Search

In this work, AFM1 was chosen as the target, and the aptamer was split to solve the low sensitivity due to unstable structure of the aptamer. The recognition ability and specificity of the split aptamer were evaluated using electrochemical methods, and the binding mechanism was explored through the circular dichroism. The results showed that the split aptamer employing a 1:1 split mode exhibited the best performance in the recognition and specificity for AFM1. The circular dichroism spectrum remained unchanged. The positive peak intensity of the circular dichroism spectrum increased significantly and the negative peak moved and the intensity increased, which demonstrated that the conformation of the aptamer changed. The sensitivity was enhanced by employing split aptamers. Superior recognition elements for the construction of sensors was obtained by the fragmentation of intact aptamers. The investigation provides a new idea to enhance the sensitivity of the detection mehtods based on the apatamer.

Abstract Land use and cover change (LUCC) significantly impacts global carbon cycles and land surface properties, accounting for 25% of the historical atmospheric CO2 increase. We explore a previously overlooked role of LUCC in driving the land carbon cycle by using a three-level meta-analysis and Land Use Harmonization data to drive an ecosystem model. Our findings reveal that a loss of 39.2% of soil organic carbon (SOC) change in China due to LUCC, mitigated by afforestation, doubles gross primary productivity at 0.02 Pg C yr−1, countering central China’s urbanization decline. Indirect climate effects, especially soil bulk density, significantly impact SOC compared to direct climate effects. LUCC has significantly increased the Chinese terrestrial carbon sink, with net ecosystem productivity reaching 0.02 ± 0.12 Pg C yr−1. Our study underscores the importance of reforestation and afforestation in addressing climate change and enhancing carbon sinks in future carbon management.

Lung cancer is a prevalent malignancy, with the rearrangement of the anaplastic lymphoma kinase (ALK) gene being responsible for a minority of cases of non-small cell lung cancer (NSCLC). NSCLC patients harboring ALK fusion proteins demonstrate sensitivity to ALK tyrosine kinase inhibitors (TKIs). In this report, we describe the case of a female patient with metastatic lung adenocarcinoma, identified through NGS to carry a rare inverted SQSTM1-ALK (S5, A20) fusion. The patient received ensartinib as first-line therapy, resulting in a partial response (PR). At the time of publication, the patient’s condition remained favorable. We have, for the first time, identified the presence of SQSTM1-ALK fusion in pericardial effusion, with the favorable response to ensartinib validating the oncogenic potential of SQSTM1-ALK fusion. The substantial advancements and extensive utilization of NGS have facilitated the identification of rare fusion variants.

Climate warming and human disturbance are supposed to have significantly impacted the alpine grasslands. However, it is still unclear how human activity affects the community composition and niche characteristics in response to warming. We conducted a two-factorial experiment in an alpine meadow, and set up four treatments: warming, mowing, warming with mowing, and control. Based on the investigation of community composition and niche characteristics, we evaluated the impacts of soil carbon, nitrogen, and phosphorus on species niche overlap. The results showed that mowing significantly increased species richness of Grass, Sedge, Forbs and the importance value of Sedge compared to warming (P < 0.05). The niche breadth of species (>50 %) was reduced by warming, but increased under mowing. The niche overlap mainly occurred between Grass and Forbs in warming, while it was evenly distributed among species after mowing, which alleviated the negative effects of warming on interspecific competitiveness. Warming increased the number of species pairs with a niche overlap value >0.9 by 24.15 %, while warming with mowing decreased it by 2.7 %. The number of species pairs with niche overlap was significantly correlated with soil total nitrogen and soil available nitrogen (P < 0.05). In particular, the species pairs with highly competitive showed a greater dependency on soil nitrogen. Our work highlights that moderate utilization and soil nitrogen are two crucial factors influencing the response of community structure in alpine meadows to future climate change. The study provides an important reference for predicting and addressing the impact of global climate change on adaptive management and grassland protection.

Summary: In this study, we present an approach to neuropharmacological research by integrating few-shot meta-learning algorithms with brain activity mapping (BAMing) to enhance the discovery of central nervous system (CNS) therapeutics. By utilizing patterns from previously validated CNS drugs, our approach facilitates the rapid identification and prediction of potential drug candidates from limited datasets, thereby accelerating the drug discovery process. The application of few-shot meta-learning algorithms allows us to adeptly navigate the challenges of limited sample sizes prevalent in neuropharmacology. The study reveals that our meta-learning-based convolutional neural network (Meta-CNN) models demonstrate enhanced stability and improved prediction accuracy over traditional machine-learning methods. Moreover, our BAM library proves instrumental in classifying CNS drugs and aiding in pharmaceutical repurposing and repositioning. Overall, this research not only demonstrates the effectiveness in overcoming data limitations but also highlights the significant potential of combining BAM with advanced meta-learning techniques in CNS drug discovery.

Seedling is a crucial stage in the growth and development of plants, and the expansion and persistence of plant populations can be achieved through seed regeneration. Sheep grazing, fertilization, light, soil moisture, vegetation diversity and biomass, and litter all have potential impacts on species regeneration. We measured vegetation diversity, annual net primary productivity (ANPP), litter, ground photosynthetically active radiation (PAR), and soil moisture of alpine meadows under sheep grazing and nitrogen addition treatments, and studied their effects on the dicotyledonous seedling abundance and diversity using linear regression models (LMs) and structural equation models (SEMs). We found that sheep grazing reduced ANPP, increased vegetation diversity and PAR, and decreased soil moisture. Fertilization increased ANPP and litter, decreased vegetation diversity and PAR, but had no effect on soil moisture. Sheep grazing and fertilization both reduced the abundance of dicotyledonous seedlings, and simultaneously fertilization can reduce the diversity of dicotyledonous seedlings, while sheep grazing had no effect on the diversity of dicotyledonous seedlings. LMs showed that vegetation diversity, ANPP, and litter, rather than light and soil moisture, affected dicotyledonous seedling abundance and diversity. SEMs revealed that sheep grazing and fertilization indirectly influenced seedling regeneration through vegetation diversity rather than ANPP and litter. Our research will increase our understanding of the dicotyledonous plant regeneration process in alpine grasslands and facilitate the development of strategies for management and protection of alpine grassland.

Abstract The purpose of this study was to explore the diagnostic implications of ubiquitination-related gene signatures in Alzheimer's disease. In this study, we first collected 161 samples from the GEO database (including 87 in the AD group and 74 in the normal group). Subsequently, through differential expression analysis and the iUUCD 2.0 database, we obtained 3450 Differentially Expressed Genes (DEGs) and 806 Ubiquitin-related genes (UbRGs). After taking the intersection, we obtained 128 UbR-DEGs. Secondly, by conducting GO and KEGG enrichment analysis on these 128 UbR-DEGs, we identified the main molecular functions and biological pathways related to AD. Furthermore, through the utilization of GSEA analysis, we have gained insight into the enrichment of functions and pathways within both the AD and normal groups. Further, using lasso regression analysis and cross-validation techniques, we identified 22 characteristic genes associated with AD. Subsequently, we constructed a logistic regression model and optimized it, resulting in the identification of 6 RUbR-DEGs: KLHL21, WDR82, DTX3L, UBTD2, CISH, and ATXN3L. In addition, the ROC result showed that the diagnostic model we built has excellent accuracy and reliability in identifying AD patients. Finally, we constructed a lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) regulatory network for AD based on six RUbR-DEGs, further elucidating the interaction between UbRGs and lncRNA, miRNA. In conclusion, our findings will contribute to further understanding of the molecular pathogenesis of AD and provide a new perspective for AD risk prediction, early diagnosis and targeted therapy in the population.

