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Abstract Systemic inflammatory response index (SIRI) has been proven to be associated with the prognosis of coronary artery disease and many other diseases. However, the relationship between SIRI and acute traumatic spinal cord injury (tSCI) has rarely been evaluated. The study aims to assess the prognostic value of SIRI for clinical outcomes in individuals with acute tSCI. A total of 190 patients admitted within eight hours after tSCI between January 2021 and April 2023 were enrolled in our study. Logistic regression analysis was used to analyze the association between SIRI and American Spinal Injury Association Impairment Scale (AIS) grade at admission and discharge, as well as neurological improvement in tSCI patients, and receiver operating characteristic (ROC) analysis was performed to assess the discriminative ability of SIRI in predicting AIS grade at discharge. After adjusting for confounding factors, SIRI positively correlated with the AIS grade (A to C) at admission and discharge, and negatively correlated with neurological improvement. The area under the curve values in ROC analysis was 0.725 (95% CI 0.647, 0.803). The study suggests that SIRI is significantly associated with an increased risk of poor clinical outcome at discharge in tSCI patients and has a certain discriminative value.

The production of industrial chemicals with renewable biomass feedstock holds potential to aid the world in pursuing a carbon-neutral society. Trimellitic and trimesic acids are important commodity chemicals in industry that are prepared by the oxidation of petroleum-derived trimethylbenzene. To reduce the dependence on the limited oil source, we develop a potential sustainable alternative towards trimellitic and trimesic acids using biomass-based 2-methyl-2,4-pentandiol (MPD), acrylate and crotonaldehyde as starting materials. The process for trimellitic acid includes dehydration/D-A reaction of MPD and acrylate, flow aromatization over Pd/C catalyst, hydrolysis and catalytic aerobic oxidation (60% overall yield). The challenging regioselectivity issue of D-A reaction is tackled by a matched combination of temperature and deep eutectic solvent ChCl/HCO2H. Crotonaldehyde can also participate in the reaction, followed by Pd/C-catalyzed decarbonylation/dehydrogenation and oxidation to provide trimesic acid in 54% overall yield. Life cycle assessment implies that compared to conventional fossil process, our biomass-based routes present a potential in reducing carbon emissions.

Abstract Background Early prognosis evaluation is crucial for decision-making in cardiogenic shock (CS) patients. Dynamic lactate assessment, for example, normalized lactate load, has been a better prognosis predictor than single lactate value in septic shock. Our objective was to investigate the correlation between normalized lactate load and in-hospital mortality in patients with CS. Methods Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The calculation of lactate load involved the determination of the cumulative area under the lactate curve, while normalized lactate load was computed by dividing the lactate load by the corresponding period. Receiver Operating Characteristic (ROC) curves were constructed, and the evaluation of areas under the curves (AUC) for various parameters was performed using the DeLong test. Results Our study involved a cohort of 1932 CS patients, with 687 individuals (36.1%) experiencing mortality during their hospitalization. The AUC for normalized lactate load demonstrated significant superiority compared to the first lactate (0.675 vs. 0.646, P

Abstract Background Metastasis renal cell carcinoma (RCC) patients have extremely high mortality rate. A predictive model for RCC micrometastasis based on pathomics could be beneficial for clinicians to make treatment decisions. Methods A total of 895 formalin-fixed and paraffin-embedded whole slide images (WSIs) derived from three cohorts, including Shanghai General Hospital (SGH), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and Cancer Genome Atlas (TCGA) cohorts, and another 588 frozen section WSIs from TCGA dataset were involved in the study. The deep learning-based strategy for predicting lymphatic metastasis was developed based on WSIs through clustering-constrained-attention multiple-instance learning method and verified among the three cohorts. The performance of the model was further verified in frozen-pathological sections. In addition, the model was also tested the prognosis prediction of patients with RCC in multi-source patient cohorts. Results The AUC of the lymphatic metastasis prediction performance was 0.836, 0.865 and 0.812 in TCGA, SGH and CPTAC cohorts, respectively. The performance on frozen section WSIs was with the AUC of 0.801. Patients with high deep learning-based prediction of lymph node metastasis values showed worse prognosis. Conclusions In this study, we developed and verified a deep learning-based strategy for predicting lymphatic metastasis from primary RCC WSIs, which could be applied in frozen-pathological sections and act as a prognostic factor for RCC to distinguished patients with worse survival outcomes.

In this study, lotus seed starch was used as the raw material for preparing RS3 resistant starch (EHP-LRS3) through thermoacidophilic type Ⅲ pullulan hydrolase synergistic high-pressure heat treatments. The parameters for this preparation process were optimized using a single-factor experimental design and response surface methodology. The morphological and crystal structures of EHP-LRS3 were observed and analyzed using scanning electron microscopy (SEM) and X-ray diffraction (XRD), respectively, and its pro-proliferative effect on Bifidobacterium longum was investigated. According to the results, the optimal conditions for preparing EHP-LRS3 with TK-PUL enzymatic hydrolysis temperature of 80 ℃ were as follows: Treatment of 35.32% lotus seed starch slurry (pH5.00) with 25.00 U/g (lotus seed starch) TK-PUL at 80 ℃ for 12.70 h, followed by high-pressure heat treatment of the mixture at 121 ℃ for 10 min and retrogradation at 4 ℃ for 24 h. An EHP-LRS3 yield of 58.46% was achieved under these optimal conditions. The SEM analysis revealed that the prepared EHP-LRS3 possessed an irregular ravine-like structure. The XRD analysis showed that the resistant starch had a B-type crystal structure, which differed from the A-type crystal structure of lotus seed starch. The pro-proliferative effect of EHP-LRS3 on B. longum was superior to that of RS3 resistant starch prepared using high-pressure heating alone (HP-LRS3). In summary, a high EHP-LRS3 yield was obtained using both TK-PUL and high-pressure heat treatments. The superior pro-proliferative effect of EHP-LRS3 on B. longum was verified. The results provide a theoretical basis for the high-value utilization of lotus seed starch.

Abstract High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‒MS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5′-monophosphate, deoxyguanosine 5′-monophosphate, guanosine, and hypoxanthine-9-β-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-β-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5′-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.

This study aimed to increase the expression and secretion of type III pullulan hydrolase (TK-PUL) by Brevibacillus choshinensis through the co-expression of molecular chaperone proteins and the optimization of fermentation conditions. By constructing multiple recombinant B. choshinensis co-expressing TK-PUL and molecular chaperone proteins, and screening them using extracellular enzyme activity as an indicator, the most favorable molecular chaperone protein and corresponding recombinant B. choshinensis for TK-PUL secretion and expression were determined. On this basis, single factor experiments and response surface methodology were used to optimize the fermentation conditions of recombinant B. choshinensis. Results showed that, the extracellular enzyme activity of the recombinant B. choshinensis strain co-expressing the molecular chaperone protein PrsABa reached 98.79 U/mL, representing a 0.31-fold increase. The optimal medium for this recombinant B. choshinensis was composed of 19.65 g/L of glucose, 21.46 g/L of yeast extract, 12.01 g/L of MgCl2·6H2O, 9.02 g/L of proline, 0.01 g/L of FeSO4·7H2O, 0.01 g/L of MnSO4·4H2O, and 0.001 g/L of ZnSO4·7H2O. Culturing the optimized recombinant B. choshinensis in the above-mentioned optimized medium for 66 hours at 35 °C and an initial pH of 7.0 increased the extracellular TK-PUL activity to 192.68 U/mL, which represented a 1.56-fold increase. Efficient secretion of TK-PUL in B. choshinensis was achieved through the co-expression of molecular chaperone proteins and the optimization of fermentation conditions. This study provides a foundation for exploring the industrial-scale application of TK-PUL.

