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Abstract Background Gender equality and the gender income gap in medicine are long-standing global problems. Although gender-related differences have been widely studied in developed countries, they remain unclear in underdeveloped regions. In 2010, China initiated a national compulsory service program (CSP) to train qualified general practitioners in rural and remote areas. This study aimed to evaluate gender income differences for early career CSP and non-CSP (NCSP) graduates in underdeveloped areas. Methods A cohort study was conducted with 3620 CSP and NCSP graduates from four medical universities in Central and Western China. Baseline surveys and six follow-up surveys were conducted between 2015 and 2022. Incomes, including monthly mean income and proportion of performance-based income, were measured as the key outcome variables. Multivariate linear regression models were used to identify the gender income gap. Results NCSP graduates had higher average monthly incomes than CSP graduates. In the seventh year after graduation, the average monthly income for NCSP graduates was 7859 CNY while was 5379 CNY for CSP graduates. After controlling for demographic characteristics, the gender monthly income gap for CSP graduates was expanded from the fourth year (3.0%) to the sixth year (5.9%) after graduation, and that for NCSP graduates was expanded from the fifth year (11.9%) to the seventh year (16.3%) after graduation. Regarding performance-based income, it was 58.9% for NCSP graduates and 45.8% for CSP graduates in the seventh year after graduation. After controlling for performance-based income proportion, the gender income gap was reduced from 5.9 to 4.0% in the sixth year after graduation for CSP graduates, and from 16.3 to 14.4% for NCSP graduates in the seventh year after graduation. Conclusion An extensive and ever-increasing gender income gap exists among young doctors in the early stages of their careers in underdeveloped areas of China. The high proportion of performance-based income among men is one of the main explanations for the observed difference. A more explicit compensation system must be established to enhance support for female health workers.

Abstract Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Abstract Background Cryptosporidium parvum is an apicomplexan zoonotic parasite causing the diarrheal illness cryptosporidiosis in humans and animals. To invade the host intestinal epithelial cells, parasitic proteins expressed on the surface of sporozoites interact with host cells to facilitate the formation of parasitophorous vacuole for the parasite to reside and develop. The gp40 of C. parvum, named Cpgp40 and located on the surface of sporozoites, was proven to participate in the process of host cell invasion. Methods We utilized the purified Cpgp40 as a bait to obtain host cell proteins interacting with Cpgp40 through the glutathione S-transferase (GST) pull-down method. In vitro analysis, through bimolecular fluorescence complementation assay (BiFC) and coimmunoprecipitation (Co-IP), confirmed the solid interaction between Cpgp40 and ENO1. In addition, by using protein mutation and parasite infection rate analysis, it was demonstrated that ENO1 plays an important role in the C. parvum invasion of HCT-8 cells. Results To illustrate the functional activity of Cpgp40 interacting with host cells, we identified the alpha-enolase protein (ENO1) from HCT-8 cells, which showed direct interaction with Cpgp40. The mRNA level of ENO1 gene was significantly decreased at 3 and 24 h after C. parvum infection. Antibodies and siRNA specific to ENO1 showed the ability to neutralize C. parvum infection in vitro, which indicated the participation of ENO1 during the parasite invasion of HCT-8 cells. In addition, we further demonstrated that ENO1 protein was involved in the regulation of cytoplasmic matrix of HCT-8 cells during C. parvum invasion. Functional study of the protein mutation illustrated that ENO1 was also required for the endogenous development of C. parvum. Conclusions In this study, we utilized the purified Cpgp40 as a bait to obtain host cell proteins ENO1 interacting with Cpgp40. Functional studies illustrated that the host cell protein ENO1 was involved in the regulation of tight junction and adherent junction proteins during C. parvum invasion and was required for endogenous development of C. parvum. Graphical Abstract

Abstract DNA methylation (5mC) is a repressive gene regulatory mark widespread in vertebrate genomes, yet the developmental dynamics in which 5mC patterns are established vary across species. While mammals undergo two rounds of global 5mC erasure, teleosts, for example, exhibit localized maternal-to-paternal 5mC remodeling. Here, we studied 5mC dynamics during the embryonic development of sea lamprey, a jawless vertebrate which occupies a critical phylogenetic position as the sister group of the jawed vertebrates. We employed 5mC quantification in lamprey embryos and tissues, and discovered large-scale maternal-to-paternal epigenome remodeling that affects ~30% of the embryonic genome and is predominantly associated with partially methylated domains. We further demonstrate that sequences eliminated during programmed genome rearrangement (PGR), are hypermethylated in sperm prior to the onset of PGR. Our study thus unveils important insights into the evolutionary origins of vertebrate 5mC reprogramming, and how this process might participate in diverse developmental strategies.

The aim of this study was to evaluate the mutation spectrum of homologous recombination repair (HRR) genes and its association with tumor immune infiltration and prognosis in triple-negative breast cancer (TNBC). TNBC patients (434 patients from Ruijin cohort) were evaluated with targeted next-generating sequencing for mutations in HRR genes. The frequencies of mutations were compared with public reference cohorts (320 TNBC patients from METABRIC, 105 from TCGA, and 225 from MSKCC 2018). Associations between mutation status and tumor immune infiltration and prognosis were analyzed. HRR genes mutations were seen in 21.89% patients, with BRCA1/2 mutations significantly enriched in tumors with breast/ovarian cancer family history (P = 0.025) and high Ki-67 levels (P = 0.018). HRR genes mutations were not related with recurrence-free survival (RFS) (adjusted P = 0.070) and overall survival (OS) (adjusted P = 0.318) for TNBC patients, regardless of carboplatin treatment (P > 0.05). Moreover, tumor immune infiltration and PD-L1 expression was positively associated with HRR or BRCA1/2 mutation (all P < 0.001). Patients with both HRR mutation and high CD8+ T cell counts had the best RFS and OS, whereas patients with no HRR mutation and low CD8+ T cell counts had the worst outcomes (RFS P < 0.001, OS P = 0.019). High frequency of HRR gene mutations was found in early TNBC, with no prognostic significance. Immune infiltration and PD-L1 expression was positively associated with HRR mutation, and both HRR mutation and high CD8+ T cell infiltration levels were associated with superior disease outcome.

Objectives The aim of this study was to assess the quality of tuberculosis (TB) care for the whole course and assess factors that affect completing treatment.Design This is an observational retrospective study using chart abstraction for the whole course of TB care conducted at two underserved provinces in China.Setting The study was conducted from June 2021 to July 2021. All medical records (outpatient and inpatient) for the whole course (6–8 months) of patients with TB newly registered from July 2020 to December 2020 were reviewed and abstracted using predetermined checklists.Participants A total of 268 outpatient medical records and 126 inpatient records were included.Primary and secondary outcome measures The primary outcome included diagnostic quality, treatment quality and management quality. The secondary outcome was completing treatment.Results For diagnostic quality, 94.2% of the diagnosis were based on adequate evidence. For treatment quality, 240 (91.6%) outpatients and 100 (85.5%) inpatients took the standard chemotherapy regimens. 234 (87.3%) patients completed treatment. 85.1% of the inpatients prescribed with second-line drugs were inappropriate. For management quality, 128 (47.9%) patients received midterm assessments, but only 47 (19.7%) received sufficient services for the whole course. Patients with TB symptoms were 1.8 times more likely to complete treatment (p=0.011).Conclusion Patients with TB received high-quality diagnosis and treatment services, but low-quality whole-course management. Integration of medical and public health services should be strengthened to improve whole-course quality.