ABSTRACT: A novel ratiometric electrochemical aptasensor based on split aptamer and Au-reduced graphene oxide (Au-rGO) nanomaterials was proposed to detect aflatoxin M1 (AFM1). In this work, Au-rGO nanomaterials were coated on the electrode through the electrodeposition method to increase the aptamer enrichment. We split the aptamer of AFM1 into 2 sequences (S1 and S2), where S1 was immobilized on the electrode due to the Au-S bond, and S2 was tagged with methylene blue (MB) and acted as a response signal. A complementary strand to S1 (CS1) labeled with ferrocene (Fc) was introduced as another reporter. In the presence of AFM1, CS1 was released from the electrode surface due to the formation of the S1-AFM1-S2 complex, leading to a decrease in Fc and an increase in the MB signal. The developed ratiometric aptasensor exhibited a linear range of 0.03 μg L−1 to 2.00 μg L−1, with a detection limit of 0.015 μg L−1 for AFM1 detection. The ratiometric aptasensor also showed a linear relationship from 0.2 μg L−1 to 1.00 μg L−1, with a detection limit of 0.05 μg L−1 in natural milk after sample pretreatment, indicating the successful application of the developed ratiometric aptasensor. Our proposed strategy provides a new way to construct aptasensors with high sensitivity and selectivity.

Abstract Background Experiences during childhood and adolescence have enduring impacts on physical and mental well-being, overall quality of life, and socioeconomic status throughout one’s lifetime. This underscores the importance of prioritizing the health of children and adolescents to establish an impactful healthcare system that benefits both individuals and society. It is crucial for healthcare providers and policymakers to examine the relationship between COVID-19 and the health of children and adolescents, as this understanding will guide the creation of interventions and policies for the long-term management of the virus. Methods In this umbrella review (PROSPERO ID: CRD42023401106), systematic reviews were identified from the Cochrane Database of Systematic Reviews; EMBASE (OvidSP); and MEDLINE (OvidSP) from December 2019 to February 2023. Pairwise and single-arm meta-analyses were extracted from the included systematic reviews. The methodological quality appraisal was completed using the AMSTAR-2 tool. Single-arm meta-analyses were re-presented under six domains associated with COVID-19 condition. Pairwise meta-analyses were classified into five domains according to the evidence classification criteria. Rosenberg’s FSN was calculated for both binary and continuous measures. Results We identified 1551 single-arm and 301 pairwise meta-analyses from 124 systematic reviews that met our predefined criteria for inclusion. The focus of the meta-analytical evidence was predominantly on the physical outcomes of COVID-19, encompassing both single-arm and pairwise study designs. However, the quality of evidence and methodological rigor were suboptimal. Based on the evidence gathered from single-arm meta-analyses, we constructed an illustrative representation of the disease severity, clinical manifestations, laboratory and radiological findings, treatments, and outcomes from 2020 to 2022. Additionally, we discovered 17 instances of strong or highly suggestive pairwise meta-analytical evidence concerning long-COVID, pediatric comorbidity, COVID-19 vaccines, mental health, and depression. Conclusions The findings of our study advocate for the implementation of surveillance systems to track health consequences associated with COVID-19 and the establishment of multidisciplinary collaborative rehabilitation programs for affected younger populations. In future research endeavors, it is important to prioritize the investigation of non-physical outcomes to bridge the gap between research findings and clinical application in this field.

Abstract The prevalence of dual usage and the relatively low cessation rate among e-cigarette (EC) users suggest that ECs have not demonstrated significant effectiveness as a smoking cessation tool. Furthermore, there has been a substantial increase in the prevalence of EC usage in recent years. Therefore, the objective of this study is to investigate the association between EC use and the incidence of respiratory symptoms and chronic obstructive pulmonary disease (COPD). A total of 10,326 participants aged between 20 and 55 years, without any respiratory diseases or COPD, were recruited for the study. These individuals attended employee physical examinations conducted at 16 public hospitals in Hebei province, China from 2015 to 2020. Logistic regression models were utilized to assess the association between EC use and the risk of respiratory symptoms and COPD using risk ratios along with their corresponding 95% confidence intervals. Restricted cubic spline functions were employed to investigate the dose–response non-linear relationship. The robustness of the logistic regression models was evaluated through subgroup analyses, and sensitivity analyses. During the 5-year follow-up period, a total of 1071 incident cases of respiratory symptoms and 146 incident cases of COPD were identified in this cohort study. After adjusting for relevant confounding factors, EC users demonstrated a respective increase in the risk of reporting respiratory symptoms and COPD by 28% and 8%. Furthermore, dual users who used both ECs and combustible cigarettes exhibited an elevated risk of incident respiratory symptoms and COPD by 41% and 18%, respectively, compared to those who had never used non-users of any cigarette products. The association between daily EC consumption and the development of respiratory symptoms, as well as COPD, demonstrated a significant J-shaped pattern. The potential adverse association between the consumption of ECs, particularly when used in combination with combustible cigarettes, and the development of respiratory symptoms and COPD necessitates careful consideration. Policymakers should approach ECs cautiously as a prospective smoking cessation tool.

Abstract Protein function annotation has been one of the longstanding issues in biological sciences, and various computational methods have been developed. However, the existing methods suffer from a serious long-tail problem, with a large number of GO families containing few annotated proteins. Herein, an innovative strategy named AnnoPRO was therefore constructed by enabling sequence-based multi-scale protein representation, dual-path protein encoding using pre-training, and function annotation by long short-term memory-based decoding. A variety of case studies based on different benchmarks were conducted, which confirmed the superior performance of AnnoPRO among available methods. Source code and models have been made freely available at: https://github.com/idrblab/AnnoPRO and https://zenodo.org/records/10012272

Abstract Pancreatic cancer (PC) has become a worldwide challenge attributed to its difficult early diagnosis and rapid progression. Treatments continue to be limited besides surgical resection. Hence, we aimed to discover novel biological signatures as clinically effective therapeutic targets for PC via the mining of public tumor databases. We found that epiphycan (EPYC) could function as an independent risk factor to predict the poor prognosis in PC based on integrated bioinformatics analysis. We downloaded associated PC data profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) online websites, then applied the software Rstudio to filter out genes under the strict criteria. After the batch survival analysis using Log-rank test and univariate cox regression, we obtained 39 candidate genes. Subsequently, we narrowed the scope to 8 genes by establishing a Lasso regression model. Eventually, we focused on 2 genes (EPYC and MET) by further building a multivariate cox regression model. Given that the role of EPYC in PC remains obscure, we then performed a series of molecular functional experiments, including RT-qPCR, CCK8, EdU, colony formation, Transwell, western blot, cell live-dead staining, subcutaneous tumor formation, to enhance our insight into its underlying molecular mechanisms. The above results demonstrated that EPYC was highly expressed in PC cell lines and could promote the proliferation of PCs via PI3K-AKT signaling pathway in vivo and in vitro. We arrived at a conclusion that EPYC was expected to be a biological neo-biomarker for PC followed by being a potential therapeutic target.

BackgroundThe majority of patients of lung cancer have already lost the chance of surgery at the time of diagnosis. Percutaneous local thermal ablation is a precise minimally invasive technique and a viable alternative to surgical treatment. Compared with radiofrequency ablation and microwave ablation, percutaneous laser ablation for the treatment of lung tumors is less commonly used and reported, especially for primary lung cancer.Case presentationA 63-year-old male patient with mixed pulmonary nodules selected computed tomography-guided electromagnetic navigation system for percutaneous biopsy and laser ablation therapy. The puncture point was determined through Computed tomography scanning, along with the placement of the electromagnetic navigation system locators. After rapid on-site evaluation and pathological examination of the puncture tissue specimen, the diagnosis of lung adenocarcinoma was confirmed. A 980-nanometer wavelength semiconductor laser fiber was inserted into the appropriate position guided by the electromagnetic navigation system. Subsequently, a power of 7 watt was applied to ablate the tumor for 30 seconds, then pause for 60 seconds before repeating the procedure. Positron emission tomography-Computed tomography examination was performed 1 month after operation, suggesting complete response of the tumor.ConclusionHere, we present a case of percutaneous laser ablation treatment for primary lung cancer guided by computed tomography-electromagnetic navigation system. As a more precise, shorter duration, impedance-independent, safe and effective minimally invasive thermal ablation method, it is expected to gain wider application and become a novel alternative for surgical treatment.