Abstract Peptide toxins found in sea anemones venom have diverse properties that make them important research subjects in the fields of pharmacology, neuroscience and biotechnology. This study used high-throughput sequencing technology to systematically analyze the venom components of the tentacles, column, and mesenterial filaments of sea anemone Heteractis crispa, revealing the diversity and complexity of sea anemone toxins in different tissues. A total of 1049 transcripts were identified and categorized into 60 families, of which 91.0% were proteins and 9.0% were peptides. Of those 1049 transcripts, 416, 291, and 307 putative proteins and peptide precursors were identified from tentacles, column, and mesenterial filaments respectively, while 428 were identified when the datasets were combined. Of these putative toxin sequences, 42 were detected in all three tissues, including 33 proteins and 9 peptides, with the majority of peptides being ShKT domain, β-defensin, and Kunitz-type. In addition, this study applied bioinformatics approaches to predict the family classification, 3D structures, and functional annotation of these representative peptides, as well as the evolutionary relationships between peptides, laying the foundation for the next step of peptide pharmacological activity research.

Summary: Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression. Conditional Chd8 deletion in astrocytes, but not microglia, suppresses reactive gliosis by impeding astrocyte proliferation and morphological elaboration. Astrocyte Chd8 ablation alleviates lipopolysaccharide-induced neuroinflammation and septic-associated hypothermia in mice. Astrocytic CHD8 plays an important role in neuroinflammation by altering the chromatin landscape, regulating metabolic and lipid-associated pathways, and astrocyte-microglia crosstalk. Moreover, we show that reactive gliosis can be directly mitigated in vivo using an adeno-associated virus (AAV)-mediated Chd8 gene editing strategy. These findings uncover a role of ASD-associated CHD8 in the adult brain, which may warrant future exploration of targeting chromatin remodelers in reactive gliosis and neuroinflammation in injury and neurological diseases.

Introduction Breast cancer has become the most common cancer worldwide. Various types of mindfulness-based interventions (e.g., mindfulness-based cognitive therapy, mindfulness-based stress reduction) have been conducted in different delivery methods (including face to face and internet delivered) to help patients with breast cancer mitigate their depression. However, at present, there are no studies that compare the effectiveness of all these types and deliveries of mindfulness-based interventions. Therefore, this protocol aims to conduct a systematic review and network meta-analysis to assess the effectiveness of various types and deliveries of mindfulness-based interventions in mitigating depression in patients with breast cancer.Methods This protocol is according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The electronic databases, including PubMed, Web of Science, the Cochrane Library, Embase, Google Scholar, The China National Knowledge Infrastructure and OpenGrey, will be comprehensively retrieved for related randomised controlled trials (RCTs) from inception to December 2023. Two reviewers will independently assess the risk of bias using the Cochrane Risk of Bias Tool for Randomised Trials 2.0 (RoB 2.0). The network meta-analysis will be performed using the STATA V.16.0, and the assessment of heterogeneity, inconsistency, publication bias, evidence quality, subgroup analyses and sensitivity analyses will be conducted.Ethics and dissemination This protocol does not require approval from an ethics committee as it is based on previous research findings. The results will be disseminated via peer-reviewed publications.PROSPERO registration number CRD42024495996.

Abstract Acute asthma exacerbation refers to the progressive deterioration of asthma symptoms that is always triggered by virus infection represented by respiratory syncytial virus (RSV). After RSV infection, exaggerated Th2‐mediated pulmonary inflammation is the critical pathological response of asthmatic patients with acute exacerbation. Significantly, airway epithelial cells, being the primary targets of RSV infection, play a crucial role in controlling the pulmonary inflammatory response by releasing airway epithelial cell‐derived exosomes (AEC‐Exos), which potentially influence the development of asthma. However, the specific role of AEC‐Exos in acute asthma exacerbation after RSV infection remains obscure. The purpose of this study was to determine the distinct function of AEC‐Exos in exacerbating acute asthma following RSV infection. Blockade of exosomes by GW reduce the enhanced pulmonary inflammation significantly. Specifically, the enhanced Th2 inflammation was induced by AEC‐Exos thorough transportation of hsa‐miR‐155‐5p–Sirtuin 1 (SIRT1) pathway during acute asthma exacerbation. Targeted inhibition of hsa‐miR‐155‐5p blocks the exaggerated Th2 inflammation effectively in mice with acute asthma exacerbation. In summary, our study showed that during acute asthma exacerbation after RSV infection, AEC‐Exos promote the enhanced Th2 inflammation through transportation of increased hsa‐miR‐155‐5p, which was mediated partly through SIRT1‐mediated pathway. hsa‐miR‐155‐5p is a potential biomarker for early prediction of acute asthma exacerbation.

Abstract Liquid–liquid phase separation (LLPS), an emerging biophysical phenomenon, can sequester molecules to implement physiological and pathological functions. LLPS implements the assembly of numerous membraneless chambers, including stress granules and P‐bodies, containing RNA and protein. RNA–RNA and RNA–protein interactions play a critical role in LLPS. Scaffolding proteins, through multivalent interactions and external factors, support protein–RNA interaction networks to form condensates involved in a variety of diseases, particularly neurodegenerative diseases and cancer. Modulating LLPS phenomenon in multiple pathogenic proteins for the treatment of neurodegenerative diseases and cancer could present a promising direction, though recent advances in this area are limited. Here, we summarize in detail the complexity of LLPS in constructing signaling pathways and highlight the role of LLPS in neurodegenerative diseases and cancers. We also explore RNA modifications on LLPS to alter diseases progression because these modifications can influence LLPS of certain proteins or the formation of stress granules, and discuss the possibility of proper manipulation of LLPS process to restore cellular homeostasis or develop therapeutic drugs for the eradication of diseases. This review attempts to discuss potential therapeutic opportunities by elaborating on the connection between LLPS, RNA modification, and their roles in diseases.

Abstract. Background:. Total human immunodeficiency virus (HIV) DNA and integrated HIV DNA are widely used markers of HIV persistence. Droplet digital polymerase chain reaction (ddPCR) can be used for absolute quantification without needing a standard curve. Here, we developed duplex ddPCR assays to detect and quantify total HIV DNA and integrated HIV DNA. Methods:. The limit of detection, dynamic ranges, sensitivity, and reproducibility were evaluated by plasmid constructs containing both the HIV long terminal repeat (LTR) and human CD3 gene (for total HIV DNA) and ACH-2 cells (for integrated HIV DNA). Forty-two cases on stable suppressive antiretroviral therapy (ART) were assayed in total HIV DNA and integrated HIV DNA. Correlation coefficient analysis was performed on the data related to DNA copies and cluster of differentiation 4 positive (CD4+) T-cell counts, CD8+ T-cell counts and CD4/CD8 T-cell ratio, respectively. The assay linear dynamic range and lower limit of detection (LLOD) were also assessed. Results:. The assay could detect the presence of HIV-1 copies 100% at concentrations of 6.3 copies/reaction, and the estimated LLOD of the ddPCR assay was 4.4 HIV DNA copies/reaction (95% confidence intervals [CI]: 3.6–6.5 copies/reaction) with linearity over a 5-log10-unit range in total HIV DNA assay. For the integrated HIV DNA assay, the LLOD was 8.0 copies/reaction (95% CI: 5.8–16.6 copies/reaction) with linearity over a 3-log10-unit range. Total HIV DNA in CD4+ T cells was positively associated with integrated HIV DNA (r = 0.76, P

