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Abstract Nuclear receptor subfamily 1, group D, member 1 (NR1D1, also known as REV-ERBα) belongs to the nuclear receptor (NR) family, and is a heme-binding component of the circadian clock that consolidates circadian oscillators. In addition to repressing the transcription of multiple clock genes associated with circadian rhythms, NR1D1 has a wide range of downstream target genes that are intimately involved in many physiopathological processes, including autophagy, immunity, inflammation, metabolism and aging in multiple organs. This review focuses on the pivotal role of NR1D1 as a key transcription factor in the gene regulatory network, with particular emphasis on the milestones of the latest discoveries of NR1D1 ligands. NR1D1 is considered as a promising drug target for treating diverse diseases and may contribute to research on innovative biomarkers and therapeutic targets for organ injury-related diseases. Further research on NR1D1 ligands in prospective human trials may pave the way for their clinical application in many organ injury-related disorders.

BackgroundThe HIV-1 molecular network is an innovative tool, using gene sequences to understand transmission attributes and complementing social and sexual network studies. While previous research focused on static network characteristics, recent studies’ emphasis on dynamic features enhances our understanding of real-time changes, offering insights for targeted interventions and efficient allocation of public health resources. ObjectiveThis study aims to identify the dynamic changes occurring in HIV-1 molecular transmission networks and analyze the primary influencing factors driving the dynamics of HIV-1 molecular networks. MethodsWe analyzed and compared the dynamic changes in the molecular network over a specific time period between the baseline and observed end point. The primary factors influencing the dynamic changes in the HIV-1 molecular network were identified through univariate analysis and multivariate analysis. ResultsA total of 955 HIV-1 polymerase fragments were successfully amplified from 1013 specimens; CRF01_AE and CRF07_BC were the predominant subtypes, accounting for 40.8% (n=390) and 33.6% (n=321) of the specimens, respectively. Through the analysis and comparison of the basic and terminal molecular networks, it was discovered that 144 sequences constituted static molecular networks, and 487 sequences contributed to the formation of dynamic molecular networks. The findings of the multivariate analysis indicated that the factors occupation as a student, floating population, Han ethnicity, engagement in occasional or multiple sexual partnerships, participation in anal sex, and being single were independent risk factors for the dynamic changes observed in the HIV-1 molecular network, and the odds ratio (OR; 95% CIs) values were 2.63 (1.54-4.47), 1.83 (1.17-2.84), 2.91 (1.09-7.79), 1.75 (1.06-2.90), 4.12 (2.48-6.87), 5.58 (2.43-12.80), and 2.10 (1.25-3.54), respectively. Heterosexuality and homosexuality seem to exhibit protective effects when compared to bisexuality, with OR values of 0.12 (95% CI 0.05-0.32) and 0.26 (95% CI 0.11-0.64), respectively. Additionally, the National Eight-Item score and sex education experience were also identified as protective factors against dynamic changes in the HIV-1 molecular network, with OR values of 0.12 (95% CI 0.05-0.32) and 0.26 (95% CI 0.11-0.64), respectively. ConclusionsThe HIV-1 molecular network analysis showed 144 sequences in static networks and 487 in dynamic networks. Multivariate analysis revealed that occupation as a student, floating population, Han ethnicity, and risky sexual behavior were independent risk factors for dynamic changes, while heterosexuality and homosexuality were protective compared to bisexuality. A higher National Eight-Item score and sex education experience were also protective factors. The identification of HIV dynamic molecular networks has provided valuable insights into the characteristics of individuals undergoing dynamic alterations. These findings contribute to a better understanding of HIV-1 transmission dynamics and could inform targeted prevention strategies.