Abstract Background Huazhuo Tiaozhi granule (HTG) is a herbal medicine formula widely used in clinical practice for hypolipidaemic effects. However, the molecular mechanisms underlying dyslipidaemia treatment have not been well elucidated. Results A significant reduction in the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) was observed in the serum of patients with dyslipidaemia after HTG treatment, without disruption in the levels of aspartate transaminase (AST), alanine transaminase (ALT), urea nitrogen (BUN), and creatinine (Cr). The dyslipidaemia rat model was induced by a high-fat diet and treated with Xuezhikang (0.14 g/kg/d) or HTG (9.33 g crude herb/kg/day) by gavage for 8 weeks. Body weight and liver index were markedly decreased in dyslipidaemic rats after treatment with Xuezhikang or HTG. HTG administration markedly ameliorated hyperlipidaemia by decreasing the levels of TC and LDL-C in serum and hepatic lipid accumulation. In vitro, lipid accumulation in LO2 and HepG2 cells was alleviated by serum treatment with HTG. High lactylation was observed in 198 proteins, including lactylation of histone H2B (K6), H4 (K80). Deep sequencing of microRNAs showed that miR-155-5p was significantly downregulated. Conclusions This study demonstrates that HTG is an effective and safe formula for treating dyslipidaemia, which promotes lactylation in hepatocytes, and the retardation of miR-155-5p biogenesis. Graphical abstract

To construct a stable and structurally controllable optical-magnetic composite nanomaterials and use it in the detection of pesticide residues, the upconversion nanomaterials (UCNPs) were prepared by the high temperature solvothermal method in this work. The effects of temperature and rotational speed on UCNPs were investigated to achieve controllable preparation of UCNPs. Three kinds of multifunctional optic-magnetic composite nanomaterials with different structures were prepared by reversed-phase microemulsion method. Scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffractometer (XRD), vibrating sample magnetometer (VSM) etc. were utilized to investigate the morphology, structure etc. of multifunctional composites. Furthermore, the response of multifunctional optic-magnetic composite nanomaterials to various pesticides in citrus was studied. The experimental results showed that temperature played a decisive role in the size of UCNPs. In different structures of UCNPs-Fe3O4 composites, the stronger fluorescence of A-structure (the satellite structure of UCNPs material with larger particle size) was obtained. B-structure (an interweave structure with similar particle sizes of UCNPs and Fe3O4) had a saturation magnetization of 20.5 emu·g−1 and high fluorescence intensity. C-structure (a satellite structure with larger particle size of Fe3O4 material) had best magnetic properties. Meanwhile, the multifunctional optic-magnetic composites had a certain response to pyrethroid pesticide, nicotine pesticide, carbamate pesticide and organophosphorus pesticide in citrus. Due to the strongest response to pyrethroid pesticide, they could be developed for the biosensor of pyrethroid pesticide. In this work, a simple and universal synthesis method was proposed to provide theoretical ideas for the synthesis of other composite materials. This material had a great application potential in drug delivery, imaging and other fields due to their good optic-magnetic properties and biocompatibility.

Traditional optical communication systems rely on single narrow-band PDs, which can expose confidential information and data to potential eavesdropping in free space. With advancements in technology, even optical communication in the UV spectrum, invisible to the sun, faces risks of interception. Consequently, broad-band PDs that combine optical encryption with algorithmic encryption hold significant promise for secure and reliable communication. This study presents a photodetector based on TiO2–α-Ga2O3 heterostructures, prepared via direct oxidation and hydrothermal reaction, demonstrating self-powered UVC/UVA broad-band detection capabilities. The PD exhibits response peaks at approximately 250 and 320 nm, with R of 42.16 and 59.88 mA/W and D* of 8.21 × 1013 and 9.56 × 1013 Jones, respectively. Leveraging the superior optical response characteristics of UVC and UVA wavelengths, this device has been employed to develop a communication system designed for data transmission. The proposed system features two independent channels: one for data transmission using UVC and another for key distribution using UVA. Secure communication is ensured through specialized encryption algorithms. In summary, this work offers a straightforward, cost-effective, and practical method for fabricating self-powered UVC/UVA broad-band PDs. This PD provides new insights into the development of multi-purpose, multi-band secure optical communication devices and holds promise for integration into multifunctional optoelectronic systems in the future.

Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market. However, investments in a new drug often go unrewarded due to the long and complex process of drug research and development (R&D). With the advancement of experimental technology and computer hardware, artificial intelligence (AI) has recently emerged as a leading tool in analyzing abundant and high-dimensional data. Explosive growth in the size of biomedical data provides advantages in applying AI in all stages of drug R&D. Driven by big data in biomedicine, AI has led to a revolution in drug R&D, due to its ability to discover new drugs more efficiently and at lower cost. This review begins with a brief overview of common AI models in the field of drug discovery; then, it summarizes and discusses in depth their specific applications in various stages of drug R&D, such as target discovery, drug discovery and design, preclinical research, automated drug synthesis, and influences in the pharmaceutical market. Finally, the major limitations of AI in drug R&D are fully discussed and possible solutions are proposed.

Abstract Interest in macrocycles as potential therapeutic agents has increased rapidly. Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds, which can contribute to the improvement of the biological activity and physicochemical properties of these molecules. In this study, we propose a computational macrocyclization method based on Transformer architecture (which we name Macformer). Leveraging deep learning, Macformer explores the vast chemical space of macrocyclic analogues of a given acyclic molecule by adding diverse linkers compatible with the acyclic molecule. Macformer can efficiently learn the implicit relationships between acyclic and macrocyclic structures represented as SMILES strings and generate plenty of macrocycles with chemical diversity and structural novelty. In data augmentation scenarios using both internal ChEMBL and external ZINC test datasets, Macformer display excellent performance and generalisability. We showcase the utility of Macformer when combined with molecular docking simulations and wet lab based experimental validation, by applying it to the prospective design of macrocyclic JAK2 inhibitors.

Background/purpose: Fibrosis is present in various physiologic and pathologic conditions of salivary glands (SGs). This study aimed to identify novel biomarkers of SG fibrosis by next-generation sequencing. Materials and methods: We established the SG fibrosis mouse model by excretory main duct ligation. Next-generation sequencing, differentially expressed gene (DEG) analysis, and gene set enrichment analysis was performed by comparing ligated and control SGs. We used algorithms of Cytohubba, molecular complex detection, Lasso logistic regression, and support vector machine to identify the key biomarkers. Selected key biomarkers were verified by the polymerase chain reaction and immunohistochemistry. We also retrieved and analyzed the key gene expression in the fibrosis of the heart, liver, lung, and kidney to ensure the generalization of key biomarkers in SG fibrosis. Results: Both interlobular and intralobular fibrosis was confirmed in the ligated SGs, with improved expressions of collagen I and transforming growth factor β. Next-generation sequencing identified 2666 upregulated DEGs and 336 downregulated DEGs, which were highly enriched in the extracellular matrix-related pathways. Multiple algorithms identified 15 key biomarkers in SG fibrosis, including Thrombospondin-1 (THBS1) and Prolyl 4-Hydroxylase Subunit Alpha 3 (P4HA3). The mRNA and protein expression of THBS1 and P4HA3 was verified in mice. THBS1 was also highly expressed in lung and kidney fibrosis, whereas P4HA3 was upregulated in liver fibrosis. Conclusion: THBS1 and P4HA3 may be potential biomarkers for SG fibrosis. They may be also applicable in the diagnosis of multi-organ fibrosis.