Abstract Five species of plant‐derived lactic acid bacteria (LAB), including Pediococcus pentosaceus, Lactococcus garvieae, Lactiplantibacillus paraplantarum, Weissella paramesenteroides, and Lactococcus lactis, were used for muskmelon fermentation to improve flavor characteristics. Comparative genomic analysis showed that a high proportion of annotated genes were related to carbohydrate metabolism and amino acid metabolism in all five strains. L. lactis P‐1 (Ll1) contained the highest proportion (2.02%) of genes from the glycoside hydrolase family associated with carbohydrate metabolism. Gas chromatography–mass spectrometry results showed that 89 volatile compounds in muskmelon purees were identified; the largest number of volatile compounds was detected in fermented muskmelon puree (FMP) inoculated with W. paramesenteroides FL3, followed by L. paraplantarum FL‐8. A total of 25 key volatile compounds were screened in muskmelon puree, and some unique key volatile compounds (e.g., β‐damascenone, phenylacetaldehyde, and 3‐penten‐2‐one) and taste compounds (e.g., mannitol) were produced by different LAB strains. L. garvieae Pa‐2 and Ll1 were considered to have greater potential due to their ability to produce a greater category of pleasant key aromas. Based on the correlations of potential pathways analyzed using comparative genomics and detected flavor profiles, flavor synthesis pathways in FMP were predicted. Some carbohydrate, amino acid, and fatty acid metabolism pathways, including tricarboxylic acid cycle, glycolysis, and cysteine and methionine metabolism pathways, are common to all five LAB strains. Furthermore, differences in the predicted flavor biosynthesis metabolic pathways in monoterpenoid biosynthesis, phenylalanine metabolism, fatty acid biosynthesis, and fructose and mannose metabolism pathways explained the differences in volatile profiles produced by different strains.

Abstract Objective Osteoporosis is the imbalance in bone homeostasis between osteoblasts and osteoclasts. In this study, we investigated the effects of the circ_0029463/miR-134-5p/Rab27a axis on RANKL-induced osteoclast differentiation. Methods RT-qPCR and western blotting were used to detect the expression of circ_0029463, miR-134-5p, and Rab27a in tissues from patients with osteoporosis and in RANKL-induced osteoclasts. Osteoclast differentiation was verified by TRAP staining. Osteoclast biomarkers, including NFATc1, TRAP, and CTSK, were measured. The target and regulatory relationships between circ_0029463, miR-134-5p, and the Rab27a axis were verified using RIP, dual-luciferase reporter gene, and RNA pull-down assays. Results Elevated expression of circ_0029463 and Rab27a and decreased miR-134-5p expression were observed in the tissues of patients with osteoporosis, and a similar expression pattern was observed in RANKL-induced osteoclasts. Suppression of circ_0029463 expression or miR-134-5p overexpression curbed RANKL-induced osteoclast differentiation, whereas such an effect was abolished by Rab27 overexpression. circ_0029463 sponges miR-134-5p to induce Rab27a expression. Conclusion circ_0029463 sponges miR-134-5p to abolish its suppressive effect of miR-134-5p on Rab27a expression, thereby promoting osteoclast differentiation.

Abstract Background To compare the impact of surgical approach on progression free survival (PFS) stratified by histologic type in women diagnosed with stage IA endometrial cancer. Methods Myometrial invasion is classified into no myometrial invasion,

Purposes Manual inspection’s lengthy time commitment, poor efficiency, and inaccurate verification make it challenging to meet practical application requirements in the daily operation of electric energy metering devices. Methods According to the collected data of electricity information, an evaluation model of metering device operation status based on deep learning is established, and the characteristics of historical data of electricity through the deep learning model are captured. By using the transfer learning optimization model training process, the prediction of the users’ future electricity usage is completed, and the threshold value is set for the difference between the expected value and the measured value of electricity to judge the running state of the energy meter. Findings The study’s findings will be a solid foundation for assessing the regional electric energy metering system’s state of operation, as well as for accurately replacing and maintaining meter. In addition, it will increase the precision of power grid fault diagnosis and location while significantly lowering the cost of on-site maintenance. Conclusions By contrasting the simulated value with the actual platform value, the correctness of the method is demonstrated. The experimental results show that the proposed evaluation model is effective.

Abstract With the rapid development of intelligent and connected vehicles, the experimental road test for the advanced driving assistance system (ADAS) is dramatically increasing around the world. Considering its high cost and hazardous situations, simulation test based on a dummy model is becoming a promising way for ADAS road test practice to reduce the experiment expanses. This study proposed a methodology for the evaluation of the performance of human and dummies with distinct designed materials based on the data extracted from the Doppler effect of millimeter-wave radar. Echo data of 8 different angles from 0 to 360 degrees, with the an interval of 45 degrees, at the same distance between the test object and the signal source is collected. Meanwhile, the echo energy is collected for correlation modeling and analysis among groups. By evaluating the performance of humans and dummies via statistical analysis, a close correlation was found which results verified the substitutability of the dummy for the ADAS experiment test. The correlation coefficient between human and dummies ranges from 0.75 to 0.93. The support vector machine (SVM) model was developed and fitted to predict the echo energy in diverse environments. The mean average error (MAE) is 5.42–11.42 in the training and testing datasets while root mean square error (RMSE) is 0.43–0.90. The methods developed in the study can simulate the real ADAS road test environment and support future experimental research.

Chelydra serpentina (Linnaeus, 1758) is native to North America, but has been introduced to numerous nations and is now globally spread. It is extremely adaptive, grow quickly, and its biological population is steadily increasing as a result of the development of aquaculture technology. Given that Chelydra serpentina has already been found alive in the natural ecosystems of China, its proliferation poses a possible threat of invasion. Using the global distribution data of the species in the current environment, a study was carried out to forecast the distribution trend of Chelydra serpentina under future climate circumstances. The study compared the changes in the distribution area under current climatic circumstances and the tendency of proliferation using 19 bioclimatic factors and the ecological niche model Maxent. Using the significance index, the study also examined the size of the appropriate region and the influencing factors to estimate the danger of Chelydra serpentina invasion better quantitatively. In our research, we hypothesized that forthcoming climate change will affect the geographical distribution of Chelydra serpentina. The study results showed that, even in high-intensity environments, the appropriate area for Chelydra serpentina will steadily increase in the future climate. The extent of their suitable habitat might expand (the highly suitable area: 7.42*105 km2 ; 2.13*107 km2 ) in contrast to the distribution area of Chelydra serpentina under the existing climate (highly suitable area: 6.01*105 km2 ; 8.48*106 km2 ). The research findings indicate that the range of the habitat area predicted to proliferate (the highly suitable area of 6.31*105 km2 ; 1.3 *107 km2 ) even in high-intensity environments, albeit at a slower rate than in the low-intensity environment model. The habitat will initially be concentrated in warmer regions before progressively expanding into the colder northern climate. This implies that Chelydra serpentina will be able to more easily adjust to future climates and spread outward over time from its concentrated home. Nonetheless, there is a chance of an invasion due to the rise in Chelydra serpentina populations. Upon establishing a regular reproductive presence in the Chinese waterways they inhabit, these turtles will engage in fierce competition with indigenous species for survival, posing a threat to the environment and potentially resulting in the extinction of some local species.