Diabetic kidney disease (DKD) is one of the chronic microvascular complications caused by diabetes, which is characterized by persistent albuminuria and/or progressive decline of estimated glomerular filtration rate (eGFR), and has been the major cause of dialysis around the world. At present, although the treatments for DKD including lifestyle modification, glycemic control and even using of Sodium-glucose cotransporter 2 (SGLT2) inhibitors can relieve kidney damage caused to a certain extent, there is still a lack of effective treatment schemes that can prevent DKD progressing to ESRD. It is urgent to find new complementary and effective therapeutic agents. Growing animal researches have shown that mitophagy makes a great difference to the pathogenesis of DKD, therefore, exploration of new drugs that target the restoration of mitophagy maybe a potential perspective treatment for DKD. The use of Chinese botanical drugs (CBD) has been identified to be an effective treatment option for DKD. There is growing concern on the molecular mechanism of CBD for treatment of DKD by regulating mitophagy. In this review, we highlight the current findings regarding the function of mitophagy in the pathological damages and progression of DKD and summarize the contributions of CBD that ameliorate renal injuries in DKD by interfering with mitophagy, which will help us further explain the mechanism of CBD in treatment for DKD and explore potential therapeutic strategies for DKD.

Accurate wind power prediction helps to stabilize the operation of the power system, improve the utilization rate of renewable energy, reduce dependence on traditional energy, and achieve sustainable energy development. An ultra short-term wind power prediction method integrating EMD-EncoderForest-TCN is proposed to address the difficulty of predicting wind power due to frequent changes in wind speed. Firstly, the time-series input data of the model is decomposed into high-frequency and low-frequency components using Empirical Mode Decomposition. Then, based on the EncoderForest model and TCN model, differential information extraction is performed on the low-frequency and high-frequency components. The EncoderForest model regularizes low-frequency information and captures trend patterns in the data. The TCN model models the high-frequency components of time series to capture complex patterns and structures in wind power. Finally, based on convolutional neural networks, the output results of each part are calculated to achieve accurate prediction of wind power. Based on the operational data of an actual wind farm, conduct a case study analysis. The results show that the proposed model can achieve accurate prediction of short-term wind power, with a prediction accuracy improvement of 2.57%.

It has been reported that selenium (Se) can reduce hepatopancreas lipid accumulation induced by high-fat diet. However, its mechanism is still unknown. This study aims to investigate the specific mechanisms by which Se alleviates high-fat diet-induced lipid accumulation. Grass carp were fed control diet (4.8% lipid, Con), high-fat diet (8.8% lipid, HFD) or HFD supplemented with 0.3 mg/kg nano-Se (HSe0.3) for 10 weeks. Growth performance, Se deposition, lipid accumulation, hepatic ultrastructure, and gene and protein expression levels associated with autophagy were examined. Furthermore, oleic acid (OA) was used to incubate the grass carp hepatocytes (L8824) for 24 h, and then the L8824 were incubated with sodium selenite in presence or absence of an autophagy inhibitor for 24 h. L8824 was analyzed for triglyceride concentration, immunofluorescence, and gene and protein expression levels associated with autophagy. We found that dietary nano-Se improved the growth of fish fed HFD and also decreased hepatosomatic index and intraperitoneal fat ratio of fish fed HFD (P

Abstract Background Most Chinese patients chose to die at home, therefore there is a reliance on the family caregivers to be involved in their palliative care. The needs and coping strategies of family caregivers in home-based palliative care are rooted in culture. Little is known about the needs and coping strategies of family caregivers taking care of dying patients at home. Methods A field study using semi-structured interview, participant observation, documents and records collection was employed. The study was conducted in two palliative care outpatient departments in tertiary hospitals and four communities in Beijing, China from March 2021 to July 2022. Using purposive sampling, twenty-five family caregivers were recruited. All collected data were analyzed using content analysis approach. Results Five themes emerged, including three care needs and two coping strategies. Family caregivers need to learn care skills and acquire care resources, including (i) decision-making about home-based palliative care, (ii) improving patient’s quality of life, and (iii) signs of final hours and funeral procedures. In facing the care burden, family caregivers coped by (iv) balancing the roles of caregivers and individuals: giving priority to patient care while maintaining their own normal life. In facing the death of a loved one, family caregivers responded by (v) making room for coming death by facing death indirectly and “rescuing” patients for consolation while preparing for the coming death. Conclusion Family caregivers strive to balance the roles of being caregivers and being themselves. As caregivers, they actively prepare patients for good death with no regrets. As individuals, they preserve themselves from being hurt to maintain normal life. The needs of family caregivers focus on caregiver role and are manifested in care skills and resources. Trial registration Not registered.

Abstract Motivated by the unexplored potential of in vitro neural systems for computing and by the corresponding need of versatile, scalable interfaces for multimodal interaction, an accurate, modular, fully customizable, and portable recording/stimulation solution that can be easily fabricated, robustly operated, and broadly disseminated is presented. This approach entails a reconfigurable platform that works across multiple industry standards and that enables a complete signal chain, from neural substrates sampled through micro‐electrode arrays (MEAs) to data acquisition, downstream analysis, and cloud storage. Built‐in modularity supports the seamless integration of electrical/optical stimulation and fluidic interfaces. Custom MEA fabrication leverages maskless photolithography, favoring the rapid prototyping of a variety of configurations, spatial topologies, and constitutive materials. Through a dedicated analysis and management software suite, the utility and robustness of this system are demonstrated across neural cultures and applications, including embryonic stem cell‐derived and primary neurons, organotypic brain slices, 3D engineered tissue mimics, concurrent calcium imaging, and long‐term recording. Overall, this technology, termed “mind in vitro” to underscore the computing inspiration, provides an end‐to‐end solution that can be widely deployed due to its affordable (>10× cost reduction) and open‐source nature, catering to the expanding needs of both conventional and unconventional electrophysiology.

The tumor-associated macrophages (TAM) play a crucial role in lung adenocarcinoma (LUAD), which can cause the proliferation, migration and invasion of tumor cells. In particular, TAMs mainly regulate changes in the tumor microenvironment thereby contributing to tumorigenesis and progression. Recently, an increasing number of studies are using single-cell RNA (Sc-RNA) sequencing to investigate changes in the composition and transcriptomics of the tumor microenvironment. We obtained Sc-RNA sequencing data of LUAD from GEO database and transcriptome data with clinical information of LUAD patients from TCGA database. A group of important genes in the state transition of TAMs was identified by analyzing TAMs at the single-cell level, while 5 TAM-related prognostic genes were obtained by omics data integration, and a prognostic model was constructed. GOBP analysis revealed that TAM-related genes were mainly enriched in tumor-promoting and immunosuppression-related pathways. After ROC analysis, it was found that the AUC of the prognosis model reached 0.751, with well predictive effectiveness. The 5 unique genes, HLA-DMB, HMGN3, ID3, PEBP1, and TUBA1B, was finally identified through synthesized analysis. The transcriptional characteristics of 5 genes were determined through GEPIA2 database and RT-qPCR. The increased expression of TUBA1B in advanced LUAD may serve as a prognostic indicator, while low expression of PEBP1 in LUAD may have the potential to become a therapeutic target.