Abstract In recent years, an increasing number of passive radiative cooling materials are proposed in the literature, with several examples relying on the use of silica (SiO2) due to its unique stability, non‐toxicity, and availability. Nonetheless, due to its bulk phonon‐polariton band, SiO2 presents a marked reflection peak within the atmospheric transparency window (8‐13 µm), leading to an emissivity decrease that poses a challenge to fulfilling the criteria for sub‐ambient passive radiative cooling. Thus, the latest developments in this field are devoted to the design of engineered SiO2 photonic structures, to increase the cooling potential of bulk SiO2 radiative coolers. This review seeks to identify the most effective photonic design and fabrication strategies for SiO2 radiative emitters by evaluating their cooling efficacy, as well as their scalability, providing an in‐depth analysis of the fundamental principles, structural models, and results (both numerical and experimental) of various types of SiO2 radiative coolers.

Abstract Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.

Abstract Background Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease. Methods Hepatocyte-specific Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were used to study their role in liver injury. Fatty liver disease and liver cancer were induced by high-fat diet (HFD) and diethylnitrosamine (DEN) administration, respectively. iTRAQ analysis was employed to screen for downstream targets affected by Ufbp1 deletion. Co-immunoprecipitation was used to determine the interactions between the Ufl1/Ufbp1 complex and the mTOR/GβL complex. Results Ufl1 Δ/Δhep or Ufbp1 Δ/Δhep mice exhibited hepatocyte apoptosis and mild steatosis at 2 months of age and hepatocellular ballooning, extensive fibrosis, and steatohepatitis at 6–8 months of age. More than 50% of Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates oncogenic mTOR signaling to drive HCC development. Conclusions These findings reveal the potential role of Ufl1 and Ufbp1 as gatekeepers to prevent liver fibrosis and subsequent steatohepatitis and HCC development by inhibiting the mTOR pathway.

Abstract Background Although molecular targets such as HER2, TP53 and PIK3CA have been widely studied in esophageal cancer, few of them were successfully applied for clinical treatment. Therefore, it is urgent to discover novel actionable targets and inhibitors. Eukaryotic translational elongation factor 2 (eEF2) is reported to be highly expressed in various cancers. However, its contribution to the maintenance and progression of cancer has not been fully clarified. Methods In the present study, we utilized tissue array to evaluate eEF2 protein expression and clinical significance in esophageal squamous cell carcinoma (ESCC). Next, we performed knockdown, overexpression, RNA-binding protein immunoprecipitation (RIP) sequence, and nascent protein synthesis assays to explore the molecular function of eEF2. Furthermore, we utilized compound screening, Surface Plasmon Resonance (SPR), Isothermal Titration Calorimetry (ITC) assay, cell proliferation and Patient derived xenograft (PDX) mouse model assays to discover an eEF2 inhibitor and assess its effects on ESCC growth. Results We found that eEF2 were highly expressed in ESCC and negatively associated with the prognosis of ESCC patients. Knocking down of eEF2 suppressed the cell proliferation and colony formation of ESCC. eEF2 bond with the mRNA of Topoisomerase II (TOP1) and Topoisomerase II (TOP2) and enhanced the protein biosynthesis of TOP1 and TOP2. We also identified Toosendanin was a novel inhibitor of eEF2 and Toosendanin inhibited the growth of ESCC in vitro and in vivo. Conclusions Our findings show that Toosendanin treatment suppresses ESCC growth through targeting eEF2 and regulating downstream TOP1 and TOP2 biosynthesis. eEF2 could be supplied as a potential therapeutic target in the further clinical studies.

Background/purpose: Analysis of endoplasmic reticulum stress (ERS)-related long noncoding RNAs (LncRNAs) may enable prognostic stratification in patients with head and neck squamous cell carcinoma (HNSCC). This study aimed to comprehensively analyze the ERS-related LncRNAs signature and its effects on the prognosis, tumorigenesis, and tumor immune microenvironment in HNSCC. Materials and methods: The transcriptome data of HNSCC were obtained from TCGA. Least absolute shrinkage selection operator algorithm, and multivariate Cox regression were used to screen LncRNAs for the signature construction. Somatic mutation, gene enrichment, and immune infiltration analyses were further performed. Results: 458 ERS-related LncRNAs were identified and 55 of which were correlated with HNSCC prognosis. Ten ERS-related LncRNAs were selected to establish a risk prediction signature. When dividing patients into high-risk and low-risk groups by signature score, high-risk group correlated with worse survival rates (hazard ratio = 1.211; 95% confidence interval 1.123–1.306, P

Background/purpose: Chronic obstructive sialadenitis (COS) is a condition that severely reduced patients’ quality of life. This study aimed to analyze the effects of SIS3, a specific inhibitor of small mothers against decapentaplegic 3 (SMAD3), on the submandibular gland (SMG) dysfunction, fibrosis, and inflammation. Materials and methods: The dominant duct in the SMG was ligated in mice, followed by intraperitoneal injection of SIS3 (2 mg/kg/day) or Dimethyl sulfoxide (DMSO) saline for 7 days. In the sham group, this duct was surgically identified but not ligated. Saliva flow, histological structure, fibrosis, Transforming growth factor-β1 (TGF-β)/SMAD3 signaling, and inflammatory cytokines, were analyzed. Results: SIS3 rescued ligation-induced SMG dysfunction and improved the saliva flow rate compared to DMSO. SIS3 alleviated acinar atrophy and ductal dilation and maintained the morphology of the basal membrane. SIS3 reduces interlobular and intralobular fibrosis and collagen deposition. We observed reduced SMAD3 phosphorylation and TGF-β expression. The SIS3 group showed downregulation of np_5318 and miR-21 and upregulation of miR-29 b compared to the DMSO group. Moreover, SIS3 controlled the inflammatory cytokine release, including interleukin-6 and interleukin-1β. Conclusion: SIS3 protected duct-ligated SMGs against fibrosis and dysfunction by inhibiting the TGF-β/SMAD3 signaling and inflammatory cytokine expression. SIS3 may serve as a promising treatment for chronic obstructive sialadenitis.

Background: The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear.Methods: Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1-phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer risk mediated by sphingolipid metabolism were calculated.Results:APOB inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70–0.92, p = 0.010), LDL (OR 0.82, 95% CI 0.71–0.96, p = 0.040), and TG (OR 0.63, 95% CI 0.46–0.83, p = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56–0.90, p = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. APOC3 inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43–0.84, p = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17–4.09, p = 0.029) via ApoB reduction by 1 SD. HMGCR inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38–6.70, p = 0.014). The LPL agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07–0.58, p = 0.012) and TG reduction (OR 0.58, 95% CI 0.43–0.77, p = 0.003) while increased the plasma S1P level. PCSK9 inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by APOB inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by APOC3 inhibition.Conclusion: We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of APOB, APOC3, and HMGCR inhibition and LPL agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by APOB and APOC3 inhibition.

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL.

IntroductionCancer is a major global health concern, and immune checkpoint inhibitors (ICIs) offer a promising treatment option for cancer patients. However, the efficacy of ICIs can be influenced by various factors, including the use of concomitant medications.MethodsWe searched databases (PubMed, Embase, Cochrane Library, Web of Science) for systematic reviews and meta-analyses for systematic reviews and meta-analyses on the impact of concomitant medications on ICIs efficacy, published from inception to January 1, 2023. We evaluated the methodological quality of the included meta-analyses, and re-synthesized data using a random-effects model and evidence stratification.ResultsWe included 23 publications, comprising 11 concomitant medications and 112 associations. Class II-IV evidence suggested that antibiotics have a negative impact on ICIs efficacy. However, ICIs efficacy against melanoma, hepatocellular carcinoma, and esophageal squamous cell carcinoma was not affected, this effect was related to the exposure window (class IV). Class III evidence suggested that proton pump inhibitors have a negative impact on ICIs efficacy; nevertheless, the efficacy against melanoma and renal cell carcinoma was not affected, and the effect was related to exposure before the initiation of ICIs therapy (class II). Although class II/III evidence suggested that steroids have a negative impact, this effect was not observed when used for non-cancer indications and immune-related adverse events (class IV). Class IV evidence suggested that opioids reduce ICIs efficacy, whereas statins and probiotics may improve ICIs efficacy. ICIs efficacy was not affected by histamine 2 receptor antagonists, aspirin, metformin, β-blockers, and nonsteroidal anti-inflammatory agents.ConclusionCurrent evidence suggests that the use of antibiotics, PPIs, steroids, and opioids has a negative impact on the efficacy of ICIs. However, this effect may vary depending on the type of tumor, the timing of exposure, and the intended application. Weak evidence suggests that statins and probiotics may enhance the efficacy of ICIs. Aspirin, metformin, β-blockers, and NSAIDs do not appear to affect the efficacy of ICIs. However, caution is advised in interpreting these results due to methodological limitations.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO,identifier, CRD42022328681.

