA patients. We observed a nonlinear positive correlation between the SII and both all-cause and cardiovascular mortality in RA patients. Of significance, at an SII level of 529.7, the hazard ratio reached 1, signifying a transition from low to high mortality risk. Moreover, subgroup analysis did not reveal any potential interactions. Our study findings indicate a nonlinear positive correlation between the inflammatory biomarker SII and both all-cause and cardiovascular mortality in patients with RA.

Abstract Synthesis of valuable chemicals from CO2 electroreduction in acidic media is highly desirable to overcome carbonation. However, suppressing the hydrogen evolution reaction in such proton-rich environments remains a considerable challenge. The current study demonstrates the use of a hollow fiber silver penetration electrode with hierarchical micro/nanostructures to enable CO2 reduction to CO in strong acids via balanced coordination of CO2 and K+/H+ supplies. Correspondingly, a CO faradaic efficiency of 95% is achieved at a partial current density as high as 4.3 A/cm2 in a pH = 1 solution of H2SO4 and KCl, sustaining 200 h of continuous electrolysis at a current density of 2 A/cm2 with over 85% single-pass conversion of CO2. The experimental results and density functional theory calculations suggest that the controllable CO2 feeding induced by the hollow fiber penetration configuration primarily coordinate the CO2/H+ balance on Ag active sites in strong acids, favoring CO2 activation and key intermediate *COOH formation, resulting in enhanced CO formation.

Abstract The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves’ disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.

Abstract A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC). Here, we report results from the phase 1 portion. Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks. Dose escalation followed a Bayesian logistic regression model that included overdose control, with subsequent selection of tolerable levels for dose expansion. Overall, 63 patients were enrolled, including 43 receiving a recommended dose for expansion of 4.8 mg/kg. All patients had HER2-mutant disease. Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort. Grade ≥ 3 treatment-related adverse events occurred in 29 (46.0%) patients. One patient in the 6.4 mg/kg cohort died due to interstitial lung disease. As of April 11, 2023, the 4.8 mg/kg cohort showed an objective response rate of 41.9% (95% CI 27.0–57.9), and a disease control rate of 95.3% (95% CI 84.2–99.4). The median duration of response was 13.7 months, with 13 of 18 responses ongoing. The median progression-free survival was 8.4 months (95% CI 7.1–15.0). SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutant NSCLC.

Background/Aims Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P

Abstract Background Despite adequate transurethral resection of the bladder tumor (TURBT) followed by intravesical bacillus-calmette guérin (BCG), high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is associated with high rates of recurrence and progression. Immune checkpoint inhibitors can improve antitumor activity in bladder cancer, but relevant evidence in HR-NMIBC is limited. Thus, we evaluated the efficacy and safety of the tislelizumab-based combination regimen in HR-NMIBC. Methods A retrospective study included 21 patients diagnosed with HR-NMIBC between July 2020 and September 2022. All patients underwent TURBT followed by combination regimens of tislelizumab plus BCG with or without gemcitabine/cisplatin (GC) chemotherapy. Clinical Data on demographics and characteristics, treatment information, outcomes, and safety were collected and analyzed. Results Among the 21 patients with HR-NMIBC, the median age was 63 years (range 39–85), with the majority of patients with stage T1 (16/21, 76.19%). The median treatment of tislelizumab was 5 cycles (range 1–12) and the median number of BCG instillations was 12 times (range 2–19). Of the 21 patients, 15 (71.43%) received combination chemotherapy with GC, with a median treatment of 2 cycles (range 0–7); others did not. Overall, after the median follow-up of 25 months (range 7–31), the estimated 2-year bladder recurrence-free survival rate was 78.64% (95% confidence intervals [CIs], 50.79–91.83%), 2-year cystectomy-free survival rate was 83.00% (95% CI 53.53–94.59%), and 2-year disease-free survival rate was 73.39% (95% CI 46.14–88.36%). Sixteen stage T1 patients achieved a distant metastasis-free survival rate of 95.45% (95% CI 71.87–99.34%) at 2 years. Fourteen (66.67%) patients experienced at least one treatment related-AEs (TRAEs), with 9.52% (2/21) of grade 3–4. Grade ≥ 3 TRAEs were hypophysitis (1/21, 4.76%) and myasthenia (1/21, 4.76%). No treatment-related deaths were observed. Conclusions The study demonstrated promising clinical benefits and a manageable safety profile of tislelizumab-based combination regimen as a bladder-sparing treatment of HR-NMIBC.