Electricity is the lifeblood of modern society. However, the predominant source of electricity generation still relies on non-renewable fossil fuels, whose combustion releases greenhouse gases contributing to global warming. The increasing demand for energy and escalating environmental concerns necessitate proactive measures to develop innovative green energy technologies capable of both cooling the Earth and generating electricity. Here, we look forward to an interdisciplinary power system integrating solar absorbers, radiative coolers, and thermoelectric generators. This system can simultaneously harvest thermal energy from the sun and from cold space, thereby transforming the challenges posed by global warming into opportunities for the production of clean electricity. We underscore recent advancements in this field and address key challenges while also exploring forward-looking opportunities in the foreseeable future. The proposed integrated energy technology achieves uninterrupted power supply through the unrestricted capture of thermal energy, offering a robust alternative pathway for next-generation sustainable energy technologies.

Helicobacter pylori infection is associated with the risk of gastrointestinal (GI) cancers; however, its impact on immunotherapy for GI cancers remains uncertain. In this study, we included 10,122 patients who underwent 13C-urea breath tests. Among 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer (GC) who were treated with anti-PD-1/PD-L1 therapy, H. pylori–positive patients exhibited significantly longer immune-related progression-free survival (irPFS) compared with H. pylori–negative patients (6.97 months versus 5.03 months, p

Summary: Background: Although the antibody–drug conjugates (ADCs) have significantly improved the survival outcomes of patients with human epidermal receptor 2 (HER2)-expressing gastric or gastroesophageal junction (G/GEJ) cancer, the efficacy of ADC used as a single agent is limited. Therefore, it is necessary to investigate effective and safe combination regimens. Preclinical data indicated a synergetic antitumour effect of RC48 and programmed cell death protein 1 (PD-1) inhibitors. We aimed to evaluate the safety and efficacy of RC48 plus toripalimab in patients with HER2-expressing G/GEJ cancer and other solid tumours. Methods: This was a open-label, multicentre, phase 1 trial performed at three hospitals in China. Eligible patients had advanced G/GEJ cancer or other solid tumours with HER2 IHC≥1 or ISH positivity and were refractory to at least one line of treatment, or standard treatment was intolerable or unavailable for these patients. This study followed a “3 + 3” design with predefined RC48 dosages of 2.0 mg/kg and 2.5 mg/kg plus toripalimab 3 mg/kg, once every 2 weeks (q2w). The primary objectives were to evaluate the safety and determine the recommended phase II dose (RP2D), and the secondary objectives included assessing the pharmacokinetics (PK) and preliminary efficacy. This study was registered with ClinicalTrials.gov, NCT04280341. Findings: Between July 13, 2020 and August 30, 2022, 56 patients, including 30 patients with G/GEJ cancer and 26 patients with other solid tumours, were enrolled and received RC48 plus toripalimab (n = 7 for RC48 2.0 mg/kg, toripalimab 3 mg/kg, q2w; n = 49 for RC48 2.5 mg/kg, toripalimab 3 mg/kg, q2w). No dose-limiting toxic effects occurred. The RP2D was declared as RC48 2.5 mg/kg plus toripalimab 3 mg/kg, q2w. The most common grade 3 adverse events were a decreased neutrophil count (n = 13), and a decreased white blood cell count (n = 7). The efficacy assessment was completed for 52 patients. Among patients with G/GEJ cancer (n = 30), the confirmed objective response rate (ORR) was 43% (12/28, 95% CI 25, 63), median progression-free survival (PFS) was 6.2 months (95% CI 4.0, 6.9), median overall survival (OS) was 16.8 months (95% CI 7.2, NE). The ORR of patients with G/GEJ cancer receiving RP2D (n = 24) reached 50% (11/22, 95% CI 28, 72), with median PFS of 5.1 months (95% CI 1.4, 7.3) and median OS of 14.0 months (95% CI 6.3, NE). Among patients with G/GEJ cancer who received RP2D, a clinical benefit was observed in both HER2-positive and low HER2 expressing populations, with an ORR of 56% (5/9, 95% CI 21, 86) vs. 46% (6/13, 95% CI 19, 75), median PFS of 7.8 months (95% CI 0.9, NE) vs. 5.1 months (95% CI 1.2, 6.9), median OS of NE months (95% CI 4.3, NE) vs. 14.0 months (95% CI 5.1, NE), respectively. Antitumour activity was also observed for other solid tumours, including breast cancer (5/13) and endometrial carcinoma (1/1). Interpretation: Our findings suggested that RC48 plus toripalimab had a manageable safety profile and showed encouraging efficacy in pretreated patients with HER2-positive and low HER2-expressing G/GEJ cancer. The findings of our phase 1 clinical trial support further investigation of HER2-targeted ADC plus immunotherapy in HER2-expressing G/GEJ cancer and pancancer treatment in the future. Funding: Beijing Municipal Medical Research Institutes, Beijing Medical Research Institute (Z200015).

Abstract Diabetic kidney disease (DKD), has become the main cause of end-stage renal disease (ESRD) worldwide. Lately, it has been shown that the onset and advancement of DKD are linked to imbalances of gut microbiota and the abnormal generation of microbial metabolites. Similarly, a body of recent evidence revealed that biological alterations of mitochondria ranging from mitochondrial dysfunction and morphology can also exert significant effects on the occurrence of DKD. Based on the prevailing theory of endosymbiosis, it is believed that human mitochondria originated from microorganisms and share comparable biological characteristics with the microbiota found in the gut. Recent research has shown a strong correlation between the gut microbiome and mitochondrial function in the occurrence and development of metabolic disorders. The gut microbiome’s metabolites may play a vital role in this communication. However, the relationship between the gut microbiome and mitochondrial function in the development of DKD is not yet fully understood, and the role of microbial metabolites is still unclear. Recent studies are highlighted in this review to examine the possible mechanism of the gut microbiota-microbial metabolites-mitochondrial axis in the progression of DKD and the new therapeutic approaches for preventing or reducing DKD based on this biological axis in the future.