BackgroundDevelopmental Dysplasia of the Hip (DDH) is a skeletal disorder where late-presenting forms often escape early diagnosis, leading to limb and pain in adults. The genetic basis of DDH is not fully understood despite known genetic predispositions.MethodsWe employed Whole Genome Sequencing (WGS) to explore the genetic factors in late-presenting DDH in two unrelated families, supported by phenotypic analyses and in vitro validation.ResultsIn both cases, a novel de novo heterozygous missense mutation in RAF1 (c.193A>G [p.Lys65Glu]) was identified. This mutation impacted RAF1 protein structure and function, altering downstream signaling in the Ras/ERK pathway, as demonstrated by bioinformatics, molecular dynamics simulations, and in vitro validations.ConclusionThis study contributes to our understanding of the genetic factors involved in DDH by identifying a novel mutation in RAF1. The identification of the RAF1 mutation suggests a possible involvement of the Ras/ERK pathway in the pathogenesis of late-presenting DDH, indicating its potential role in skeletal development.

Objective: To explore the treatment effect and potential mechanism on gut microbiota, nutrition, and metabolism of Fufang Duzheng Tablet (DZGP) on rheumatoid arthritis (RA). Methods: Collagen-induced arthritis rats’ models were established and divided into three groups: model control group (FK), DZGP group (FZ, 0.45 g/kg/d), and methotrexate group (FM, 1.35 mg/kg), which were treated by gavage for 28 days. The physiopathologic changes of joints and body weight in each group were recorded; the morphology of synovial and ankle tissues was observed by hematoxylin-eosin staining, and the level of serum TNF-α and IL-1β was tested by ELISA. UPLC/MS-MS and network pharmacological analysis were used to identify the serum components, and 16S rDNA sequencing analysis was applied to the intestinal contents of rats. Results: DZGP treatment significantly alleviated arthritis symptoms, pathological manifestations, toe thickness, and TNF-α and IL-1β levels in RA rats. We identified 105 metabolites and 18 components in the serum of DZGP-group rats. The main therapeutic targets of DZGP for anti-RA were TP53, epidermal growth factor receptor, and AKT1. Molecular docking showed that there was good binding efficiency between core components and main targets. 16S rDNA sequencing showed that DZGP treatment regulated the structure of the gut microbiota. Conclusion: DZGP showed a good anti-inflammatory effect on RA and played an important role in improving the structure of the gut microbiota in RA rats.

Summary: The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory mechanisms in relation to cervical cancer remain insufficiently understood. Through bioinformatics analysis, we revealed that ESM1 was highly expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and correlated with dismal clinicopathological features. The activation of ESM1 is facilitated by the presence of oncogenic HPV E6 and E7. HPV E6 and E7 enhance the expression of ESM1 by diminishing the levels of miR-205-5p, which specifically targets the 3′ untranslated region of ESM1 mRNA. In addition, we demonstrated that ESM1 facilitates aerobic glycolysis of cervical cancer cells via the Akt/mTOR pathway. Suppression of ESM1 led to a reduction in the expression of HIF-1α and multiple glycolytic enzymes. Taken together, our findings provide insights into the mechanisms by which HPV infections regulate oncogenes, thereby contributing to cervical carcinogenesis.

The introduction of PARP inhibitors (PARPis) and immune checkpoint inhibitors (ICIs) has marked a significant shift in the treatment landscape for solid tumors. Emerging preclinical evidence and initial clinical trials have indicated that the synergistic application of PARPis and ICIs may enhance treatment efficacy and potentially improve long-term patient outcomes. Nonetheless, how to identify specific tumor types and molecular subgroups most likely to benefit from this combination remains an area of ongoing research. This review thoroughly examines current studies on the co-administration of PARPis and ICIs across various solid tumors. It explores the underlying mechanisms of action, evaluates clinical efficacy, identifies potential responder populations, and delineates common adverse events alongside strategic management approaches. The aim is to offer a detailed understanding of this combination therapy, potentially guiding future therapeutic strategies for solid tumors.

Hydrogen peroxide (H2O2) functions as a signaling molecule in diverse cellular processes. While cells have evolved the capability to detect and manage changes in H2O2 levels, the mechanisms regulating key H2O2-producing enzymes to maintain optimal levels, especially in pancreatic beta cells with notably weak antioxidative defense, remain unclear. We found that the protein EI24 responds to changes in H2O2 concentration and regulates the production of H2O2 by controlling the translation of NOX4, an enzyme that is constitutively active, achieved by recruiting an RNA-binding protein, RTRAF, to the 3′-UTR of Nox4. Depleting EI24 results in RTRAF relocating into the nucleus, releasing the brake on NOX4 translation. The excessive production of H2O2 by liberated NOX4 further suppresses the translation of the key transcription factor MafA, ultimately preventing its binding to the Ins2 gene promoter and subsequent transcription of insulin. Treatment with a specific NOX4 inhibitor or the antioxidant NAC reversed these effects and alleviated the diabetic symptoms in beta-cell specific Ei24-KO mice. This study revealed a new mechanism through which cells regulate oxidative stress at the translational level, involving an ER-tethered RNA-binding protein that controls the expression of the key H2O2-producing enzyme NOX4.

Introduction Up to 78% of patients who had a stroke develop post-stroke dysphagia (PSD), a significant consequence. Life-threatening aspiration pneumonia, starvation, and water and electrolyte abnormalities can result. Several meta-analyses have shown that repeated transcranial magnetic stimulation (rTMS) improves swallowing in patients who had a stroke; however, the optimum model is unknown. This study will be the first Bayesian network meta-analysis (NMA) to determine the best rTMS modalities for swallowing of patients who had a stroke.Methods and analysis PubMed, Web of Science, Embase, Google Scholar, Cochrane, the Chinese National Knowledge Infrastructure, the Chongqing VIP Database and WanFang Data will be searched from their creation to 2 September 2023. All randomised controlled trials associated with rTMS for PSD will be included. Only Chinese or English results will be studied. Two researchers will independently review the literature and extract data, then use the Cochrane Collaboration’s Risk of Bias 2.0 tool to assess the included studies’ methodological quality. The primary outcome is swallowing function improvement, whereas secondary outcomes include side effects (eg, paraesthesia, vertigo, seizures) and quality of life. A pairwise meta-analysis and NMA based on a Bayesian framework will be conducted using Stata and R statistical software. The Grading of Recommendations Assessment, Development, and Evaluation system will assess outcome indicator evidence quality.Ethics and dissemination As all data in this study will be taken from the literature, ethical approval is not needed. We will publish our work in peer-reviewed publications and present it at academic conferences.PROSPERO registration number CRD42023456386.

【Objective】The effect of exogenous methyl jasmonate on resistance to bacterial leaf stripe (BLS) was studied, which would provide a theoretical basis for the prevention and control of BLS in rice.【Method】With rice BLS-resistant and susceptible near isogenic lines (K9 and G9) as materials, 0.1 mmol/L methyl jasmonate (MeJA) were sprayed on BLS-resistant and susceptible near isogenic lines (K9 and G9) plants respectively at tillering stage, and water spraying was used as control (CK). The inoculation with Xanthomonas oryzae pv. Oryzicola (Xoc) were conducted at 0, 12, 24, 48, 72 h after MeJA treatment, then the symptoms of BLS were investigated. In K9 and G9 plants sprayed with MeJA for 48 h then inoculated with Xoc, the expression changes of hormone-pathway related genes were further analyzed at 0, 6, 12, 24 and 48 h after inoculation.【Result】In K9 plants, the lesion lengths of leaves inoculated at 0, 24, 48, 72h after being sprayed with MeJA were significantly shorter than those in CK; in G9 plants, the lesion lengths of leaves inoculated at 0 h and 12 h after being sprayed with MeJA were significantly longer than those in CK, while inoculated at 72 h after being sprayed with MeJA were significantly shorter than those in CK. Compared with the CK, relative expression levels of jasmonate-pathway related genes LOX2 and AOS2, and pathogenesis-related gene PR10 were upregulated, while relative expression levels of alicylic acid-pathway related genes PAD4 and PAL, ethylene-pathway related genes EIN2 and ERF70, and pathogenesis-related gene PR1a were downregulated in K9 plants inoculated at 48h after being sprayed with MeJA; relative expression levels of jasmonate-pathway related genes LOX2 and AOS2, salicylic acid-pathway related genes PAD4 and PAL and pathogenesis-related genes PR1a and PR10 were upregulated, while relative expression level of ethylene-pathway related gene EIN2 was downregulated in G9 plants inoculated at 48h after being sprayed with MeJA.【Conclusion】Exogenous MeJA affects the BLS-resistance in rice resistant and susceptible near isogenic lines. The resistance responses of resistant and susceptible near isogenic lines to Xoc are different at different inoculation time points after MeJA treatment. Exogenous MeJA involves in the defense response to Xoc infection by inducing the expression changes of jasmonate, salicylic acid and ethylene pathway-related genes and pathogenesis-related genes.