Abstract Deep learning (DL) and machine learning contribute significantly to basic biology research and drug discovery in the past few decades. Recent advances in DL-based generative models have led to superior developments in de novo drug design. However, data availability, deep data processing, and the lack of user-friendly DL tools and interfaces make it difficult to apply these DL techniques to drug design. We hereby present ReMODE (Receptor-based MOlecular DEsign), a new web server based on DL algorithm for target-specific ligand design, which integrates different functional modules to enable users to develop customizable drug design tasks. As designed, the ReMODE sever can construct the target-specific tasks toward the protein targets selected by users. Meanwhile, the server also provides some extensions: users can optimize the drug-likeness or synthetic accessibility of the generated molecules, and control other physicochemical properties; users can also choose a sub-structure/scaffold as a starting point for fragment-based drug design. The ReMODE server also enables users to optimize the pharmacophore matching and docking conformations of the generated molecules. We believe that the ReMODE server will benefit researchers for drug discovery. ReMODE is publicly available at http://cadd.zju.edu.cn/relation/remode/ . Graphical Abstract

To intervene and control the toxic effects of the hazard factors using nature products is one of the research hotspots recently in the field of food safety. Curcumin, as a hydrophobic polyphenolic compound extracted from the traditional spice turmeric, has strong anti-inflammatory, anti-oxidation, anti-cancer, enhancing immunity and other activities. Recent studies have shown that curcumin can intervene some toxicities induced by mycotoxins such as Aflatoxin B1, Ochratoxin A, Zearalenone, Fumonisin B1 and Deoxynivalenol, thereby reducing damages and enhancing resistance in body. In this paper, the toxicities of main mycotoxins were briefly summarized at first. And then, the intervention effects and its related mechanism of curcumin on the mycotoxin-induced toxicities in the latest five years were emphatically elaborated, mainly from the aspects of reducing ROS production and lipid peroxidation, regulating related pathways and improving intestinal flora. Finally, the potential problems that to be urgently solved are discussed. Our review aimed at providing the theoretical bases for the in-depth development and utilization of curcumin in the health industry as well as to broaden the ideas for the research and development of other plant-derived functional components.

Background: Metastasis, a leading cause of cancer-related deaths, involves complex mechanisms. The premetastatic niche (PMN) is a crucial contributor to this process. Myeloid-derived suppressor cells (MDSCs) play an important role in PMN formation and promote tumor progression and metastasis. The Xiaoliu Pingyi recipe (XLPYR), a traditional Chinese medicine, is effective in preventing postoperative recurrence and metastasis in cancer patients. Objective: This study investigated the effects of XLPYR on MDSCs recruitment and on the expression of PMN markers and elucidated the mechanisms involved in the prevention of tumor metastasis. Methods: C57BL/6 mice were subcutaneously injected with Lewis cells and treated with cisplatin and XLPYR. Tumors were resected after 14 days after the establishment of a model of lung metastasis, and tumor volume and weight were measured. Lung metastases were observed 21 days after resection. MDSCs in the lung, spleen, and peripheral blood were detected by flow cytometry. Western blotting, qRT-PCR and ELISA were used to detect the expression of S100A8, S100A9, MMP9, LOX, and IL-6/STAT3 in premetastatic lung tissue. Results: XLPYR treatment inhibited tumor growth and prevented lung metastasis. Compared to mice without subcutaneous tumor cell transplantation, the model group had an increased proportion of MDSCs, higher expression of S100A8, S100A9, MMP9, and LOX in the premetastatic lung. XLPYR treatment reduced the proportion of MDSCs, S100A8, S100A9, MMP9, and LOX expression, and downregulated the IL-6/STAT3 pathway. Conclusions XLPYR may prevent MDSCs recruitment and reduce the expression of S100A8, MMP9, LOX, and IL6/STAT3 in premetastatic lung tissue, thus reducing lung metastases.

Seeds are one of the most important characteristics of plant evolution. Within a seed, the embryo, which will grow into a plant, can survive harsh environments. When the seeds are mature, the mother plant will disperse them from its body, allowing them to be taken away to grow in a new place. Otherwise, if the young generation grows alongside the mother plants in the same place, they will compete for sunlight and nutrition. The mother plants use different strategies to send away their seeds. One of these strategies is endozoochory, which means that the seeds disperse via ingestion by animals. There is a conflict between the seeds’ abilities to attract animals and protect the embryo within the digestion systems of animals. Magnolia seeds exhibit typical endozoochory. The seed coats of Magnolia feature sarcotestas and sclerotestas. The sarcotesta, which is fleshy, bright-colored, and edible, attracts animals. The sclerotesta is hard and woody, protecting the embryo from the digestive systems of animals. In this study, we used scanning electron and light microscopes to examine the development of the sarcotesta and sclerotesta of Magnolia stellata seed coats. The results showed that the sarcotesta and sclerotesta come from the outer integument. This result confirms the hypothesis of Asa Gray from 1848. The dependence of the seed dispersal strategy on structural development is discussed.

The accurate prediction of binding free energy is a major challenge in structure-based drug design. Quantum mechanics (QM)-based approaches show promising potential in predicting ligand–protein binding affinity by accurately describing the behavior and structure of electrons. However, traditional QM calculations face computational limitations, hindering their practical application in drug design. Nevertheless, the fragment molecular orbital (FMO) method has gained widespread application in drug design due to its ability to reduce computational costs and achieve efficient ab initio QM calculations. Although the FMO method has demonstrated its reliability in calculating the gas phase potential energy, the binding of proteins and ligands also involves other contributing energy terms, such as solvent effects, the ‘deformation energy’ of a ligand’s bioactive conformations, and entropy. Particularly in cases involving ionized fragments, the calculation of solvation free energy becomes particularly crucial. We conducted an evaluation of some previously reported implicit solvent methods on the same data set to assess their potential for improving the performance of the FMO method. Herein, we develop a new QM-based binding free energy calculation method called FMOScore, which enhances the performance of the FMO method. The FMOScore method incorporates linear fitting of various terms, including gas-phase potential energy, deformation energy, and solvation free energy. Compared to other widely used traditional prediction methods such as FEP+, MM/PBSA, MM/GBSA, and Autodock vina, FMOScore showed good performance in prediction accuracies. By constructing a retrospective case study, it was observed that incorporating calculations for solvation free energy and deformation energy can further enhance the precision of FMO predictions for binding affinity. Furthermore, using FMOScore-guided lead optimization against Src homology-2-containing protein tyrosine phosphatase 2 (SHP-2), we discovered a novel and potent allosteric SHP-2 inhibitor (compound 8).