This study introduces newly discovered chrysin derivatives that show potential as candidate molecules for treating inflammatory bowel disease (IBD). Compound 4b, among the synthesized compounds, displayed significant inhibitory effects on monocyte adhesion to colon epithelium induced by TNF-α, with an IC50 value of 4.71 μM. Further mechanistic studies demonstrated that 4b inhibits the production of reactive oxygen species (ROS) and downregulates the expression of ICAM-1 and MCP-1, key molecules involved in monocyte-epithelial adhesion, as well as the transcriptional activity of NF-κB. In vivo experiments have shown that compound 4b exhibits a dose-dependent inhibition of 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats, thereby validating its effectiveness as a colitis inhibitor in animal models. These results indicate that 4b shows considerable promise as a therapeutic agent for managing IBD.

Abstract According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs.

Objectives There was no evidence regarding the relationship between septic shock and tracheal injury scores. Investigate whether septic shock was independently associated with tracheal injury scores in intensive care unit (ICU) patients with invasive ventilation.Design Prospective observational cohort study.Setting Our study was conducted in a Class III hospital in Hebei province, China.Participants Patients over 18 years of age admitted to the ICU between 31 May 2020 and 3 May 2022 with a tracheal tube and expected to be on the tube for more than 24 hours.Primary and secondary outcome measures Tracheal injuries were evaluated by examining hyperaemia, ischaemia, ulcers and tracheal perforation by fiberoptic bronchoscope. Depending on the number of lesions, the lesions were further classified as moderate, severe or confluent.Results Among the 97 selected participants, the average age was 56.6±16.5 years, with approximately 64.9% being men. The results of adjusted linear regression showed that septic shock was associated with tracheal injury scores (β: 2.99; 95% CI 0.70 to 5.29). Subgroup analysis revealed a stronger association with a duration of intubation ≥8 days (p=0.013).Conclusion Patients with septic shock exhibit significantly higher tracheal injury scores compared with those without septic shock, suggesting that septic shock may serve as an independent risk factor for tracheal injury.Trial registration number ChiCTR2000037842, registered 03 September 2020. Retrospectively registered, https://www.chictr.org.cn/edit.aspx?pid=57011&htm=4.

Objective: Primary squamous cell thyroid carcinoma (PSCTC) is an extremely rare carcinoma, accounting for less than 1% of all thyroid carcinomas. However, the factors contributing to PSCTC outcomes remain unclear. This study aimed to identify the prognostic factors and develop a prognostic predictive model for patients with PSCTC. Methods: The analysis included patients diagnosed with thyroid carcinoma between 1975 and 2016 from the Surveillance, Epidemiology, and End Results database. Prognostic differences among the 5 pathological types of thyroid carcinomas were analyzed. To determine prognostic factors in PSCTC patients, the Cox regression model and Fine–Gray competing risk model were utilized. Based on the Fine–Gray competing risk model, a nomogram was established for predicting the prognosis of patients with PSCTC. Results: A total of 198,757 thyroid carcinoma patients, including 218 PSCTC patients, were identified. We found that PSCTC and anaplastic thyroid cancer had the worst prognosis among the 5 pathological types of thyroid carcinoma ( P

Arsenic (As) accumulation in plants is a global concern. Although the application of arbuscular mycorrhizal fungi (AMF) has been suggested as a potential solution to decrease As concentration in plants, there is currently a gap in a comprehensive, quantitative assessment of the abiotic and biotic factors influencing As accumulation. A meta-analysis was performed to quantitatively investigate the findings of 76 publications on the impacts of AMF, plant properties, and soil on As accumulation in plants. Results showed a significant dose-dependent As reduction with higher mycorrhizal infection rates, leading to a 19.3% decrease in As concentration. AMF reduced As(V) by 19.4% but increased dimethylarsenic acid (DMA) by 50.8%. AMF significantly decreased grain As concentration by 34.1%. AMF also improved plant P concentration and dry biomass by 33.0% and 62.0%, respectively. The most significant reducing effects of As on AMF properties were seen in single inoculation and experiments with intermediate durations. Additionally, the benefits of AMF were significantly enhanced when soil texture, soil organic carbon (SOC), pH level, Olsen-P, and DTPA-As were sandy soil, 0.8%–1.5%, ≥7.5, ≥9.1 mg/kg, and 30–60 mg/kg, respectively. AMF increased easily extractable glomalin-related soil protein (EE-GRSP) and total glomalin-related soil protein (T-GRSP) by 23.0% and 28.0%, respectively. Overall, the investigated factors had significant implications in developing AMF-based methods for alleviating the negative effects of As stress on plants.