AbstractContext Da-Cheng-Qi Decoction (DCQD) has a significant effect on Severe Acute Pancreatitis-Associated Acute Lung Injury (SAP-ALI).Objective To explore the mechanism of DCQD in the treatment of SAP-ALI based on intestinal barrier function and intestinal lymphatic pathway.Materials and methods Forty-five Sprague-Dawley rats were divided into three groups: sham operation, model, and DCQD. The SAP model was induced by a retrograde infusion of 5.0% sodium taurocholate solution (1 mg/kg) at a constant rate of 12 mL/h using an infusion pump into the bile-pancreatic duct. Sham operation and model group were given 0.9% normal saline, while DCQD group was given DCQD (5.99 g/kg/d) by gavage 1 h before operation and 1, 11 and 23 h after operation. The levels of HMGB1, RAGE, TNF-α, IL-6, ICAM-1, d-LA, DAO in blood and MPO in lung were detected using ELISA. The expression of HMGB1, RAGE, NF-κB p65 in mesenteric lymph nodes and lung were determined.Results Compared with SAP group, DCQD significantly reduced the histopathological scoring of pancreatic tissue (SAP, 2.80 ± 0.42; DCQD, 2.58 ± 0.52), intestine (SAP, 3.30 ± 0.68; DCQD, 2.50 ± 0.80) and lung (SAP, 3.30 ± 0.68; DCQD, 2.42 ± 0.52). DCQD reduced serum HMGB1 level (SAP, 134.09 ± 19.79; DCQD, 88.05 ± 9.19), RAGE level (SAP, 5.05 ± 1.44; DCQD, 2.13 ± 0.54). WB and RT-PCR showed HMGB1-RAGE pathway was inhibited by DCQD (p

Objective(s): Tumor metastasis is the leading cause of death in breast cancer (BC) patients and is a complicated process. Mitochondrial calcium uniporter (MCU), a selective channel responsible for mitochondrial Ca2+ uptake, has been reported to be associated with tumorigenesis and metastasis. The molecular mechanisms of MCU contributing to the migration of BC cells are partially understood. This study investigated the role of MCU in BC cell metastasis and explored the underlying mechanism of MCU-mediated autophagy in BC cell migration.Materials and Methods: The Kaplan-Meier plotter database was used to analyze the prognostic value of MCU mRNA expression. Western blotting was used to examine the expression level of MCU in 4 paired BC and adjacent normal tissues. The cellular migration capability of BC was measured by transwell migration assay and wound healing assay. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression levels of autophagy-related markers. The effects of MCU activation or inhibition on TFEB nuclear translocation in BC cells were detected by laser scanning confocal microscopy.Results: Expression of MCU was found to be negatively correlated with BC patient prognosis in the Kaplan-Meier plotter database. Compared with the adjacent normal tissues, MCU was markedly up-regulated in the BC tissues. MCU overexpression promoted cellular migration, activated autophagy, and increased TFEB nuclear translocation in BC cells, whereas its knockdown produced the opposite effects.Conclusion: MCU activates TFEB-driven autophagy to promote BC cell metastasis and provides a potential novel therapeutic target for BC clinical intervention.

Abstract Background The risk factors for mucus plug in children with adenovirus (ADV) pneumonia. Methods and materials A retrospective analysis was conducted of children diagnosed ADV pneumonia and underwent fiberoptic bronchoscopy admitted to the Xiamen Children's Hospital from September 2018 to September 2021.The patients were divided into a mucus plug group (39 cases) and a non-mucus plug group (53 cases). The children's data including sex, age, clinical presentation, laboratory test parameters, imaging and bronchoscopic data were collected. The risk factors for the development of airway mucus plug were analysed by multifactorial logistic regression. Results There were no statistically significant differences in sex, age, fever, hospitalization days, mixed infection, white blood cells (WBC) count, percentage of neutrophils (NE%), C-reactive protein(CRP), and D-dimer (all P > 0.05); Thermal range, procalcitonin (PCT), lactate dehydrogenase (LDH), Pleural effusion and associated decreased breath sounds was significantly higher in mucus plug group than in non-mucus plug group, and the differences were statistically significant (all P

With the rapid development of the pipeline transportation and exploitation of mineral resources, there is an urgent requirement for high-performance polymer matrix composites with low friction and wear, especially under oxidative and prolonged working conditions. In this work, ultra-high-molecular-weight polyethylene (UHMWPE) matrix composites with the addition of carbon fibers (CFs), TiC, and MoS2 were prepared by the hot press sintering method. The influence of thermal oxygen aging time (90 °C, 0 h–64 h) on their mechanical and frictional performance was investigated. The results showed that TiC ceramic particles can increase wear resistance, especially by aging times up to 32 and 64 h. The wear mechanisms were analyzed based on the results of SEM images, EDS, and Raman spectra. The knowledge obtained herein will facilitate the design of long-service-life polymer matrix composites with promising low friction and wear performances.

Avian pathogenic Escherichia coli (APEC) is a bacterial disease that harms the poultry industry worldwide, but its effect on Chinese Silkie has not been reported. Studies on whether there are differences in Silkie individual resistance to APEC and the regulatory role of spleen miRNAs lay the foundation for strategies against APEC. Therefore, 270 Silkie chickens were infected with the median lethal dose of an E. coli O1, O2, and O78 mixture. These chickens were divided into a susceptible group (Group S) and a recovery group (Group R) according to whether they survived 15 days postinfection (dpi). Moreover, 90 uninfected APEC Silkie served as controls (Group C). The splenic miRNA expression profile was examined to evaluate the role of miRNAs in the APEC infection response. Of the 270 Silkies infected with APEC, 144 were alive at 15 dpi. Cluster analysis and principal component analysis (PCA) of splenic miRNAs revealed that the four Group R replicates were clustered with the three Group C replicates and were far from the three Group S replicates. Differentially expressed (DE) miRNAs, especially gga-miR-146b-5p, play essential roles in immune and inflammatory responses to APEC. Functional enrichment analyses of DEmiRNAs suggested that suppression of immune system processes (biological processes) might contribute to susceptibility to APEC and that FoxO signaling pathways might be closely associated with the APEC infection response and postinfection repair. This study paves the way for screening anti-APEC Silkies and provides novel insights into the regulatory role of miRNAs in APEC infection.