With the improvement of the exploration degree, small complex fault block traps have become the key field of oil and gas exploration in the current uplift area. To clarify the reasons for the differential enrichment of oil and gas in the fault block trap in the West Liaoning uplift, the characteristics of weathering crust on the top of the buried hill in the uplift slope area are analysed by using three-dimensional seismic, logging, thin section and other data through three-dimensional streamline quantitative simulation. The "crust-fault" coupling migration model is established to describe the dominant migration path of oil and gas in the slope area to clarify the control effect of hydrocarbon migration along weathered crust on the differential enrichment of oil and gas in the convex fault block. The results show that ① the buried hill in the study area has experienced multistage tectonic movements, and the lithology of the buried hill is mainly lower Paleozoic carbonate rock and Archean granite. The lithology is brittle and easily weathered and denuded. The denudation pores and structural fractures of the weathering crust are widely developed and stably distributed, forming the main channel of lateral long-distance migration of oil and gas in the slope area. ② The middle zone of the slope is controlled by reverse faults to forma fault uplift structure. The migration of oil and gas along the weathering crust is blocked by the slope fault uplift zone, forming a "crust-fault" coupling oil and gas migration model. The fault throw of the fault uplift zone controls the lateral migration ability of oil and gas in the weathering crust. ③ Using the method of three-dimensional streamline quantitative simulation, the four-level dominant oil and gas migration channels in the study area are characterized, and the control effect of different levels of oil and gas migration channels on the degree of oil and gas enrichment in convex fault blocks is clarified. The research results effectively guide the practice of oil and gas exploration in the Liaoxi Uplift and fill the gap of the understanding and research method of oil and gas accumulation in mature uplift areas of oil-rich sags.

Abstract Optical chemical structure recognition from scientific publications is essential for rediscovering a chemical structure. It is an extremely challenging problem, and current rule-based and deep-learning methods cannot achieve satisfactory recognition rates. Herein, we propose SwinOCSR, an end-to-end model based on a Swin Transformer. This model uses the Swin Transformer as the backbone to extract image features and introduces Transformer models to convert chemical information from publications into DeepSMILES. A novel chemical structure dataset was constructed to train and verify our method. Our proposed Swin Transformer-based model was extensively tested against the backbone of existing publicly available deep learning methods. The experimental results show that our model significantly outperforms the compared methods, demonstrating the model’s effectiveness. Moreover, we used a focal loss to address the token imbalance problem in the text representation of the chemical structure diagram, and our model achieved an accuracy of 98.58%.

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, the 5-year survival rate of patients with HNSCC is still about 50% due to frequent metastasis and recurrence. Circular RNAs (circRNAs) have been characterized as key regulators of gene expression in numerous malignancies. However, the role of circRNA in HNSCC metastasis remains largely unknown. Here, we demonstrated that the circRFWD3 was significantly upregulated in HNSCC tissues and cell lines by circRNA microarray analysis and qPCR. Notably, high expression of circRFWD3 is related to highly aggressive HNSCC cell lines and lymph node metastasis in HNSCC patients. After that, Sanger sequencing, RNase R, and actinomycin D assay were performed to verify the ring structure of circRFWD3. Then functional experiments found it could promote the metastasis of HNSCC cells both in vitro and in vivo. Mechanistically, a dual-luciferase reporter assay, FISH, RIP, RNA pull-down, RNA-seq, and western blot experiments were employed and found that circRFWD3 served as a miRNAs sponge for miR-27a/27b, leading to the upregulation of PPARγ, and then promoted HNSCC metastasis via NF-κB/MMP13 pathway. Finally, ISH and IHC were carried out to determine the expression levels and clinical significances of circRFWD3 and PPARγ in clinical cohorts of HNSCC. According to the analysis results from two independent HNSCC cohorts, upregulated expression of circRFWD3 and PPARγ were positively associated with worse survival in patients with HNSCC. Overall, our results uncover that circRFWD3 acts a critical role in promoting the aggressiveness of HNSCC cells and is a prognostic marker for the disease, indicating that circRFWD3 may act as a potential therapeutic target in HNSCC.

Introduction The prevalence of traumatic brain injury (TBI) among older adults is increasing exponentially. The sequelae can be severe in older adults and interact with age-related conditions such as multimorbidity. Despite this, TBI research in older adults is sparse. Minder, an in-home monitoring system developed by the UK Dementia Research Institute Centre for Care Research and Technology, uses infrared sensors and a bed mat to passively collect sleep and activity data. Similar systems have been used to monitor the health of older adults living with dementia. We will assess the feasibility of using this system to study changes in the health status of older adults in the early period post-TBI.Methods and analysis The study will recruit 15 inpatients (>60 years) with a moderate-severe TBI, who will have their daily activity and sleep patterns monitored using passive and wearable sensors over 6 months. Participants will report on their health during weekly calls, which will be used to validate sensor data. Physical, functional and cognitive assessments will be conducted across the duration of the study. Activity levels and sleep patterns derived from sensor data will be calculated and visualised using activity maps. Within-participant analysis will be performed to determine if participants are deviating from their own routines. We will apply machine learning approaches to activity and sleep data to assess whether the changes in these data can predict clinical events. Qualitative analysis of interviews conducted with participants, carers and clinical staff will assess acceptability and utility of the system.Ethics and dissemination Ethical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (REC) (REC number: 17/LO/2066). Results will be submitted for publication in peer-reviewed journals, presented at conferences and inform the design of a larger trial assessing recovery after TBI.

Background There is commonly a discrepancy between conference abstracts and published article abstracts in prosthodontic randomized controlled trials (RCTs), which may mislead the scholars those attend conferences. Objective To identify the characteristics predicting inconsistency between conference abstracts and published article abstracts in prosthodontic RCTs. Methods The conference abstracts of prosthodontic RCTs presented at the IADR general sessions from 2002 to 2015 were searched. Electronic searches of MEDLINE, EMBASE, the Cochrane Library, and Google Scholar databases were conducted to match full-text publications for conference abstracts. Two investigators extracted basic characteristics and assessed the consistency and reporting quality independently and in duplicate. The linear regression model was used to analyze the predictors of inconsistency. Results A total of 147 conference abstracts were matched with published articles. Results for the secondary outcome measure, Statistical analysis, and precision measure were less than 50% consistent, and even nearly 5% of the studies had opposite conclusions. Multiple linear regression analysis showed that three factors were correlated with lower inconsistency, including continent of origin (p = 0.011), presentation type (p = 0.017), and difference in reporting quality (p = 0.013). Conclusion Conference attendees should cautiously treat the findings of the conference abstracts. Researchers should improve the precision of the information delivered at conferences. We recommend the authors of RCTs to explain the primary difference between conference abstracts and article abstracts.

Abstract Hydrothermal activity on mid‐ocean ridges plays an important role in shaping marine chemistry, yet the variability of hydrothermal venting and its forcing mechanism remain elusive. Here, we analyzed a sediment core obtained near the tectonic‐controlled Tianxiu vent field, Carlsberg Ridge, to reconstruct the hydrothermal venting history. The core documented two significant hydrothermal events (H1 and H2) in the past 30 ka. H1 occurred at 24.1–24.5 ka during the Last Glacial Maximum (LGM), while H2 occurred at 10.5–11.6 ka during the deglacial period. Compared to H2, H1 was relatively weak, and it occurred concurrently with a tectonic event. We suggest that H2 was caused by the increased melt production associated with the decompression melting of the upper mantle during sea‐level fall, which is consistent with previously published records, whereas H1 was likely triggered by an intense tectonic event associated with depressurization during the LGM, which was previously unrecognized.

Abstract Epidemiological evidence of the effect of high-level air pollution and its interaction with meteorological factors on the risk of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is limited. Daily data on AECOPD cases, air pollutants and meteorological factors were collected from 2015 to 2018 in Shijiazhuang. A distributed lag non-linear model (DLNM) was used to explore the lag and cumulative effect of PM2.5 on the risk of AECOPD. The effect of the interaction between PM2.5 and meteorological factors on AECOPD was estimated by a generalized additive model (GAM) and a stratification model. A total of 4766 patients with AECOPD were enrolled. After controlling for confounders, each 10 μg/m3 increase in PM2.5 led to a 5.8% increase in the risk of AECOPD on day lag 0. The cumulative effect of PM2.5 on AECOPD risk showed an increasing trend after 3 days. Similar results were observed in both smoking and non-smoking patients. There was an interaction between PM2.5 and meteorological factors, and the risk of AECOPD was higher in cold and lower humidity conditions than in other conditions. High-level PM2.5 exposure is positively associated with the risk of AECOPD onset, and the effect of PM2.5 can be modified by the temperature and relative humidity. Public health guidelines should pay close attention to AECOPD risk under the condition of high-level PM2.5 with low temperature or low humidity.