Objective Mobile health (mHealth) technologies are emerging to support the delivery of pulmonary rehabilitation (PR). This study aimed to explore the ease of use, satisfaction and acceptability of an Australian mobile pulmonary rehabilitation app (m-PR™) in people with chronic obstructive pulmonary disease (COPD). Methods In this mixed methods observational study, participants with COPD were recruited following PR assessment. Participants were educated on m-PR™ which contained symptom monitoring, individualised exercise training with exercise videos, education videos, goal setting, health notifications and medication action plan. Participants used m-PR™ for 4–8 weeks. At baseline, participants were surveyed to assess level of technology engagement. At follow-up, participants completed the system usability survey (SUS), a satisfaction survey and a semi-structured interview. Results Fifteen participants (mean age 70 [SD 10] years, 53% female) completed the study. Technology usage was high with 73% (n = 11) self-rating their technology competence as good or very good. The SUS score of 71 (SD 16) demonstrated above average perceived usability of m-PR™. The satisfaction survey indicated that 67% (n = 10) enjoyed m-PR™ and 33% (n = 5) were neutral. Most participants found the different m-PR™ components somewhat easy or very easy to use (range 69–100%) and somewhat helpful or very helpful (range 76–100%). Interview responses revealed that m-PR™ elicited divergent feelings among participants, who reported both positive and negative feelings towards the app's features, the effort required to use it and data security. Conclusion The majority of participants found m-PR™ enjoyable, easy to use and helpful in managing their COPD. Further research is warranted to understand the effectiveness of mHealth to deliver PR.

Brooks are significant ecological sources and migration channels of material flow as well as energy flow in urban–rural fringes. Despite their significance, the absence of monitoring data poses challenges in assessing brook pollution risk. Taking Muli Brook as an example, a spatiotemporal variability of water quality was revealed through sample collection and water chemistry analysis. We reveal spatiotemporal variability of pollution and then developed an Exposure Index (EPI), verifying its substitution effect in assessing brook pollution risk. Our findings demonstrate a downward trend in pollution from 2020 to 2022, with exceptions in dissolved oxygen (DO) and pH. Notably, more severe pollution is observed during spring and summer, influenced by seasonal production activities and extreme weather events. Despite the diminishing disparity near urban areas, the cumulative influence of upstream pollutants outweighs that of surrounding human activities. Stronger associations between pollution risks and water area EPI were observed, compared to those of construction land and farm land. In conclusion, EPI emerges as a valuable tool for assessing brook pollution risks in urban–rural fringes, offering precise insights into brook habitat characteristics, especially in the absence of consistent monitoring data.