Abstract Background Tumor regression grade (TRG) is a measure of histopathological response to neoadjuvant therapy (NAT). Post‐therapy lymph node (ypN) metastasis was reported as a prognostic factor. However, the evaluation of the treatment effectiveness of NAT has not been well studied. Here, we explored whether TRG combined with ypN status could be a prognostic factor for gastroesophageal junction (GEJ) and gastric cancer (GC). Besides, we aimed at making clear the association of different neoadjuvant regimens with different TRG and ypN status. Methods 376 patients with GEJ or GC accepting NAT in Peking University Cancer Hospital were retrospectively collected from January 1, 2003 to June 30, 2021. According to TRG and ypN status, patients were innovatively categorized into four groups: TRG0N0, TRG1‐3N0, TRG0‐1N+, and TRG2‐3N+. We applied Kaplan–Meier method and log‐rank test to testify the differences in disease free survival (DFS) and overall survival (OS) among four groups. Univariate and multivariate analyses were performed to examine the relationships between TRG combined with ypN status and prognosis. Results We observed significant survival differences among the four groups (p

Abstract Background The clinicopathological features of MET‐amplified gastric cancer (GC) and real‐world data on the efficacy of MET‐targeted therapies remain unknown. Pulmonary lymphangitis carcinomatosis (PLC) is a peculiar manifestation of GC, whose management has not been thoroughly described. Methods This study analyzed patients diagnosed with MET‐amplified GC or GC with PLC at any time point of the disease course from 2011 to 2021 in two centers. Clinicopathological features and survival outcomes of MET‐amplified GC were analyzed. The clinical and molecular implications of GC with PLC were discussed. Results Fifty‐eight patients with MET‐amplified GC and 20 patients with GC accompanied by PLC were finally enrolled for analysis (including 13 overlapped patients). GC with PLC was more common in female patients (p = 0.010), diagnosed at a younger age (p = 0.002), presented with a higher baseline ECOG PS (p = 0.016), and was more likely to develop lung metastasis (p

Abstract Pancreatic cancer lacks effective therapy. Here, we reported two metastatic pancreatic cancer patients administrated with Claudin 18.2 (CLDN 18.2) CART therapy after the failure of standard therapy (NCT04581473 and NCT03874897). In case 1, with CLDN 18.2 expression of 2+, 70%, 250 × 106 cells were infused after lymphodepletion. Grade 1 cytokine release syndrome (CRS) occurred on d1 which was later controlled by tocilizumab. Partial response (PR) was achieved according to RECIST v1.1, with great shrinkage of lung metastasis. An increasing CD8+ T cell and Treg cells and declining CD4+ T cell and B cell were observed. In case 2, IHC result of ClDN18.2 showed 3+, 60%. 250 × 106 CLDN18.2 CART cells were subsequently administered. Patient experienced grade 2 CRS, which was controlled with tocilizumab. Target lesions of lung metastasis further achieved complete response. Similar increasing CD8+ T cell and Treg cell was detected from peripheral blood. Elevating IL-8 and declining TGF-β1 were also observed. The tumor is still under well control until the last follow-up on July 18, 2023.

In this work, a permanent connection of a high-nitrogen steel plate is achieved by using layer-by-layer powder-filled laser welding of high-nitrogen steel powder, and the stability levels of the welding process, microstructures and mechanical properties are analyzed. Compared with other processes, powder-filled laser welding is smooth without bursts and spatters, and the nitrogen content of the welding seam is obviously improved. The welding seam consists mainly of austenite, with few ferrite and manganese oxides. There is a nitrogen concentration gradient between the inside and the upper part of the melt pool, which leads to nitrogen escape. Laser remelting exacerbates this process, resulting in more severe nitrogen loss in the bottom layer than in the upper layer of the welding seam. The differences in the nitrogen solubilities in austenite and ferrite and the high-nitrogen content in the melt pool are the main reasons for the formation of micropores. Tensile experiments and impact experiments are conducted on the welding joint. The average tensile strength and elongation of the welding joint are 1032.36 MPa and 19.70%, respectively, contributing to 94% and 53.4% of the total values for the base metal. The grain refinement and relatively high nitrogen content are the reasons for the better tensile strength relative to other processes. The average impact energy of the welding joint is 24.68 J, which is approximately 63.74% of the base metal. Pores are the main reason for the reduced impact energy of the welding joint.

This is an essay in the field of metallurgical engineering. With the sharp increase in battery-grade lithium carbonate prices in 2020, research on lithium extraction technology from clay-type lithium ore has become a topic of great interest in the industry. This article takes clay type lithium resources as the research object, outlines the distribution of clay type lithium resources, summarizes the main lithium extraction processes related to clay type lithium mines in China in recent years, and analyzes the advantages and disadvantages of different methods. Given the composition of the leachate from clay-type lithium ore, it is emphasized that the comprehensive utilization of valuable components such as aluminum in the leachate and more research on the utilization of leaching residue are important for the development and utilization of clay-type lithium ore. This article looks ahead to potential leaching and lithium extraction methods for clay-type lithium ore and methods for removing impurities and enriching lithium in leachate, with the aim of contributing to the development of more economically reasonable utilization processes for clay-type lithium ore.

This is an essay in the field of material engineering. In recent years, the new energy has been growing fast than ever. Apparently, in the upcoming future, a large number of lithium iron phosphate batteries will be retired. Out of the need to protect China's strategic mineral resources and reduce environmental pollution, research and development of a green, efficient and sustainable recycling process of spent lithium iron phosphate batteries is urgent. This essay takes the main components and general recycling process of waste lithium iron phosphate battery as the research object and introduces the principle, advantages and disadvantages, and research status of various recovery processes such as pretreatment, cathode material, negative electrode material and electrolyte. On this basis, future perspectives of lithium iron phosphate battery recycling are presented, aiming to provide support for the industrialization and development of the spent lithium iron phosphate battery recycling technology in China.

Bisphenol A (BPA) is easily enriched in many human-disturbed watersheds, particularly lakes with poor water mobility, which is posing a threat to aquatic biota. While previous studies have focused on the concentration of BPA in water and its toxicity to aquatic organisms, a small amount of measured data is not enough to reveal the temporal and spatial distribution and threats of BPA, and estimate the ecological risk in watersheds. Therefore, we collected 164 measured BPA data points from Taihu Lake to develop machine learning models using random forest (RF), support vector machine (SVM) and least square regression (LSR) and created month-by-month watershed prediction maps in temperate lakes to estimate the spatiotemporal distribution and threats of BPA. Due to RF's superior robustness to noisy data, the RF model exhibits the best performance among the three algorithms. The RF model showed acceptable predictive performance on the modeling dataset (coefficients of determination and root-mean-square error for the training set were 0.927 and 17.499, respectively, and 0.607, 39.645 for the validation set, respectively). The maps indicated that areas susceptible to anthropogenic activities were more severely polluted by BPA, and rainy climate may favor the migration of BPA to aquatic ecosystems. The model was also applied to predict 42 data points of BPA collected from Dianchi Lake, and the results showed that most predicted data were within a factor of 10 of the measured data, but the prediction accuracy of the model has declined. The ecological risks in the two lakes were evaluated and attention should be paid to the regions with higher risks. Our study provided a novel idea for comprehensive monitoring of an unconventional trace pollutant with endocrine disrupting effects in aquatic ecosystems and analyzing their spatiotemporal distribution, which will contribute to the scientific assessment of the ecological risk of BPA.