This paper presents a study on the determination of synthetic pigments using high performance liquid chromatography (HPLC) method combined. A retention value qualitative approach, combined with an uncertainty assessment algorithm for the determination of pigment content, was used for the simultaneous determination of nine synthetic pigments, namely, lemon yellow, amaranthine red, indigo, carmine, sunset yellow, brilliant blue, seductive red, erythrosine, and seductive red, in foodstuffs by reversed-phase high-performance liquid chromatography (RP-HPLC). The sample pretreatment method was optimized, and the chromatographic conditions were set to investigate the UV determination wavelength, mobile phase, column temperature, and wavelength of synthetic pigments. Under the same mobile phase and column conditions, the results indicated that the components’ retention times did not significantly fluctuate with the change in column temperature. The results showed that the chromatographic response signals of lemon yellow, sunset yellow and seductive red were higher at the UV determination wavelength of 254 nm, so 254 nm was finally determined as the UV detection wavelength in this experiment. Mobile phase A: methanol, B: ammonium acetate (0.02mo/L) using gradient elution, the separation degree R>1.5, and the symmetry and stability of the chromatogram were better. The separation of the components was good, and the peak shape was sharp and symmetric when the column temperature was 35 ℃, so the column temperature was chosen to be 35 ℃, and the establishment of the chromatographic conditions was thus completed.

Abstract Background We aimed to investigate the clinical characteristics of severe influenza virus-associated pneumonia complicated with bacterial infection in children. Methods We retrospectively analysed data concerning 64 paediatric patients with severe influenza virus-associated pneumonia who had been treated at our hospital. The patients were divided into observation (44 patients) and control (20 patients) groups, based on the presence or absence of concomitant bacterial infection, and clinical data were compared between the groups. Results The mean age in the observation group was 2.71 ± 1.44 years, 42 (95.45%) were aged ≤ 5 years, and 18 (40.9%) had underlying diseases. The mean age in the control group was 4.05 ± 2.21 years, 13 (65%) were aged ≤ 5 years, and 3 (15%) had underlying diseases. There was a statistically significant difference in patient age and the proportion of patients with underlying diseases (P

Abstract Background To investigate the expression of EBV products and frequency of gallstone disease (GD) among different microsatellite status in colorectal cancer (CRC) with BRAFV600E mutation. Methods We collected 30 CRC patients with BRAFV600E mutation and 10 BRAF ( −) CRC patients as well as 54 healthy subjects. Tumor tissue samples were collected to detect the mutation of BRAF, KRAS, and TP53. Microsatellite status was determined by immunohistochemistry and PCR. EBER in situ hybridization was performed to detect EBV. In addition, we also collected clinical information about the patients. Results We found that although EBV products were detected in CRC, there were no significant differences in the EBV distribution between the different BRAF groups. Our study demonstrated that BRAFV600E mutation and BRAFV600E with MSI were significantly more frequent in the right CRC. Furthermore, the KRAS mutation rate in the BRAF-wild-type group was proved to be significantly higher than that in the BRAF mutation group. In addition, we revealed that BRAF mutation and MSI were independent risk factors of TNM stage. The frequency of GD was higher in CRC patients than in general population, and although there was no significant difference between CRC with or without BRAFV600E mutation, the highest frequency of GD was found in MSS CRC with BRAFV600E mutation. Conclusions EBV plays a role in CRC, but is not a determinant of different microsatellite status in CRC with BRAFV600E mutation. The frequency of GD in MSS CRC with BRAFV600E mutation is significantly higher than that in the general population.

To analyze the endogenous plasmid pDX of Lactobacillus acidophilus, and construct the Escherichia coli-Lactobacillus acidophilus shuttle vector based on the plasmid. In this study, the endogenous plasmid pDX was isolated from Lactobacillus acidophilus XW118, its sequence determination and functional analysis were performed, and then the promotor of plasmid pDX was used to construct a vector that could shuttle between Escherichia coli and lactic acid bacteria. The activity of the endogenous plasmid replicon of L. acidophilus in E. coli and the host range, transformation efficiency and passage stability of the shuttle vector in lactic acid bacteria were studied. The results showed that the size of Lactobacillus acidophilus plasmid pDX was 2062 bp, the GC content was 38.2%, and the plasmid contained four open reading frames (ORFs), which was presumed to be a rolling loop replication plasmid. The copy number of plasmid pDX in L. acidophilus was 31.05. In this study, an E. coli-lactic acid bacteria shuttle vector based on the replicon and promoter of plasmid pDX was constructed. The transformation efficiency of the vector was 0.24×102 to 2.75×103 CFU/μg (plasmid weight), and the plasmid loss rate was 25.45% to 48.36%. In this study, a vector capable of shuttling between E. coli and lactic acid bacteria was constructed, and the promoter of the endogenous plasmid of lactic acid bacteria with activity in E. coli was obtained, which provided a new operational approach for genetic engineering of lactic acid bacteria and metabolic engineering of E. coli.

Abstract Background Alternative splicing (AS)‐related single nucleotide polymorphisms (SNPs) are associated with risk of cancers, but the potential mechanism has not been fully elucidated. Methods Two‐stage case–control studies comprising 1630 cases and 2504 controls were conducted to investigate the association between the AS‐SNPs and bladder cancer susceptibility. A series of assays were used to evaluate the functional effect of AS‐SNPs on bladder cancer risk. Results We observed that SNP rs558814 A>G located in lncRNA BCLET (Bladder Cancer Low‐Expressed Transcript, ENSG00000245498) can decrease the risk of bladder cancer (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.76–0.92, p = 3.26 × 10−4). Additionally, the G allele of rs558814 had transcriptional regulatory effects and facilitated the expression of BCLET transcripts, including BCLET‐long and BCLET‐short. We also found decreased BCLET expression in bladder cancer tissues and cells, and BCLET transcript upregulation substantially inhibited tumor growth of both bladder cancer cells and xenograft models. Mechanistically, BCLET recognized and regulated AS of MSANTD2 to participate in bladder carcinogenesis, preferentially promoting the production of MSANTD2‐004. Conclusions SNP rs558814 was associated with the expression of BCLET, which mainly increased the expression of MSANTD2‐004 through AS of MSANTD2.

Mg-0.7Al-0.3Ca-0.4Mn (AXM070304, wt.%) alloy was subjected to extrusion with a ram speed of 1 mm/s and an extrusion ratio of 25:1. The extrusion temperature varies from 170 °C to 400 °C. The influence of extrusion temperature on microstructure and mechanical properties of the dilute AXM070304 alloy was systematically explored. With raising the extrusion temperature, the average size of the dynamic recrystallized (DRXed) grains was increased, while the intensity of the basal fiber texture was decreased. When the extrusion temperature was escalated from 170 °C to 400 °C, the tensile yield strength (YS) of the low-alloy AXM070304 extrusion alloy was decreased from 437 to 246 MPa, while the elongation to failure (EL) was increased from 2.9 to 16.9%. The alloy extruded at 200 °C obtains an YS of 412 MPa, an ultimate tensile strength (UTS) of 418 MPa and an EL of 14.8%, exhibiting excellent ductility and ultrahigh strength. The ultrahigh YS was mainly due to the strengthening from ultra-fine recrystallized grains (0.61 μm) with grain boundary segregation of solute Al and Ca atoms. The growth of DRXed grains was inhibited mainly by the co-segregation of Al atoms and Ca atoms, nanosized Al2Ca and β-Mn particle phases at the grain boundaries. Plastic instability occurred under tensile loading in the ultrafine-grained AXM070304 alloy, which may be due to the fact that the grain boundary segregation of Al atoms and Ca atoms requires a high energy barrier for dislocation emission. Once the tensile stress reaches the peak value, the mobile dislocation density increases suddenly.