Background Ischemic stroke (IS) is the main cause of death and adult disability. However, the pathogenesis of this complicated disease is unknown. The present study aimed to assess the relationship between ITLN1 single nucleotide polymorphisms (SNPs) and the susceptibility to IS in Xi’an population, Shaanxi province. Methods In this study, we designed polymerase chain reaction (PCR) primers located at −3,308 bp upstream of the transcription initiation site within promoter region of the ITLN1 gene. The target fragment was amplified by PCR and identified by agarose gel electrophoresis. Sanger sequencing was then performed in the samples extracted from a cohort comprising 1,272 participants (636 controls and 636 cases), and the obtained sequences were compared with the reference sequences available on the National Center for Biotechnology Information (NCBI) website to detect SNPs in the ITLN1 gene promoter region. Logistic regression analysis was employed to assess the relationship between ITLN1 polymorphisms and IS risk, with adjustments for age and gender. Significant positive results were tested by false-positive report probability (FPRP) and false discovery rate (FDR). The interaction among noteworthy SNPs and their predictive relationship with IS risk were explored using the Multi-Factor Dimensionality Reduction (MDR) software. Results The results of Sanger sequencing were compared with the reference sequences on the NCBI website, and we found 14 SNPs in ITLN1 gene promoter satisfied Hardy-Weinberg equilibrium (HWE). Logistic regression analysis showed that ITLN1 was associated with a decreased risk of IS (rs6427553: Homozygous C/C: adjusted OR: 0.69, 95% CI [0.48–0.97]; Log-additive: adjusted OR: 0.83, 95% CI [0.70–0.98]; rs7411035: Homozygous G/G: adjusted OR: 0.66, 95% CI [0.47–0.94]; Dominant G/T-G/G: adjusted OR: 0.78, 95% CI [0.62–0.98]; Log-additive: adjusted OR: 0.81, 95% CI [0.69–0.96]; rs4656958: Heterozygous G/A: adjusted OR: 0.74, 95% CI [0.59–0.94]; Homozygous A/A: adjusted OR: 0.51, 95% CI [0.31–0.84]; Dominant G/A-A/A: adjusted OR: 0.71, 95% CI [0.57–0.89]; Recessive A/A: adjusted OR: 0.59, 95% CI [0.36–0.96]; Log-additive: adjusted OR: 0.73, 95% CI [0.61–0.88]), especially in people aged less than 60 years and males. Conclusions In short, our study revealed a correlation between ITLN1 variants (rs6427553, rs7411035 and rs4656958) and IS risk in Xi’an population, Shaanxi province, laying a foundation for ITLN1 gene as a potential biomarker for predicting susceptibility to IS.

Summary: Graphene, known for its ultrahigh carrier mobility and broadband optical absorption, holds significant potential in optoelectronics. However, the carrier mobility of graphene on silicon substrates experienced a marked decrease due to surface roughness, phonon scattering affects. Here we report carrier mobility enhancement of graphene dielectric engineering. Through the fabrication of devices utilizing Si/SiO2/Al2O3/graphene layers and subsequent electrical characterization, our findings illustrate the navigable nature of the Al2O3 dielectric layer is navigable for reducing the SiO2 phonon scattering and increasing graphene’s carrier mobility by up to ∼8000 cm2V−1s−1. Furthermore, the improvement in carrier mobility of graphene has been utilized in the hybrid near-infrared photodetector, resulting in outstanding responsivity of ∼400 AW-1, detectivity of ∼2.2 ✕ 1011 Jones in the graphene/Ag2Te detector. Our study establishes pathways for the seamless integration of graphene or other 2D materials within the standard CMOS processes, thereby facilitating the fabrication of advanced optoelectronic devices.

Abstract A simulation study was carried out to investigate the temporal evolution of H2S in the Huangcaoxia underground gas storage (UGS), which is converted from a depleted sulfur-containing gas field. Based on the rock and fluid properties of the Huangcaoxia gas field, a multilayered model was built. The upper layer Jia-2 contains a high concentration of H2S (27.2 g/m3), and the lower layer Jia-1 contains a low concentration of H2S (14.0 mg/m3). There is also a low-permeability interlayer between Jia-1 and Jia-2. The multi-component fluid characterizations for Jia-1 and Jia-2 were implemented separately using the Peng-Robinson equation of state in order to perform the compositional simulation. The H2S concentration gradually increased in a single cycle and peaked at the end of the production season. The peak H2S concentration in each cycle showed a decreasing trend when the recovery factor (RF) of the gas field was lower than 70%. When the RF was above 70%, the peak H2S concentration increased first and then decreased. A higher reservoir RF, a higher maximum working pressure, and a higher working gas ratio will lead to a higher H2S removal efficiency. Similar to developing multi-layered petroleum fields, the operation of multilayered gas storage can also be divided into multi-layer commingled operation and independent operation for different layers. When the two layers are combined to build the storage, the sweet gas produced from Jia-1 can spontaneously mix with the sour gas produced from Jia-2 within the wellbore, which can significantly reduce the overall H2S concentration in the wellstream. When the working gas volume is set constant, the allocation ratio between the two layers has little effect on the H2S removal. After nine cycles, the produced gas’s H2S concentration can be lowered to 20 mg/m3. Our study recommends combining the Jia-2 and Jia-1 layers to build the Huangcaoxia underground gas storage. This plan can quickly reduce the H2S concentration of the produced gas to 20 mg/m3, thus meeting the gas export standards as well as the HSE (Health, Safety, and Environment) requirements in the field. This study helps the engineers understand the H2S removal for sulfur-containing UGS as well as provides technical guidelines for converting other multilayered sour gas fields into underground storage sites.