Abstract Background Autophagy has been found to be involved in the multidrug resistance (MDR) of cancers, but whether it is associated with resistance of small cell lung cancer (SCLC) has not been studied. Here, we hypothesized that a potential autophagy-regulating miRNA, miR-199a-5p, regulated cisplatin-resistant SCLC. Methods We validated the MDR of H446/EP using CCK-8 and LDH. We tested the binding of miR-199a-5p to p62 using the Dual-Luciferase assay and validated the association of miR-199a-5p and p62 in SCLC samples. We overexpressed (OE) and knocked down (KD) miR-199a-5p in H446 and H446/EP and determined the expression of miR-199a-5p, autophagy-related proteins, and the formation of autophagolysosomes using QPCR, western blotting, and MDC staining respectively. These results were validated in an orthotopic H446 mouse model of SCLC. Results H446/EP was resistant to cisplatin, etoposide, paclitexal, epirubicin, irinotecan, and vinorelbine. Exposure of cisplatin at 5 μg/ml for 24 h increased LC3II/LC3I, ATG5, p62, and the formation of autophagolysosomes in H446 cells, but not in H446/EP cells. The expression of miR-199a-5p was up-regulated in H446/EP compared to H446. MiR-199a-5p directly targeted the p62 gene. The expression of miR-199a-5p and p62 were correlated in SCLC samples. In H446 and H69PR, the OE of miR-199a-5p increased LC3II/LC3I, p62, and the formation of autophagolysosomes, but not ATG5, while the KD of miR-199a-5p decreased p62, but did not affect LC3II/LC3I, ATG5, and the formation of autophagolysosomes. In H446/EP, the OE of miR-199a-5p decreased p62 only. These results were generally consistent to results in the animal tumor samples. Conclusions The regulation of autophagy by the miR-199a-5p/p62 axis was a potential mechanism of small cell lung cancer cisplatin resistance.

With the concern for biodiversity conservation and ecological sustainability, the traditional method of assessing conservation management based on single elements such as timber production, stand structure, and forest area is no longer applicable. Especially for China, where the primary goal of national park conservation management is to “protect and maintain the authenticity and integrity of natural ecosystems”, it is necessary to construct a set of indicators that can comprehensively evaluate the effectiveness of natural ecosystem conservation management. Therefore, in this study, we take Jiuzhaigou and Giant Panda National Park, in Sichuan, China, as examples, and construct a set of ecological integrity evaluation indices system from the perspective of attributes of forest ecosystems. Initially, we screened the candidate indicators based on the coefficient of variation, distribution range, and redundancy analysis and identified 16 indicators as the evaluation indices of ecological integrity. Next, the model fit and the interrelationship of the components of the ecological integrity model were verified using a combination of structural equation modeling and actual data. The model validation results showed that: (1) CMIN/DF = 1.66, RMSEA = 0.058, GFI = 0.954, and other model fit metrics have reached the best reference standard, indicating that the ecological integrity model overall fit is high. (2) In the parameter estimation results of the model observed and latent variables, the ecological integrity model explained 96%, 85% and 89% of the variance in species composition, stand structure and ecological processes, respectively, indicating that the evaluation indices selected can effectively predict the ecological integrity of forests. In addition, we used the factor loadings in the structural equation model to calculate the weights of the indices and used the weighted sum to calculate the ecological integrity. A one-way ANOVA was conducted to compare the differences among the ecological integrity of forests of different origins, forest types and life forms. The relative importance and linear regression were used to elucidate the main factors affecting forest ecological integrity. The results showed that (1) except for the scrub community, the mean value of forest ecological integrity was >0.45, which was in the middle-to-upper level. (2) the ecological integrity of forests of different origins and different forest types showed a changing pattern: natural forest > plantation forest, mixed forest > pure forest. (3) Stand age and elevation strongly influenced the ecological integrity of forests, with relative contribution rates of 64.54% and 11.88%, respectively.

ObjectiveTo explore factors related to the postoperative recurrence of lumbar disc herniation treated by percutaneous transforaminal endoscopy.MethodsPubMed, EMBASE, Cochrane Library, CNKI, Wanfang database and VIP database were systematically searched from the time of each library's construction to October 20, 2022. The studies that compared the influencing factors of recurrent lumbar disc herniation were included based on the PICO search structure. The Newcastle–Ottawa Scale was used to evaluate the quality of observational studies. The effects of the patient's age, gender, BMI, smoking, drinking, hypertension, diabetes, course of the disease, Pfirrmann grade, and the surgical segment on recurrent lumbar disc herniation were systematically evaluated using Revman 5.3. The odds ratio (OR) and 95% confidence interval (CI) were calculated.ResultsThirteen studies involving 3,393 patients (323 patients with recurrent lumbar disc herniation) treated with percutaneous transforaminal endoscopy were included in this study. The results of the systematic evaluation showed that the effects of gender, smoking, drinking, hypertension, type of lumbar disc herniation and the surgical segment on recurrent lumbar disc herniation were not statistically significant. However, age ≥60 years (OR = 2.23; 95% CI: 1.13, 4.41), BMI ≥25 (OR = 2.89; 95% CI: 1.23, 6.80), diabetes (OR = 1.73; 95% CI: 1.18, 2.55), course of disease ≥4 years (OR = 2.93; 95% CI: 1.58, 5.43), Pfirrmann grades 3–4 (OR = 3.10; 95% CI: 2.18, 4.40), incomplete removal of nucleus pulposus (OR = 3.26; 95% CI: 1.69, 6.27) and intraoperative fibre breakage (OR = 3.18; 95% CI: 1.56, 6.50) increased the risk of recurrence after treatment.ConclusionThe recurrence of lumbar disc herniation after percutaneous transforaminal endoscopic treatment is related to demographic characteristics, disease history and surgical conditions. In the future, more high-quality studies are needed to explore the influencing factors of recurrent lumbar disc herniation.

As an increasingly prevalent form of human activity, roads drive the taxonomic homogenization of mountain plant assemblages, threatening global biodiversity. However, little is known about how mountain roads impact functional and phylogenetic beta diversity and how these effects are related to taxonomic homogenization. To understand the mechanism of taxonomic homogenization triggered by mountain roads, we used species absence/presence data from 76 plots (2 m*50 m) and values for 12 traits measured on 978 species from the interior and roadside communities in the Qionglai mountain range, one of the temperate regions with the highest plant species richness in the world. We used a structural equation modeling approach (SEM) to consider several surrogates of road disturbance (changes in soil physicochemical properties and the presence or absence of roads) and the causal relationship between three facets of beta diversity (taxonomic beta diversity, TBD; functional beta diversity, FBD and phylogenetic beta diversity, PBD). The results suggest that TBD, FBD and PBD respond inconsistently to mountain roads, despite strong positive correlations between the three facets of plant beta diversity in the study area. Compared with the interior community, the βtotal.tax and βtotal.func of the roadside community decreased by 2.54% and 2.22%, respectively, which were related to the reduction of species and trait richness differences and replacements; however, we did not find the same results when assessing the changes in βtotal.phy, which represents tip-weighted PBD (twPBD). Furthermore, the largest effect of roads on beta diversity was reflected in basal-weighted PBD (bwPBD), which decreased by 9.97%, indicating that those species with fewer extant relatives and longer evolutionary histories are more sensitive to mountain roads. Therefore, it is necessary to take targeted protection measures for ancient species in roadside communities. In addition, we believe that it is still necessary to take measures to prevent the further dispersal of nonnative species, although the presence of non-native species in roadside plots has led to small changes in three facets of beta diversity. There were causal relationships between the three facets of beta diversity, but their intensity and sign different in the SEM of different components of beta diversity (i.e., richness difference and replacement). Our findings suggest that the homogenization of community species composition at the landscape scale arises by a combination of adaptive responses of the functional traits of organisms to environmental consistency (e.g., reduced the differences in soil variables) caused by roads and resorting or reassembly of community clades composition due to environmental filtering. These results contribute to our comprehensive understanding of the impact of mountain roads on plant diversity, which highlights the complex relationship between human pressure and biodiversity loss.