Abstract Background There are few large-scale studies evaluating the safety of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, in Chinese patients with type 2 diabetes. DONATE, a multicentre, single-arm, prospective, non-interventional study, is the first real-world study evaluating the safety of dapagliflozin in Chinese patients with type 2 diabetes in routine clinical practice. Methods Between August 2017 and July 2020, patients with type 2 diabetes who had initiated dapagliflozin therapy and received ≥1 dose were prospectively recruited from 88 hospitals in China. Patients were subsequently followed up for 24 weeks; if patients discontinued dapagliflozin they were followed up for an additional 7 days after treatment discontinuation. The primary outcome was the proportion of patients with adverse events and serious adverse events, particularly key adverse events of special interest (AESI) including urinary tract infection, genital tract infection (typical symptoms with or without microbiological diagnosis) and hypoglycaemia (typical symptoms with or without blood glucose ≤3.9 mmol/L, or blood glucose ≤3.9 mmol/L without symptoms). Exploratory outcomes included the absolute change in metabolic parameters and the proportion of patients with other AESI including volume depletion, abnormal blood electrolytes, polyuria, renal impairment, diabetic ketoacidosis, hepatic impairment and haematuria. Results A total of 3000 patients were enrolled, of whom 2990 (99.7%) were included in the safety analysis set. Mean (SD) age was 52.6 (12.0) years, and 65.8% of patients were male. Mean (SD) duration of type 2 diabetes at enrolment was 8.4 (7.1) years. Mean (SD) treatment duration of dapagliflozin was 209.1 (157.6) days. Adverse events were reported in 35.4% (n = 1059) of patients during the 24-week follow-up period. Overall, 9.0% (n = 268) were related to treatment and 6.2% (n = 186) were serious. Urinary tract infection, genital tract infection and hypoglycaemia were reported in 2.3% (n = 70), 1.3% (n = 39) and 1.1% (n = 32) of patients, respectively. The proportion of patients with other AESI was also low: polyuria (0.7%; n = 21), volume depletion (0.3%; n = 9), renal impairment (0.3%; n = 8), hepatic impairment (0.2%; n = 7), haematuria (0.2%; n = 6) and diabetic ketoacidosis (0.1%; n = 2). Conclusions This study demonstrated that once-daily dapagliflozin was well tolerated in Chinese patients with type 2 diabetes and the overall safety profile of dapagliflozin in clinical practice in China was consistent with that reported in clinical trials. Trial registration ClinicalTrials.gov, NCT03156985. Registered on 16 May, 2017.

Organic polymethine fluorophores with emission in the NIR-II window (1000–1700 nm) are receiving enormous attention in biomolecular medicine and bioimaging, attributed to the high absorption coefficients, bright NIR-II emission, excellent biocompatibility, and molecule adjustability. Recently, researchers have devoted significant effort to designing and improving NIR-II polymethine fluorophores and making notable progress in the NIR-II fluorescence imaging performance. This review summarizes recent developments in the molecular engineering design mentality of polymethine fluorophores and probes and highlights their extensive bioimaging and biosensing applications. Furthermore, we elucidate the potential challenges and perspectives of these NIR-II polymethine dyes in chemical and biomedicine imaging, which may stimulate the further development of high-performance NIR-II polymethine dye contrast agents for their future clinical applications.

With the widespread adoption of ultrasound guidance, Seldinger puncture techniques, and intracardiac electrical positioning technology for the placement of peripherally inserted central catheters in recent years, an increasing number of medical staff and patients now accept peripheral placement of totally implantable venous access devices (TIVADs) in the upper arm. This approach has the advantage of completely avoiding the risks of hemothorax, pneumothorax, and neck and chest scarring. Medical specialties presently engaged in this study in China include internal medicine, surgery, anesthesiology, and interventional departments. However, command over implantation techniques, treatment of complications, and proper use and maintenance of TIVAD remain uneven among different medical units. Moreover, currently, there are no established quality control standards for implantation techniques or specifications for handling complications. Thus, this expert consensus is proposed to improve the success rate of TIVAD implantation via the upper-arm approach, reduce complication rates, and ensure patient safety. This consensus elaborates on the technical indications and contraindications, procedures and technical points, treatment of complications, and the use and maintenance of upper-arm TIVAD, thus providing a practical reference for medical staff.

Abstract Background This study aimed to analyze the clinical characteristics of severe pediatric adenoviral pneumonia combined with invasive pulmonary aspergillosis. Methods We retrospectively analyzed the clinical data of five children clinically diagnosed with severe adenoviral pneumonia combined with invasive pulmonary aspergillosis at Xiamen Children’s Hospital. Results These five children included one boy and four girls, with ages of onset ranging from 8 months and 15 days to 2 years and 2 months. All of them had fever with a mean duration of 11–35 days and cough. Pulmonary imaging was performed, which revealed solid pulmonary opacification in all five children, pleural effusion in two children, and emphysema and multiple small cavity formations in one child. Multiple microbiological tests were performed on the 5 children, and adenovirus was positive in the alveolar lavage fluid for the first time, and aspergillus culture was positive in the second test. On tracheoscopy, the bronchial mucosa was seen to be congested and edematous or pale and eroded; white moss-like material was seen adhering to the tracheal wall or even blocking the airway. The five children were treated with a combination of two or more broad-spectrum antimicrobials, glucocorticoids, and gamma globulins and underwent bronchoscopy. Voriconazole was added in the treatment regimen after the diagnosis of aspergillosis (28–34 days of treatment). Four of the children were discharged in good condition with a mean total length of hospital stay of 17–47 days. The other child leave against medical advice. Follow-up 3–5 months after discharge showed that one child had been cured; two children had developed obliterative bronchiolitis; one child had developed bronchiectasis; and the remaining child who had been discharged spontaneously was not contactable via telephone. Conclusions Immune disorders and antibiotic and steroid treatments for adenovirus infection are high-risk factors for secondary invasive pulmonary aspergillosis in children. Prolonged fever and cough are the main manifestations, but which lack specificity, and bronchoscopic mucosal-specific injury evaluation and alveolar lavage fluid culture are helpful in the diagnosis of aspergillosis. The long-term prognosis of severe pediatric adenoviral pneumonia combined with invasive pulmonary aspergillosis maybe poor.

In this study, a series of flexible neutron/gamma shielding composites are fabricated through the doping of Gd2O3 into the matrix of SEBS with (MGd2O3: MSEBS) % from 5% to 100%. Neutron transmittance test shows an exponential attenuation with the increase of areal density of Gd, in which the transmittance T ranges from 59.1440% to 35.3026%, with standard deviation less than 2.2743%, mass attenuation coefficient μm from 0.3194 cm2/g to 0.4999 cm2/g, and half value layer-HVL value from 2.4530 mm to 1.1313 mm. Shielding efficiency of the Gd2O3/SEBS composites is basically improved in comparison with that of B4C/SEBS. The transmittance T, mass/linear attenuation coefficient μm and μ, HVL and effective atomic number Zeff for the shielding of γ rays (39 keV, 59 keV and 122 keV) are measured and calculated with XCOM as well as MCX programs. Finally, plots of the three dimensional relationships between transmittance, doping amount and thickness are provided to the guidance for engineering shielding design. In summary, the Gd2O3/SEBS composite is proved to be an effective flexible neutron/low energy γ rays shielding material, which could be of potential applications in the field of nuclear technology and nuclear engineering.