Abstract Background Cerebral stroke (CS) is the leading cause of death in China, and a complex disease caused by both alterable risk factors and genetic factors. This study intended to investigate the association of MMP3, MMP14, and MMP25 single nucleotide polymorphisms (SNPs) with CS risk in a Chinese Han population. Methods A total of 1,348 Han Chinese were recruited in this case-control study. Four candidate loci including rs520540 A/G and rs679620 T/C of MMP3, rs2236302 G/C of MMP14, and rs10431961 T/C of MMP25 were successfully screened. The correlation between the four SNPs and CS risk was assessed by logistic regression analysis. The results were analyzed by false-positive report probability (FPRP) for chance or significance. The interactions between four SNPs associated with CS risk were assessed by multifactor dimensionality reduction (MDR). Results rs520540 A/G and rs679620 C/T SNP in MMP3 were associated with risk of CS in allele, codominant, dominant and log-additive models. Ischemic stroke risk were significantly lower in carriers with rs520540-A allele and rs679620-T allele than those with G/G or C/C genotypes. However, rs520540-A allele and rs679620-T allele were associated with higher risk of hemorrhagic stroke. Stratified analysis showed that these two SNPs were associated with reduced risk of CS in aged

Abstract This paper presents comprehensive research of the advantages and applicability of various concrete carbonation detection methods. Employing a combination of Phenolphthalein indicator (PI), Thermogravimetric analysis (TGA), X-ray phase analysis (XRD), Fourier transform infrared spectroscopy (FTIR), and Quantitative calcium carbonate analysis (CA), a detailed comparison to determine the carbonation depth in the partial carbonation zone of concrete specimens is conducted. Among the quantitative analysis methods, CA measures CaCO3 content based on chemical reactions, while TGA obtains the concentration distribution of Ca(OH)2 and CaCO3. Among qualitative analysis methods, XRD tested the intensity distribution of Ca(OH)2 and CaCO3, while FTIR traced the characteristic peaks of C-O functional groups in a specific spectral range to determine the depth of carbonation of concrete. Results indicate that the depth of carbonation values measured by CA, TGA, XRDA, and FTIR are 2–3 times higher than those measured by PI. This research may provide valuable insights for the design of carbonation detection in concrete.

Abstract The process of post-transcriptional regulation has been recognized to be significantly impacted by the presence of N6-methyladenosine (m6A) modification. As an m6A demethylase, ALKBH5 has been shown to contribute to the progression of different cancers by increasing expression of several oncogenes. Hence, a better understanding of the key targets of ALKBH5 in cancer cells could potentially lead to the development of new therapeutic targets. However, the specific role of ALKBH5 in pancreatic neuroendocrine neoplasms (pNENs) remains largely unknown. Here, we demonstrated that ALKBH5 was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, ALKBH5 over-expression was found to increase the expression of FABP5 in an m6A-IGF2BP2 dependent manner, leading to disorders in lipid metabolism. Additionally, ALKBH5 was found to activate PI3K/Akt/mTOR signaling pathway, resulting in enhanced lipid metabolism and proliferation abilities. In conclusion, our study uncovers the ALKBH5/IGF2BP2/FABP5/mTOR axis as a mechanism for aberrant m6A modification in lipid metabolism and highlights a new molecular basis for the development of therapeutic strategies for pNENs treatment. Graphical Abstract