This paper thoroughly examines the time distribution, author collaboration, research institutions, research hotspots, theme clustering, and research changes and trends based on 345 CNKI literatures in the field of blended learning for Business English majors in China from 2012 to 2022. It reveals that: Research on blended learning for Business English majors in China from 2012 to 2022 can be divided into Steady Start Stage (2012–2017), Rapid Growth Stage (2018–2020) and Stable Development Stage (2021–2022). High-frequency keywords such as blended teaching mode, MOOC, flipped classroom, SPOC, etc. are hotspots of current scholars' attention. The themes of research on blended learning of business English majors in China mainly include Teaching Reform of Business English Majors, Exploration of Blended Teaching Mode and Design, and Application of Internet Teaching Platform. “Teaching Reform”, “Online and Offline”, “Application of Smart Platform” are the current research frontier issues in the development of blended learning for Business English majors in China. In general, China's research on blended learning for business English majors has achieved fruitful results under China's policies. Future research should concentrate on the construction of a technology environment for blended learning between learners, a variety of intelligent learning tools and mobile devices, and should be steadily bolstered in the field of blended learning for business English majors, particularly in practical application, effectiveness analysis, distance education, training and continuing education, innovation education, etc.

ABSTRACTObjective: To explore the prognostic value of red blood cell distribution width (RDW) in newly diagnosed aplastic anemia (AA) patients treated with cyclosporine A (CsA) plus androgen or CsA alone.Methods: We retrospectively analyzed the clinical outcome of 220 patients with AA. According to the baseline level of RDW before treatment, the patients were divided into the high-RDW group (RDW ≥ 15%) and the normal-RDW group (RDW

Traumatic brain injury (TBI) is caused by acquired damage that includes cerebral edema after a mechanical injury and may cause cognitive impairment. We explored the role of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2; NOX2) and aquaporin-4 (AQP4) in the process of edema and cognitive abilities after TBI in NOX2−/− and AQP4−/− mice by using the Morris water maze test (MWM), step-down test (STD), novel object recognition test (NOR) and western blotting. Knockout of NOX2 in mice decreased the AQP4 and reduce edema in the hippocampus and cortex after TBI in mice. Moreover, inhibiting AQP4 by 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) or genetic deletion of AQP4 could attenuate neurological deficits without changing reactive oxygen species (ROS) levels after TBI in mice. Taken together, we suspected that inhibiting NOX2 could improve cognitive abilities by modulating ROS levels, then affecting AQP4 levels and brain edema after in TBI mice. Our study demonstrated that NOX2 play a key role in decreasing edema in brain and improving cognitive abilities by modulating AQP4 after TBI.

Amidst the COVID-19, which has necessitated the widespread use of distant learning, there has been a notable increase in the recognition and utilization of inventive pedagogical methods and technological tools in the field of language teaching. The primary objective of this research is to assess the effects of DingTalk-based PBL on the business vocabulary growth of Chinese undergraduates during the pandemic, with a particular focus on remote learning environments. This mixed-methods research employed a sample of 58 participants. The study involved both quantitative vocabulary assessments and qualitative interviews. The quantitative assessments aimed to measure the impact on vocabulary scores, while qualitative interviews were conducted to gather insights into participants’ experiences and perceptions regarding DingTalk-based PBL. The quantitative assessment revealed a significant improvement in business vocabulary scores among the participants who underwent DingTalk-based PBL. This result indicates the platform’s potential to enhance language acquisition. The qualitative interviews provided further insights, with participants expressing positive attitudes toward DingTalk-based PBL. They emphasized its capacity to sustain engagement, foster collaboration, and bridge the gap between remote learning and effective language acquisition. These findings underscore the transformative potential of DingTalk-based PBL in language education, especially in the context of challenges posed by the pandemic. While recognizing the constraints of this study, such as its limited duration and restricted contextual applicability, the research encourages further investigation into sustainable vocabulary expansion, the development of multifaceted language abilities, and the integration of these platforms into emerging hybrid educational frameworks. This study makes a valuable contribution to the ongoing discourse regarding novel technology-based methods in language instruction, providing relevant insights applicable to both present and future educational contexts.

Abstract Cutting fluid is crucial in ensuring surface quality and machining accuracy during machining. However, traditional mineral oil-based cutting fluids no longer meet modern machining’s health and environmental protection requirements. As a renewable, pollution-free alternative with excellent processing characteristics, vegetable oil has become an inevitable replacement. However, vegetable oil lacks oxidation stability, extreme pressure, and antiwear properties, which are essential for machining requirements. The physicochemical characteristics of vegetable oils and the improved methods’ application mechanism are not fully understood. This study aims to investigate the effects of viscosity, surface tension, and molecular structure of vegetable oil on cooling and lubricating properties. The mechanisms of autoxidation and high-temperature oxidation based on the molecular structure of vegetable oil are also discussed. The study further investigates the application mechanism and performance of chemical modification and antioxidant additives. The study shows that the propionic ester of methyl hydroxy-oleate obtained by epoxidation has an initial oxidation temperature of 175 ℃. The application mechanism and extreme pressure performance of conventional extreme pressure additives and nanoparticle additives were also investigated to solve the problem of insufficient oxidation resistance and extreme pressure performance of nanobiological lubricants. Finally, the study discusses the future prospects of vegetable oil for chemical modification and nanoparticle addition. The study provides theoretical guidance and technical support for the industrial application and scientific research of vegetable oil in the field of lubrication and cooling. It is expected to promote sustainable development in the manufacturing industry.

Abstract Background BRAF mutation occurs in 5%–10% of metastatic colorectal cancers (mCRCs). Patients with BRAF mutant mCRC exhibit a specific metastatic pattern and poor prognosis. Survival outcomes are heterogeneous in cases of mCRC with a BRAF mutation. The optimal first‐line therapy is still controversial. Methods We retrospectively reviewed the medical records of patients with mCRC between June 2010 and December 2021. Clinicopathologic characteristics, treatment and BRAF mutation testing results were collected. Patients with a BRAF mutation were included. Kaplan–Meier methods and log‐rank tests were used to analyze and compare survival. Cox proportional hazards regression was used to establish the predictive nomogram model. Results Of the 4475 mCRC, 261 have a BRAF mutation, including 240 V600E and 21 non‐V600E mutants. The median overall survival (OS) was 18.2 months in the BRAF V600E mutant group versus 38.0 months in the non‐V600E mutant group (p = 0.022). ECOG score, tumor differentiation, liver metastasis, bone metastasis and primary tumor resection were independent prognostic factors for the OS of BRAF V600E mutant mCRC. A nomogram model was established using these factors. The median OS was 39.3 m, 18.2 m and 10.7 m for the low‐risk, intermediate‐risk and high‐risk groups defined by this model, respectively (p

Abstract Aim Pyrotinib (an irreversible pan‐ErbB small‐molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)‐positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2‐positive GC. Methods This multicenter, phase I study followed a standard “3 + 3” design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1‐21, q3W) combined with docetaxel (60 mg/m2, d1, q3W) at dose levels of 240, 320, and 400 mg. Primary endpoints were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of pyrotinib as monotherapy or coadministered with docetaxel. Results A total of 25 patients were enrolled and received pyrotinib (n = 15) or pyrotinib plus docetaxel (n = 10). One DLT was observed in pyrotinib monotherapy part (Grade 3 uncontrolled diarrhea after supportive care) and pyrotinib plus docetaxel part (Grade 4 neutropenia and leukopenia). In the pyrotinib monotherapy part, MTD was not reached. Diarrhea, anemia, neutropenia, and leukopenia were the most common treatment‐related adverse events (TRAEs). The RP2D for pyrotinib monotherapy was recommended as 400 mg. After combining with docetaxel, the risk of leukopenia and neutropenia was increased. Grade ≥3 TRAEs were reported for four patients in the monotherapy part and for eight patients in the combination part. Mean t1/2 was approximately 20 h. Pyrotinib exposure was dose‐dependent with a nonlinear relationship versus dose. There were five patients who had confirmed partial response (monotherapy: one each at 240, 400, and 480 mg dose cohort; combination therapy: two at 240 mg dose cohort), resulting in an objective response rate of 21% and 20%, respectively. Conclusions Pyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2‐positive GC. Trial Registration This study was registered with ClinicalTrials.gov, NCT02378389.