J-aggregation, is an effective strategy to extend the wavelength of organic NIR-II fluorescence dyes but weak intermolecular interactions often lead to decomposition of the aggregates in biological environment. Here, the authors demonstrate a series of activatable quinazoline derivatives which can self-assemble in vivo into highly stable NIR-IIJ-aggregates.

ABSTRACTHost innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium, and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.

ObjectiveThe global mortality rates have surged due to the ongoing coronavirus disease 2019 (COVID-19), leading to a worldwide catastrophe. Increasing incidents of patients suffering from cutaneous lupus erythematosus (CLE) exacerbations after either contracting COVID-19 or getting immunized against it, have been observed in recent research. However, the precise intricacies that prompt this unexpected complication are yet to be fully elucidated. This investigation seeks to probe into the molecular events inciting this adverse outcome.MethodGene expression patterns from the Gene Expression Omnibus (GEO) database, specifically GSE171110 and GSE109248, were extracted. We then discovered common differentially expressed genes (DEGs) in both COVID-19 and CLE. This led to the creation of functional annotations, formation of a protein-protein interaction (PPI) network, and identification of key genes. Furthermore, regulatory networks relating to these shared DEGs and significant genes were constructed.ResultWe identified 214 overlapping DEGs in both COVID-19 and CLE datasets. The following functional enrichment analysis of these DEGs highlighted a significant enrichment in pathways related to virus response and infectious disease in both conditions. Next, a PPI network was constructed using bioinformatics tools, resulting in the identification of 5 hub genes. Finally, essential regulatory networks including transcription factor-gene and miRNA-gene interactions were determined.ConclusionOur findings demonstrate shared pathogenesis between COVID-19 and CLE, offering potential insights for future mechanistic investigations. And the identification of common pathways and key genes in these conditions may provide novel avenues for research.

Abstract Identification of cancer‐associated variants, especially those in functional regions of long noncoding RNAs (lncRNAs), has become an essential task in tumor etiology. However, the genetic function of lncRNA variants involved in bladder cancer susceptibility remains poorly understood. Herein, it is identified that the rs62483508 G > A variant in microRNA response elements (MREs) of lncRNA Bladder cancer Cell Cytoplasm‐Enriched abundant transcript 4 (BCCE4) is significantly associated with decreased bladder cancer risk (odds ratio = 0.84, P = 7.33 × 10−8) in the Chinese population (3603 cases and 4986 controls) but not in the European population. The protective genetic effect of the rs62483508 A allele is found in smokers or cigarette smoke‐related carcinogen 4‐aminobiphenyl (4‐ABP) exposure. Subsequent biological experiments reveal that the A allele of rs62483508 disrupts the binding affinity of miR‐328‐3p to facilitate USP18 from miRNA‐mediated degradation and thus specifically attenuates the downstream PD‐L1/PD‐1 interaction. LncRNA BCCE4 is also enriched in exosomes from bladder cancer plasma, tissues, and cells. This comprehensive study clarifies the genetic mechanism of lncRNA BCCE4 in bladder cancer susceptibility and its role in the regulation of the immune response in tumorigenesis. The findings provide a valuable predictor of bladder cancer risk that can facilitate diagnosis and prevention.

Summary: The itch-scratching cycle is mediated by neural dynamics in the brain. However, our understanding of the neural dynamics during this cycle remains limited. In this study, we examine the neural dynamics of 126 mouse brain areas by measuring the calcium signal using fiber photometry. We present numerous response patterns in the mouse brain during the itch-scratching cycle. Interestingly, we find that a group of brain areas exhibit activation only at the end of histamine-induced scratching behavior. Additionally, several brain areas exhibit transient activation at the onset of scratching induced by chloroquine. Both histamine- and chloroquine-induced itch evoke diverse response patterns across the mouse brain. In summary, our study provides a comprehensive dataset for the diverse activity pattern of mouse brain during the itch-scratching cycle, paving the way for further exploration into the neural mechanisms underlying the itch-scratching cycle.

Introduction: CircRNA-protein binding plays a critical role in complex biological activity and disease. Various deep learning-based algorithms have been proposed to identify CircRNA-protein binding sites. These methods predict whether the CircRNA sequence includes protein binding sites from the sequence level, and primarily concentrate on analysing the sequence specificity of CircRNA-protein binding. For model performance, these methods are unsatisfactory in accurately predicting motif sites that have special functions in gene expression.Methods: In this study, based on the deep learning models that implement pixel-level binary classification prediction in computer vision, we viewed the CircRNA-protein binding sites prediction as a nucleotide-level binary classification task, and use a fully convolutional neural networks to identify CircRNA-protein binding motif sites (CPBFCN).Results: CPBFCN provides a new path to predict CircRNA motifs. Based on the MEME tool, the existing CircRNA-related and protein-related database, we analysed the motif functions discovered by CPBFCN. We also investigated the correlation between CircRNA sponge and motif distribution. Furthermore, by comparing the motif distribution with different input sequence lengths, we found that some motifs in the flanking sequences of CircRNA-protein binding region may contribute to CircRNA-protein binding.Conclusion: This study contributes to identify circRNA-protein binding and provides help in understanding the role of circRNA-protein binding in gene expression regulation.

Summary: Background: Heterologous vaccine schedules have been recommended to provide superior immunity and protection against emergent SARS-CoV-2 variants of concern. We aimed to evaluate the safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine RQ3013 compared with adenoviral vectored vaccine Ad5-nCoV and protein subunit vaccine ZF2001 as the fourth dose in adults primed with three doses of inactivated vaccines in China. Methods: We conducted a double-blinded, randomised, controlled, phase 3b trial among healthy Chinese adults at Lancang County, Yunnan, China. Adults who had received three doses of inactivated COVID-19 vaccines at least 6 months prior were randomly allocated (3:1:1) to receive heterologous boosters with RQ3013, Ad5-nCoV, or ZF2001. We assessed safety within 28 days post boost and the serum geometric mean titres (GMTs) of neutralising antibodies (NAbs) against the live SARS-CoV-2 omicron variant BA.5 on day 14 post-boost. We used Poisson regression to assess the vaccine efficacy against the first episode of virologically confirmed symptomatic COVID-19 occurring at least 7 days post boost. Subgroup analyses categorized by age and sex were also performed for safety and immunogenicity outcomes. This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2200065281) and is now complete. Findings: Between December 12 and December 18, 2022, a total of 1382 adults were screened, and 1250 were enrolled and randomly assigned to receive one dose of RQ3013 (n = 750), Ad5-nCoV (n = 250), or ZF2001 (n = 250). Although solicited adverse reactions within 28 days post boost were more frequent in the RQ3013 group (175 [23.3%]) compared to the control groups (24 [9.6%] in both the Ad5-nCOV and ZF2001 groups, P 0.05). On day 14 post-boost, RQ3013 (GMT 69.14, 95% CI 47.90–99.81) elicited 4.8-fold and 5.6-fold higher concentrations of NAbs against BA.5 than did Ad5-nCoV (14.37, 7.78–26.56) and ZF2001 (12.21, 5.13–29.06), respectively. On day 28 post-boost, RQ3013 demonstrated a relative efficacy of 62.2% (95% CI 13.7–83.1, P = 0.02) compared to Ad5-nCoV, and of 69.0% (33.5–85.7, P = 0.002) compared to ZF2001. Interpretation: The administrations of all the three heterologous boosters were well tolerated. The heterologous prime-boost regimen with RQ3013 elicited superior immune responses and demonstrated better protection against symptomatic SARS-CoV-2 infections compared with Ad5-nCoV or ZF2001, supporting the use of RQ3013 as a booster vaccination in adults. Funding: Yunnan Province Science and Technology Department (grant no.202302AA310047).