Abstract The interruption of normal cell cycle execution acts as an important part to the development of leukemia. It was reported that microRNAs (miRNAs) were closely related to tumorigenesis and progression, and their aberrant expression had been demonstrated to play a crucial role in numerous types of cancer. Our previous study showed that miR-1246 was preferentially overexpressed in chemo-resistant leukemia cell lines, and participated in process of cell cycle progression and multidrug resistant regulation. However, the underlying mechanism remains unclear. In present study, bioinformatics prediction and dual luciferase reporter assay indicated that CADM1 was a direct target of miR-1246. Evidently decreased expression of CADM1 was observed in relapsed primary leukemia patients and chemo-resistant cell lines. Our results furtherly proved that inhibition of miR-1246 could significantly enhance drug sensitivity to Adriamycin (ADM), induce cell cycle arrest at G0/G1 phase, promote cell apoptosis, and relieve its suppression on CADM1 in K562/ADM and HL-60/RS cells. Interference with CADM1 could reduce the increased drug sensitivity induced by miR-1246 inhibition, and notably restore drug resistance by promoting cell cycle progression and cell survival via regulating CDKs/Cyclins complexes in chemo-resistant leukemia cells. Above all, our results demonstrated that CADM1 attenuated the role of miR-1246 in promoting cell cycle progression and cell survival, thus influencing multidrug resistance within chemo-resistant leukemia cells via CDKs/Cyclins. Higher expression of miR-1246 and lower expression of CADM1 might be risk factors for leukemia.

Abstract Backgrounds Gait disorder is associated with cognitive functional impairment, and this disturbance is more pronouncedly when performing additional cognitive tasks. Our study aimed to characterize gait disorders in mild cognitive impairment (MCI) under three dual tasks and determine the association between gait performance and cognitive function. Methods A total of 260 participants were enrolled in this cross-sectional study and divided into MCI and cognitively normal control. Spatiotemporal and kinematic gait parameters (31 items) in single task and three dual tasks (serial 100-7, naming animals and words recall) were measured using a wearable sensor. Baseline characteristics of the two groups were balanced using propensity score matching. Important gait features were filtered using random forest method and LASSO regression and further described using logistic analysis. Results After matching, 106 participants with MCI and 106 normal controls were recruited. Top 5 gait features in random forest and 4 ~ 6 important features in LASSO regression were selected. Robust variables associating with cognitive function were temporal gait parameters. Participants with MCI exhibited decreased swing time and terminal swing, increased mid stance and variability of stride length compared with normal control. Subjects walked slower when performing an extra dual cognitive task. In the three dual tasks, words recall test exhibited more pronounced impact on gait regularity, velocity, and dual task cost than the other two cognitive tests. Conclusion Gait assessment under dual task conditions, particularly in words recall test, using portable sensors could be useful as a complementary strategy for early detection of MCI.