BackgroundWith the rapid development of higher education in China, the scale of colleges and universities is expanding, and the phenomenon of campus socialization is becoming more and more obvious. In particular, the campus and its surrounding environment are becoming more and more complex, which brings many hidden dangers in university life.ObjectiveIn order to improve the effectiveness of safety education in colleges and universities and maintain the long-term effectiveness of college students’ safety awareness, the paper proposes the construction and practice path of college safety education mechanism that integrates the psychological characteristics of students in the new era.MethodsSecurity issues facing universities at home, this track identifies the relationship between campus security incidents and security education and advocacy. Eight solutions to prevent and reduce incidents in schools. The paper proposes to give importance to the study of the security of college students, to create an awareness of security questions in the bank based on the recommendation algorithm, and to create to have online learning and testing for safety awareness.ResultsThe passing rate of 10 majors such as humanities, composition and theory of composition technology was 100%, accounting for 12% of the 83 enrolled majors, and the passing rate of 54 majors such as clinical medicine was over 90%.ConclusionThe safety online learning and testing system of college students’ safety education is lively in form and highly accepted by students. The development of college students’ safety education starts from the time of receiving the university admission notice, making full use of the “golden time,” so as to effectively prevent and reduce the occurrence of campus safety accidents.

Hyperactivation of the Janus kinase 2 (JAK2) signaling pathway leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 can be used as an effective strategy for the treatment of MPNs. Here, our study indicated that WWQ-131 was a highly selective JAK2 inhibitor (IC50 =2.36 nM), with 182-fold and 171-fold more selective to JAK1 and JAK3, respectively. In JAK2V617F-dependent cell lines, WWQ-131 efficaciously inhibited cell proliferation, induced cell cycle arrest at the G2/M phase and apoptosis, and blocked the aberrant activation of JAK2 signaling pathway. In a mouse Ba/F3_JAK2V617F driven disease model, WWQ-131 effectively suppressed STAT5 phosphorylation in spleen and liver, and inhibited Ba/F3_JAK2V617F cells spreading and proliferation in vivo. In addition, WWQ-131 suppressed rhEPO-induced extramedullary erythropoiesis and polycythemia in mice, as well as hematocrits and spleen sizes, especially had no effect on white blood cell count. Furthermore, WWQ-131 (75 mg/kg) exhibited stronger therapeutic effects than fedratinib (120 mg/kg) in these two MPN models. Taken together, this study suggests that WWQ-131 will be a promising candidate for the treatment of MPNs.

With the development of new broadband semiconductor materials and the expansion of solar‐blind deep‐ultraviolet (SBDU) optoelectronics, the demand for high‐performance fully transparent array integration has also increased. Herein, metal–semiconductor–metal (MSM)‐type fully transparent SBDU photodetector arrays (PDAs), based on commercially available ε‐Ga2O3 films, are constructed using indium tin oxide (ITO), indium gallium zinc oxide (IGZO), and aluminum zinc oxide (AZO) transparent conductive oxides as electrodes. The experimental results show that the overall performance of the fully transparent SBDU PDAs used in this study places them at the forefront of ε‐Ga2O3‐based photodetectors (PDs). All three PDs not only exhibit ultra‐high responsivity (286.2, 284.1, and 262.1 A W−1), remarkable detectivity (4.73 × 1014, 5.06 × 1014, and 2.16 × 1015 Jones), and excellent stability, but also fast photoresponse time (5.6/7.2, 6.9/9.5, and 70/200 ms). It is found that the resistivity and carrier concentration of transparent conductive oxides significantly influence device performance. Consequently, it is demonstrated, for the first time, that fully transparent ε‐Ga2O3‐based SBDU PDAs can be used as ultraviolet imagers and signal receivers integrated into a homemade solar‐blind ultraviolet communication (SBUC) system to transmit text data. These results indicate great potential for future applications of fully transparent ε‐Ga2O3 thin‐film solar‐blind photodetectors in next‐generation artificial intelligence eyes, smart windows, light field cameras, and solar‐blind imaging, among others.

A comprehensive understanding of the effects of mountain roads on plant diversity is critical to finding the most effective solutions for managing this particular driver. Little is known, however, about the simultaneous effects that road have on the multiple facets of biodiversity, although roads are considered to be one of the major disturbances in the Qionglai mountain range. In this study, we analyzed the impact of roads on the multiple facets of plant diversity (taxonomic, functional and phylogenetic diversity) in the study area using Hill numbers by comparing plant diversity between roadside and interior plots at the landscape scale, then, we used linear mixed models to analyze the effect of mountain roads on the multiple facets of plant diversity along an elevational gradient. The results showed that the roadside plots lacked 29.45% of the total number of species with particular functional traits (such as a relatively high specific leaf area (SLA), a relatively low leaf dry matter content (LDMC) and relatively old clades) and exclusively contained 14.62% of the total number of species. Compared with the interior community, the taxonomic, functional and phylogenetic diversity of roadside community decreased by no more than 26.78%, 24.90% and 16.62%, respectively. Taxonomic and functional diversity of dominant and common species showed greater changes to road disturbances, while rare species showed the greatest change in phylogenetic diversity. Taxonomic homogenization of roadside communities was accompanied by functional and phylogenetic homogenization. Additionally, the impact of roads on these three facets of plant diversity showed the characteristics of peak clipping along the elevation gradient. Our findings highlight the negative impact of roads on the taxonomic, functional and phylogenetic diversity of the Qionglai mountain range, as roads promote communities that are more similar in taxonomic, functional, and phylogenetic composition, and to a greater extent contributed to compositional evenness. These effects tend to be functionally and phylogenetically non-random, and species in some clades or with some functional traits are at higher risk of loss. Our results are important for the conservation and management of nature reserves, especially for local governments aiming to create new infrastructure to connect natural mountainous areas.

Protein modification by ubiquitin fold modifier 1 (UFM1), termed ufmylation, regulates various physiological and pathological processes. Among emerging UFM1 targets, UFM1 binding protein 1 (UFBP1) is the first identified ufmylation substrate. Recent clinical and animal studies have demonstrated the pivotal roles of UFBP1 in development, hematopoiesis, intestinal homeostasis, chondrogenesis, and neuronal development, which has been linked to its function in maintaining endoplasmic reticulum (ER) homeostasis. However, the importance of UFBP1 ufmylation in these cellular and physiological processes has yet to be determined. It has been proposed that ufmylation of lysine 268 (267 in humans) in UFBP1 plays a critical role in mediating the effects of the ufmylation pathway. In this study, we for the first time probe the pathophysiological significance of UFBP1 ufmylation in vivo by creating and characterizing a mouse UFBP1 knockin (KI) model in which the lysine 268 of UFBP1, the amino acid accepting UFM1, was mutated to arginine. Our results showed that the K268R mutation reduced the total ufmylated proteins without altering the expression levels of individual ufmylation enzymes in mouse embryonic fibroblasts. The K268R mutation did not alter ER stress–stimuli–induced ER stress signaling or cell death in mouse embryonic fibroblasts. The homozygous KI mice were viable and morphologically indistinguishable from their littermate wild–type controls up to one year of age. Serial echocardiography revealed no cardiac functional impairment of the homozygous KI mice. Furthermore, the homozygous KI mice exhibited the same susceptibility to dextran sulfate sodium (DSS) –induced colitis as wild-type mice. Taken together, these results suggest that UFBP1 K268 is dispensable for ER stress response, embryonic development, cardiac homeostasis under physiological conditions, and intestinal homeostasis under pathological conditions. Our studies call for future investigations to understand the biological function of UFBP1 ufmylation and offer a new mouse model to determine the roles of UFBP1 ufmylation in different tissues under stress conditions.