Initial public offerings and mergers and acquisitions represent important opportunities for investors to exit and harvest their entrepreneurial success. Some firms are acquired shortly after their initial public offerings. This exit strategy is known as a double exit. In addition, issuing firms may choose to reincorporate in Delaware during their IPOs. In this study, we use hand-collected data from 1993 to 2020 to investigate whether and to what extent Delaware reincorporation may affect the M&As in the post-IPO stage. We use a Cox proportional hazard model to test the relation between Delaware reincorporation and the likelihood of being acquired for our sample IPOs. Recognizing that Delaware reincorporation is not a random decision, we adopt a Heckman switching regression method to estimate the relation between Delaware reincorporation and takeover premiums and announcement returns. We report that IPO firms choosing to reincorporate in Delaware experience a higher likelihood of being acquired compared to those IPO firms choosing to remain incorporated in their home states. We further document that IPO firms choosing to reincorporate in Delaware receive lower premiums in acquisitions, and experience lower abnormal returns on announcements.

With the acceleration of transportation infrastructure and the densification of transportation networks, there has been an increase in bridge pile construction near oil and gas pipelines. Selecting bridge pile construction methods with minimal impact and reducing the adverse effects of bridge pile construction on nearby oil and gas pipelines are of great importance. This paper uses FLAC3D 6.0 software to simulate and analyze the impact of two different pile construction methods, rotary drilling and impact drilling, on adjacent oil pipelines. The results show that the horizontal displacement of oil pipelines during rotary drilling construction is nearly 90% lower than that of the traditional impact drilling method, and the axial stress is reduced by nearly 85%. Furthermore, numerical simulations of rotary drilling under different conditions were conducted to analyze and summarize the patterns of how different conditions affect construction vibration and stress. This study provides a reference for bridge pile construction near oil and gas pipelines or important buildings.

Insulin-like growth factors (IGFs) play central roles in the growth and development of vertebrates. Blotched snakehead (Channa maculata), an economically significant fish, exhibits obvious sexual dimorphism and achieves sexual maturity in one year. However, the role of IGFs in C. maculata remains unknown. Three IGF genes were identified in C. maculata, designated as CmIGF1-1, CmIGF1-2, and CmIGF2. The cDNA sequences of these genes are 1184, 655, and 695 bp, encoding putative proteins of 168, 131, and 215 amino acids, respectively, and all three proteins contain a conserved IGF domain. Quantitative real-time PCR (qPCR) revealed the predominant expression of CmIGFs in the liver of adult fish, with higher expression levels observed in males. Notably, CmIGF1-1, CmIGF1-2, and CmIGF2 displayed analogous expression profiles in the liver across various developmental stages, peaking at 365 days after hatching (dah). Subsequently, 600 individuals at 75 dah, at an early developmental stage, were randomly divided equally into six groups and reared in aerated 2 m × 2 m × 2 m cement ponds at 26.0 ± 1.0 °C. Following a one-week acclimatization period, fish without observed abnormalities were intraperitoneally injected with either 17α-ethynylestradiol (EE2) or 17α-methyltestosterone (MT) at a dose of 10 μg/g body weight. Three groups underwent short-term hormone treatment, and the remaining three groups underwent long-term hormone treatment, which included five injections at two-week intervals over ten weeks. The analysis of CmIGFs expression levels in the liver under different hormone treatments revealed that EE2 suppressed the expression of CmIGF1-1 and CmIGF1-2 while promoting CmIGF2 expression. In females, MT up-regulated the expression of CmIGF1-1 and CmIGF2 in a time-dependent manner, but consistently inhibited CmIGF2 expression. In males, MT promoted the expression of CmIGFs in a time-dependent manner, reaching peak levels for CmIGF1-1, CmIGF1-2, and CmIGF2 after 8, 10, and 2 weeks of injection, respectively. Additionally, CmIGF1 and CmIGF2 might exhibit a complementary relationship, with a compensatory increase in CmIGF2 expression in response to low CmIGF1 concentration. These findings highlight the potential key role of IGFs upon growth and their regulation by sex steroid hormones in C. maculata, providing a crucial foundation for future research aimed at elucidating the molecular mechanisms underlying the growth dimorphism between female and male blotched snakeheads.

Figla is one of the earliest expressed genes in the oocyte during ovarian development. In this study, Figla was characterized in C. maculata, one of the main aquaculture species in China, and designated as CmFigla. The length of CmFigla cDNA was 1303 bp, encoding 197 amino acids that contained a conserved bHLH domain. CmFigla revealed a female-biased expression patterns in the gonads of adult fish, and CmFigla expression was far higher in ovaries than that in testes at all gonadal development stages, especially at 60~180 days post-fertilization (dpf). Furthermore, a noteworthy inverse relationship was observed between CmFigla expression and the methylation of its promoter in the adult gonads. Gonads at 90 dpf were used for in situ hybridization (ISH), and CmFigla transcripts were mainly concentrated in oogonia and the primary oocytes in ovaries, but undetectable in the testes. These results indicated that Figla would play vital roles in the ovarian development in C. maculata. Additionally, the frame-shift mutations of CmFigla were successfully constructed through the CRISPR/Cas9 system, which established a positive foundation for further investigation on the role of Figla in the ovarian development of C. maculata. Our study provides valuable clues for exploring the regulatory mechanism of Figla in the fish ovarian development and maintenance, which would be useful for the sex control and reproduction of fish in aquaculture.

Abstract This paper proposes a transformer type dc power flow controller (DCPFC) based on stacks composed of sub‐modules (SMs). The converter can perform dc power flow control independently on point‐to‐point as well as multi‐terminal connection, which can be applied to either high voltage or medium voltage dc grids. In order to explain the operation principle, different operating states of the proposed DCPFC are analysed. With phase‐shift modulation and the closed‐loop current control, the proposed DCPFC can achieve bidirectional power flow regulation. Following the theoretical analysis of the proposed DCPFC, simulation results have verified the feasibility of bidirectional power flow control. A downscaled experimental prototype is also built to demonstrate the operation principle and performance of the proposed DCPFC.