Abstract Background The mechanisms whereby CYFIP2 acts in tumor development and drives immune infiltration have been poorly explored. Thus, this study aimed to identifying the role of CYFIP2 in tumors and immune response. Methods In this study, we first explored expression patterns, diagnostic role and prognostic value of CYFIP2 in cancers, particularly in lung adenocarcinoma (LUAD). Then, we performed functional enrichment, genetic alterations, DNA methylation analysis, and immune cell infiltration analysis of CYFIP2 to uncover its potential mechanisms involved in immune microenvironment. Results We found that CYFIP2 significantly differentially expressed in different tumors including LUAD compared with normal tissues. Furthermore, CYFIP2 was found to be significantly correlated with clinical parameters in LUAD. According to the diagnostic and survival analysis, CYFIP2 may be employed as a potential diagnostic and prognostic biomarker. Moreover, genetic alterations revealed that mutation of CYFIP2 was the main types of alterations in different cancers. DNA methylation analysis indicated that CYFIP2 mRNA expression correlated with hypomethylation. Afterwards, functional enrichment analysis uncovered that CYFIP2 was involved in tumor-associated and immune-related pathways. Immune infiltration analysis indicated that CYFIP2 was significantly correlated with immune cells infiltration. In particular, CYFIP2 was strongly linked with immune microenvironment scores. Additionally, CYFIP2 exhibited a significant relationship with immune regulators and immune-related genes including chemokines, chemokines receptors, and MHC genes. Conclusion Our results suggested that CYFIP2 may serve as a prognostic cancer biomarker for determining prognosis and might be a promising therapeutic strategy for tumor immunotherapy.

Abstract Background Arginase-1 (ARG1) promotes collagen synthesis and cell proliferation. ARG1 is highly expressed in various tumour cells. The mechanisms of ARG1 in epithelial-to-mesenchymal transition (EMT)-associated cataracts were studied herein. Methods C57BL/6 mice, a human lens epithelial cell line (HLEC-SRA01/04), and human lens capsule samples were used in this study. The right lens anterior capsule of the mouse eye was punctured through the central cornea with a 26-gauge hypodermic needle. Human lens epithelial cells (HLECs) were transfected with ARG1-targeted (siARG1) or negative control siRNA (siNC). For gene overexpression, HLECs were transfected with a plasmid bearing the ARG1 coding sequence or an empty vector. Medium containing 0.2% serum with or without transforming growth factor beta-2 (TGF-β2) was added for 6 or 24 h to detect mRNA or protein, respectively. The expression of related genes was measured by quantitative real-time polymerase chain reaction (RT–qPCR), western blotting, and immunohistochemical staining. Transwell assays and wound healing assays were used to determine cell migration. Cell proliferation, superoxide levels, nitric oxide (NO) levels, and arginase activity were estimated using Cell Counting Kit-8 assays, a superoxide assay kit, an NO assay kit, and an arginase activity kit. Results ARG1, alpha-smooth muscle actin (α-SMA), fibronectin, and Ki67 expression increased after lens capsular injury, while zonula occludens-1 (ZO-1) expression decreased. Fibronectin and collagen type I alpha1 chain (collagen 1A1) expression increased, and cell migration increased significantly in ARG1-overexpressing HLECs compared with those transfected with an empty vector after TGF-β2 treatment. These effects were reversed by ARG1 knockdown. The arginase-related pathway plays an important role in EMT. mRNAs of enzymes of the arginase-related pathway were highly expressed after ARG1 overexpression. ARG1 knockdown suppressed these expression changes. Numidargistat (CB-1158) dihydrochloride (CB-1158), an ARG1 inhibitor, suppressed TGF-β2-induced anterior subcapsular cataract (ASC) by reducing the proliferation of lens epithelial cells (LECs) and decreasing fibronectin, α-SMA, collagen 1A1, and vimentin expression. Compared with that in nonanterior subcapsular cataract (non-ASC) patients, the expression of ARG1, collagen 1A1, vimentin, fibronectin, and Ki67 was markedly increased in ASC patients. Conclusions ARG1 can regulate EMT in EMT-associated cataracts. Based on the pathogenesis of ASC, these findings are expected to provide new therapeutic strategies for patients. Graphical abstract