Abstract Alcohol consumption is a heritable behavior seriously endangers human health. However, genetic studies on alcohol consumption primarily focuses on common variants, while insights from rare coding variants are lacking. Here we leverage whole exome sequencing data across 304,119 white British individuals from UK Biobank to identify protein-coding variants associated with alcohol consumption. Twenty-five variants are associated with alcohol consumption through single variant analysis and thirteen genes through gene-based analysis, ten of which have not been reported previously. Notably, the two unreported alcohol consumption-related genes GIGYF1 and ANKRD12 show enrichment in brain function-related pathways including glial cell differentiation and are strongly expressed in the cerebellum. Phenome-wide association analyses reveal that alcohol consumption-related genes are associated with brain white matter integrity and risk of digestive and neuropsychiatric diseases. In summary, this study enhances the comprehension of the genetic architecture of alcohol consumption and implies biological mechanisms underlying alcohol-related adverse outcomes.

Abstract The construction of a large-scale quantum internet requires quantum repeaters containing multiple entangled photon sources with identical wavelengths. Semiconductor quantum dots can generate entangled photon pairs deterministically with high fidelity. However, realizing wavelength-matched quantum-dot entangled photon sources faces two difficulties: the non-uniformity of emission wavelength and exciton fine-structure splitting induced fidelity reduction. Typically, these two factors are not independently tunable, making it challenging to achieve simultaneous improvement. In this work, we demonstrate wavelength-tunable entangled photon sources based on droplet-etched GaAs quantum dots through the combined use of AC and quantum-confined Stark effects. The emission wavelength can be tuned by ~1 meV while preserving an entanglement fidelity f exceeding 0.955(1) in the entire tuning range. Based on this hybrid tuning scheme, we finally demonstrate multiple wavelength-matched entangled photon sources with f > 0.919(3), paving the way towards robust and scalable on-demand entangled photon sources for quantum internet and integrated quantum optical circuits.

Abstract Background Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent–offspring trios and proband only analysis. Methods We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation. Results Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications. Conclusion CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.

Abstract Background The management of preoperative blood glucose levels in reducing the incidence of postoperative delirium (POD) remains controversial. This study aims to investigate the impact of preoperative persistent hyperglycemia on POD in geriatric patients with hip fractures. Methods This retrospective cohort study analyzed medical records of patients who underwent hip fracture surgery at a tertiary medical institution between January 2013 and November 2023. Patients were categorized based on preoperative hyperglycemia (hyperglycemia defined as ≥ 6.1mmol/L), clinical classification of hyperglycemia, and percentile thresholds. Multivariate logistic regression and propensity score matching analysis (PSM) were employed to assess the association between different levels of preoperative glucose and POD. Subgroup analysis was conducted to explore potential interactions. Results A total of 1440 patients were included in this study, with an incidence rate of POD at 19.1% (275/1440). Utilizing multiple logistic analysis, we found that patients with hyperglycemia had a 1.65-fold increased risk of experiencing POD compared to those with normal preoperative glucose levels (95% CI: 1.17–2.32). Moreover, a significant upward trend was discerned in both the strength of association and the predicted probability of POD with higher preoperative glucose levels. PSM did not alter this trend, even after meticulous adjustments for potential confounding factors. Additionally, when treating preoperative glucose levels as a continuous variable, we observed a 6% increase in the risk of POD (95% CI: 1-12%) with each 1mmol/L elevation in preoperative glucose levels. Conclusions There exists a clear linear dose-response relationship between preoperative blood glucose levels and the risk of POD. Higher preoperative hyperglycemia was associated with a greater risk of POD. Clinical trial number NCT06473324.

Abstract Background Information complementarity can be achieved by fusing MR and CT images, and fusion images have abundant soft tissue and bone information, facilitating accurate auxiliary diagnosis and tumor target delineation. Purpose The purpose of this study was to construct high-quality fusion images based on the MR and CT images of intracranial tumors by using the Residual-Residual Network (Res2Net) method. Methods This paper proposes an MR and CT image fusion method based on Res2Net. The method comprises three components: feature extractor, fusion layer, and reconstructor. The feature extractor utilizes the Res2Net framework to extract multiscale features from source images. The fusion layer incorporates a fusion strategy based on spatial mean attention, adaptively adjusting fusion weights for feature maps at each position to preserve fine details from the source images. Finally, fused features are input into the feature reconstructor to reconstruct a fused image. Results Qualitative results indicate that the proposed fusion method exhibits clear boundary contours and accurate localization of tumor regions. Quantitative results show that the method achieves average gradient, spatial frequency, entropy, and visual information fidelity for fusion metrics of 4.6771, 13.2055, 1.8663, and 0.5176, respectively. Comprehensive experimental results demonstrate that the proposed method preserves more texture details and structural information in fused images than advanced fusion algorithms, reducing spectral artifacts and information loss and performing better in terms of visual quality and objective metrics. Conclusion The proposed method effectively combines MR and CT image information, allowing the precise localization of tumor region boundaries, assisting clinicians in clinical diagnosis.