Objective Assess whether local health facilities can adequately support the performance of general practitioners (GPs) trained by China’s national compulsory services programme (CSP).Design Prospective cohort study.Setting Health facilities in middle and western rural areas in China, 2015–2022.Participants Cohorts of CSP graduates from 2015 to 2019 in four major medical universities.Main outcomes Job performance measured by a 12-item Job Performance Scale; productivity measured by outpatient volume per day; turnover measured by ever changing jobs within the past year.Results 91.2%, 92.0% and 90.5% GPs working in township health centres reported inadequate medication, equipment and external assistance from higher level hospitals, while CSP graduates working in secondary or tertiary hospitals reported a lower rate of less than 60%. The top three tests reported as lacking were blood gases (67.7%), microbiology (61.6%) and cancer biomarkers (49.7%); the top three lacked procedures were CT scan (64.8%), MRI scan (58.1%) and ambulatory BP monitoring (55.8%); and the top three lacked drugs were drugs for cardiovascular diseases (23.3%), systematic hormonal preparations (17.7%) and traditional Chinese medicines (13.0%). Multivariable analysis showed that facility support was positively associated with job performance—adequate medication increased job performance by 2.2 points (95% CI 0.7 to 3.8), and adequate external assistance increased job performance by 3.3 points (95% CI 1.8 to 4.8). Facility support was also positively associated with productivity—adequate medication increased outpatients seen per day by 20% (95% CI 0.1 to 0.3), and adequate equipment increased outpatients seen per day by 12% (95% CI 0.0 to 0.2). Facility support did not have significant impact on turnover, but GPs who changed jobs in the past year were 1.9–2.3 times more likely to report adequate facility support.Conclusion GPs in township health centres experienced a high prevalence of shortage in facility support. The identification of a positive association between facility support and performance and productivity has implications for future research and resources deployment in primary healthcare.

Abstract The application of immunotherapy in gastrointestinal (GI) cancers remains challenging because of the limited response rate and emerging therapeutic resistance. Combining clinical cohorts, multi‐omics study, and functional/molecular experiments, it is found that ANO1 amplification or high‐expression predicts poor outcomes and resistance to immunotherapy for GI cancer patients. Knocking‐down or inhibiting ANO1 suppresses the growth/metastasis/invasion of multiple GI cancer cell lines, cell‐derived xenograft, and patient‐derived xenograft models. ANO1 contributes to an immune‐suppressive tumor microenvironment and induces acquired resistance to anti‐PD‐1 immunotherapy, while ANO1 knockdown or inhibition enhances immunotherapeutic effectiveness and overcomes resistance to immunotherapy. Mechanistically, through inhibiting cancer ferroptosis in a PI3K‐Akt signaling‐dependent manner, ANO1 enhances tumor progression and facilitates cancer‐associated fibroblast recruitment by promoting TGF‐β release, thus crippling CD8+ T cell‐mediated anti‐tumor immunity and generating resistance to immunotherapy. This work highlights ANO1's role in mediating tumor immune microenvironment remodeling and immunotherapeutic resistance, and introduces ANO1 as a promising target for GI cancers’ precision treatment.

Abstract Background This paper seeks to assess the sustainability of the reformed maternity insurance system and the extent to which China’s current maternity insurance system can support different levels of fertility incentives in the future. Our findings will serve as a reference for countries in a similar demographic predicament and those about to face it. Methods This study used a combination of qualitative and quantitative methods. In the qualitative assessment, we used a grounded theory model to generalize the factors influencing the sustainability of maternity insurance funds. For the quantitative analysis, we used a novel and comprehensive system dynamics model to visualize the status of the combined operation of maternity and health insurance. Data are mainly derived from the historical data of the Statistical Yearbook of Jiangsu Province and the National Bureau of Statistics of China. Results In the short term, fertility incentive payments can be set to motivate people to have children. It is therefore recommended that when the scope of the fertility incentive policy is limited to two children, and an average amount above RMB 10 000 could be set, it would be prudent to set the amount at a level not exceeding RMB 10 000 when the scope of the fertility incentive policy is for all newborns. In the long term, a system of incentives for childbirth should be built from education policy, house price regulation, tax relief and childcare services. Conclusion Our research not only highlights the significance of improving the resilience of maternity insurance by combining maternity insurance and health insurance funds, but also suggests a way to economically incentivize beneficiaries to have children so as to mitigate the decline in China’s birth rate and cope with the crisis of an ageing population.

Abstract Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first “tumor agnostic” drugs approved for pan‐cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second‐generation drugs designed to overcome first‐generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription‐polymerase chain reaction, and (DNA and/or RNA‐based) next‐generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first‐ and second‐generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Abstract Background Common treatments for metastatic/unresectable HER2‐negative gastric cancer include chemotherapy, immune checkpoint inhibitor monotherapy and chemotherapy plus immune checkpoint inhibitor. However, significant drug resistance exists regardless of the treatment regimen. Methods Patients with metastatic/unresectable HER2‐negative gastric/gastroesophageal junction adenocarcinoma were enrolled. All patients were divided into three groups according to the treatment regimen and were further divided into responders and non‐responders according to efficacy evaluation. Metagenomics sequencing were performed to analyze gut microbiome signature of patients receiving different treatments at baseline and throughout treatment. Results One hundred seventeen patients with HER2‐negative advanced gastric or gastroesophageal junction adenocarcinoma receiving chemotherapy alone, anti PD‐1/PD‐L1 immunotherapy alone or combined regimen were included in this study. Microbiome signatures related to clinical response are distinct among the three treatment groups. Among which, 14, 8 and 13 species were significantly different between responders and non‐responders in immunotherapy, immunotherapy plus chemotherapy and chemotherapy group, respectively. Patients with higher relative abundance of Lactobacillus possessed higher microbiome diversity and significantly better response to anti‐PD‐1/PD‐L1 immunotherapy and had a trend to achieve better progression‐free survival. Another cohort of 101 patients has been used as an external validation set to confirm the stability and reliability of these findings. Conclusions Gut microbiome affects response of treatments in HER2‐negative advanced gastric cancer in a treatment‐specific way, immunotherapy plus chemotherapy did not equal to a simple superposition of immunotherapy and chemotherapy. Lactobacillus is expected to become a novel choice as an adjuvant agent in promoting the efficacy of immunotherapy in gastric cancer.

Aiming at the problems of insufficient power system regulation capacity and lack of flexible resources caused by source-load uncertainty, the flexible resource planning of power systems is studied with the goal of improving flexibility. Uncertainty and flexibility are combined in this article, and a probability index of an insufficiently flexible supply-demand ratio is proposed based on the probability characteristics of flexibility. A bi-level programming model of power system flexibility resources considering the probability of an insufficiently flexible supply demand ratio is constructed. Optimal economics is used as the objective function of the planning layer, and the proposed minimum probability index of the flexible supply-demand ratio is used as the objective function of the operations layer. Economics and flexibility are studied, taking the power system in a certain area in Northeast China as the research object. A flexible resource planning scheme that meets different flexibility expectations is obtained, and the scheme is discussed in detail from the aspects of system flexibility, economic cost, and new energy consumption capacity. The effectiveness of quantitative indicators and planning methods are verified.