Abstract Background With Primary Health Care (PHC) being a cornerstone of accessible, affordable, and effective healthcare worldwide, its efficiency, especially in developing countries like China, is crucial for achieving Universal Health Coverage (UHC). This study evaluates the efficiency of PHC systems in a southwest China municipality post-healthcare reform, identifying factors influencing efficiency and proposing strategies for improvement. Methods Utilising a 10-year provincial panel dataset, this study employs an enhanced Data Envelopment Analysis (DEA) model integrating Slack-Based Measure (SBM) and Directional Distance Function (DDF) with the Global Malmquist-Luenberger (GML) index for efficiency evaluation. Tobit regression analysis identifies efficiency determinants within the context of China’s healthcare reforms, focusing on horizontal integration, fiscal spending, urbanisation rates, and workforce optimisation. Results The study reveals a slight decline in PHC system efficiency across the municipality from 2009 to 2018. However, the highest-performing county achieved a 2.36% increase in Total Factor Productivity (TFP), demonstrating the potential of horizontal integration reforms and strategic fiscal investments in enhancing PHC efficiency. However, an increase in nurse density per 1,000 population negatively correlated with efficiency, indicating the need for a balanced approach to workforce expansion. Conclusions Horizontal integration reforms, along with targeted fiscal inputs and urbanisation, are key to improving PHC efficiency in underdeveloped regions. The study underscores the importance of optimising workforce allocation and skillsets over mere expansion, providing valuable insights for policymakers aiming to strengthen PHC systems toward achieving UHC in China and similar contexts.

Abstract Background Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). Methods The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). Results The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. Conclusions These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

Abstract Background Bladder cancer is a common malignancy with high recurrence rate. Early diagnosis and recurrence surveillance are pivotal to patients’ outcomes, which require novel minimal-invasive diagnostic tools. The urinary microbiome is associated with bladder cancer and can be used as biomarkers, but the underlying mechanism is to be fully illustrated and diagnostic performance to be improved. Methods A total of 23 treatment-naïve bladder cancer patients and 9 non-cancerous subjects were enrolled into the Before group and Control group. After surgery, 10 patients from the Before group were further assigned into After group. Void mid-stream urine samples were collected and sent for 16S rDNA sequencing, targeted metabolomic profiling, and flow cytometry. Next, correlations were analyzed between microbiota, metabolites, and cytokines. Finally, receiver operating characteristic (ROC) curves of the urinary biomarkers were plotted and compared. Results Comparing to the Control group, levels of IL-6 (p

Abstract The main cause of corneal blindness worldwide is keratitis, especially the infectious form caused by bacteria, fungi, viruses, and Acanthamoeba. The key to effective management of infectious keratitis hinges on prompt and precise diagnosis. Nevertheless, the current gold standard, such as cultures of corneal scrapings, remains time-consuming and frequently yields false-negative results. Here, using 23,055 slit-lamp images collected from 12 clinical centers nationwide, this study constructed a clinically feasible deep learning system, DeepIK, that could emulate the diagnostic process of a human expert to identify and differentiate bacterial, fungal, viral, amebic, and noninfectious keratitis. DeepIK exhibited remarkable performance in internal, external, and prospective datasets (all areas under the receiver operating characteristic curves > 0.96) and outperformed three other state-of-the-art algorithms (DenseNet121, InceptionResNetV2, and Swin-Transformer). Our study indicates that DeepIK possesses the capability to assist ophthalmologists in accurately and swiftly identifying various infectious keratitis types from slit-lamp images, thereby facilitating timely and targeted treatment.

The Southern Highland Fold and Thrust Belt (SHFTB), the boundary of the Australian plate and the New Guinea Highland block, significantly contributes to the convergent deformation along the plate boundary. However, due to the lack of observation data, the detailed slip pattern of the SHFTB and the orogenic mechanism beneath the New Guinea Highlands remains controversial. On 25 February 2018, the MW7.5 Papua New Guinea (PNG) earthquake struck the southeastern segment of the SHFTB. The detailed rupture characteristics of this event is significant for further clarifying the inter-seismic slip pattern along the SHFTB. Here, the coseismic deformation field of this earthquake was obtained using high-resolution ALOS-2 satellite images. We find that the 2018 MW7.5 PNG earthquake ruptured a large-scaled fault (SHFTB) extending to the lower crust (deeper than 20 km) beneath the New Guinea Highlands, with a dip angle of 24°. The slips on the fault plane are equivalent to moment magnitudes of MW7.51. Three major asperities with thrust-dominated slip of up to 3.94 m are detected on the fault plane. This finding implies that the slip pattern on the eastern segment of the SHFTB is dominated by thrust, rather than with significant sinistral movement, as previously reported. The tectonic deformation across the New Guinea Highlands is possibly concentrated on the large-scale fault SHFTB and primarily controls the intra-continental orogeny in the central Papua New Guinea.