Background Systemic Immune-inflammation Index (SII) and body composition parameters are easily assessed, and can predict overall survival (OS) in various cancers, allowing early intervention. This study aimed to assess the correlation between CT-derived body composition parameters and SII and OS in patients with advanced gastric cancer receiving dual programmed death-1 (PD-1) and human epidermal growth factor receptor 2 (HER2) blockade.Materials and methods This retrospective study enrolled patients with advanced gastric cancer treated with dual PD-1 and HER2 blockade from March 2019 to June 2022. We developed a deep learning model based on nnU-Net to automatically segment skeletal muscle, subcutaneous fat and visceral fat at the third lumbar level, and calculated the corresponding Skeletal Muscle Index, skeletal muscle density, subcutaneous fat area (SFA) and visceral fat area. SII was computed using the formula that total peripheral platelet count×neutrophil/lymphocyte ratio. Univariate and multivariate Cox regression analysis were used to determine the associations between SII, body composition parameters and OS.Results The automatic segmentation deep learning model was developed to efficiently segment body composition in 158 patients (0.23 s/image). Multivariate Cox analysis revealed that high SII (HR=2.49 (95% CI 1.54 to 4.01), p

This work examined the physical and chemical properties and biocompatibility in vivo and in vitro of a unique triple composite scaffold incorporating silk fibroin, chitosan, and extracellular matrix. The materials were blended, cross-linked, and freeze-dried to create a composite scaffold of silk fibroin/chitosan/colon extracellular matrix (SF/CTS/CEM) with varying CEM contents. The SF/CTS/CEM (1:1:1) scaffold demonstrated the preferable shape, outstanding porosity, favorable connectivity, good moisture absorption, and acceptable and controlled swelling and degradation properties. Additionally, HCT-116 cells cultivated with SF/CTS/CEM (1:1:1) showed excellent proliferation capacity, cell malignancy, and delayed apoptosis, according to the in vitro cytocompatibility examination. We also examined the PI3K/PDK1/Akt/FoxO signaling pathway and discovered that cell culture using a SF/CTS/CEM (1:1:1) scaffold may prevent cell death by phosphorylating Akt and suppressing FoxO expression. Our findings demonstrate the potential of the SF/CTS/CEM (1:1:1) scaffold as an experimental model for colonic cancer cell culture and for replicating the three-dimensional in vivo cell growth environment.

Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.

Objective: Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer. Methods: We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment. Results: In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration. Conclusions: The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy.

Abstract Background The FAST study identified claudin-18 (CLDN18.2) as a promising novel therapeutic target for gastric cancer (GC). However, the tumor immune microenvironment and clinicopathological features of CLDN18.2-positive GC are unclear, making it difficult to develop and optimize CLDN18.2-targeted treatments. Methods This study included 80 GC patients, 60 of whom received anti-PD-1/PD-L1 treatment. CD4/CD8/CD20/CD66b/CD68/CD163/PD-1/PD-L1/TIM-3/LAG-3/FoxP3/CTLA-4/HLA-DR/STING, and CLDN18.2 were labeled using multiplex immunohistochemistry (m-IHC) to decipher the rate and spatial distribution of T cells, B cells, macrophages, and neutrophils in formalin-fixed, paraffin-embedded tumor tissues isolated from these patients. Tumor immune-microenvironmental features and patient survival stratified by CLDN18.2 expression were analyzed using two independent-sample t-tests and log-rank tests, respectively. Results We considered moderate-to-strong CLDN18.2 expression ≥ 40% of tumor cells as the cut-off for positivity. The proportion of CD8+PD-1−, CD8+LAG-3−, and CD8+TIM-3− T cells was significantly higher in CLDN18.2-positive tumors than in negative tumors (0.039 vs. 0.026, P = 0.009; 0.050 vs.0.035, P = 0.024; 0.045 vs. 0.032, P = 0.038, respectively). In addition, the number of neutrophils (CD66b+) was higher in the CLDN18.2-positive group than in the negative group (0.081 vs. 0.055, P = 0.031, respectively), while the rates of M1 (CD68+CD163−HLA-DR+), M2 macrophages (CD68+CD163+HLA-DR−), and B cells (CD20+) were comparable between the CLDN18.2-positive and negative groups. The average numbers of CD8+PD-1−, CD8+LAG-3−, and CD8+TIM-3−T cells surrounding tumor cells within a 20-μm range were higher in CLDN18.2-positive tumors than in the CLDN18.2-negative tumors (0.16 vs. 0.09, P = 0.011; 0.20 vs. 0.12, P = 0.029; 0.18 vs. 0.12, P = 0.047, respectively). In addition, in the CLDN18.2-positive group, tumor cells surrounded by CD8+PD-1−, CD8+LAG-3− T cells, or M1 macrophages within a 20-μm range accounted for a higher proportion of all tumor cells than those in the CLDN18.2-negative group (10.79% vs. 6.60%, P = 0.015; 12.68% vs. 8.70%, P = 0.049; 9.08% vs. 6.56%, P = 0.033, respectively). These findings suggest that CLDN18.2-positive GC harbors complex immune-microenvironmental features. Additionally, CLDN18.2-positive group had shorter OS and irOS than CLDN18.2-negative group (median OS: 23.33 vs.36.6 months, P

Abstract Background Both the protein domains and transcript structures influence protein functional variation. The genomic location of both protein domains and transcript structural features can be described using the genomic coordinates of their encoded sequences. However, the coordinates of protein domains and transcriptional features often differ greatly, and it is difficult to view them in combination at the genome-wide level. In this paper, we describe the development of a new tool that allows users to visualize domains and transcript features together, using either built-in or uploaded genome datasets, and export publication-ready figures. Results We developed a user-friendly, independent R package and Shiny web application named “VisProDom”. VisProDom consists of a genome-wide database containing entire annotated transcripts merged with annotated protein domains from the Pfam database. The built-in dataset includes 82 files, which merge genome general feature format (GFF) annotations with rpsblast tabular outputs from protein sequence searches in the Pfam database. Multiple genomes can be simultaneously screened for protein domains or transcript names. VisProDom includes step-by-step introductions and clickable elements for ease of use. Conclusion VisProDom can display hundreds of transcripts alongside protein domains and export figures in a publication-ready format. This makes it a valuable tool for molecular evolution and comparative genomics.

Rye (Secale cereale genome RR), a close relative of common wheat, possesses valuable resistance genes for wheat improvement. Due to the co-evolution of pathogen virulence and host resistance, some resistance genes derived from rye have lost effectiveness. Development and identification of new, effective resistance genes from rye is thus required. In the current study, wheat-rye line WR56 was produced through distant hybridization, embryo rescue culture, chromosome doubling and backcrossing. WR56 was then proved to be a wheat-rye 2RL ditelosomic addition line using GISH (genomic in situ hybridization), mc-FISH (multicolor fluorescence in situ hybridization), ND-FISH (non-denaturing FISH), mc-GISH (multicolor GISH) and rye chromosome arm-specific marker analysis. WR56 exhibited a high level of adult plant resistance to powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt). This resistance was carried by the added 2RL telosomes and presumed to be different from Pm7 which is also located on chromosome arm 2RL but confers resistance at the seedling and adult stages. WR56 will be a promising bridging parent for transfer of the resistance to a more stable wheat breeding line. A newly developed 2RL-specific KASP (kompetitive allele specific PCR) marker should expedite that work.