Abstract Background Varicella zoster virus (VZV), which is a human restricted alpha-herpesvirus, causes varicella (chickenpox) and zoster (shingles). The subsequent post-herpetic neuralgia (PHN) due to VZV infection is excruciating for most patients. Thus, developing specific therapeutics against VZV infection is imperative. RNA interference (RNAi) represents an effective approach for alternative antiviral therapy. This study aimed to develop a novel anti-VZV therapeutics based on RNAi. Results In this study, we screened and found the open reading frame 7 (ORF7) of the VZV genome was an ideal antiviral target based on RNAi. Therefore, a novel siRNA targeting ORF7 (si-ORF7) was designed to explore the potential of RNAi antiviral treatment strategy toward VZV. We used a bio-engineering approach to manufacture recombinant siRNA agents with high yield in E. coli. Then, the efficacy of recombinant ORF7-siRNA (r/si-ORF7) in inhibiting VZV infection both in cellular level and 3D human epidermal skin model was evaluated. The r/si-ORF7 was proved to inhibit the VZV replication and reduce the virus copy numbers significantly in vitro. Furthermore, flexible nano-liposomes were established to deliver r/si-ORF7 to 3D human epidermal skin model and found r/si-ORF7 also could inhibit the VZV infection, thus maintaining normal skin morphology. Conclusions Taken together, our results highlighted that transdermal administration of antiviral r/si-ORF7 was a promising therapeutic strategy for functional cure of VZV infection.

Abstract Background The clinical indications of extracorporeal membrane oxygenation (ECMO) in immunosuppressed patients are not clear. This study aimed to analyse the effectiveness of ECMO and to identify the risk factors for the mortality of ECMO in immunocompromised patients with acute respiratory failure. Methods This retrospective, cohort study included 46 confirmed immunocompromised patients with acute hypoxemic respiratory failure treated with ECMO between July 2014 and August 2020. The clinical features and outcomes of the survival group and the non‐survival group were statistically analysed. Results The mean age of the enrolled patients was 60.0 (50.0, 66.0) years; male patients accounted for 60.9% of patients, and the mean CD4 level was 213 cells/μL (150.3, 325.3). The hospital mortality rate of the cohort was 67.4% (31/46 patients). Patients in the survival group showed a higher rate of receiving awake ECMO (11/15 vs. 4/31; p = 0.006), a lower rate of acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT) (1/15 vs. 12/31; p = 0.035), fewer platelet transfusion units (0/15 vs. 2/31 units; p = 0.039) and a lower rate of ventilator‐associated pneumonia (2/15 vs. 19/31; p = 0.006). In a multivariate Cox regression analysis model, intubated ECMO (hazard ratio = 1.77, 95% confidence interval: 1.34–2.32, p

Abstract The quantum Hall effect, fundamental in modern condensed matter physics, continuously inspires new theories and predicts emergent phases of matter. Here we experimentally demonstrate three types of Chern insulators with synthetic dimensions on a programable 30-qubit-ladder superconducting processor. We directly measure the band structures of the 2D Chern insulator along synthetic dimensions with various configurations of Aubry-André-Harper chains and observe dynamical localisation of edge excitations. With these two signatures of topology, our experiments implement the bulk-edge correspondence in the synthetic 2D Chern insulator. Moreover, we simulate two different bilayer Chern insulators on the ladder-type superconducting processor. With the same and opposite periodically modulated on-site potentials for two coupled chains, we simulate topologically nontrivial edge states with zero Hall conductivity and a Chern insulator with higher Chern numbers, respectively. Our work shows the potential of using superconducting qubits for investigating different intriguing topological phases of quantum matter.

Abstract Background Intrinsically disordered regions (IDRs) are widely distributed in proteins and related to many important biological functions. Accurately identifying IDRs is of great significance for protein structure and function analysis. Because the long disordered regions (LDRs) and short disordered regions (SDRs) share different characteristics, the existing predictors fail to achieve better and more stable performance on datasets with different ratios between LDRs and SDRs. There are two main reasons. First, the existing predictors construct network structures based on their own experiences such as convolutional neural network (CNN) which is used to extract the feature of neighboring residues in protein, and long short-term memory (LSTM) is used to extract the long-distance dependencies feature of protein residues. But these networks cannot capture the hidden feature associated with the length-dependent between residues. Second, many algorithms based on deep learning have been proposed but the complementarity of the existing predictors is not fully explored and used. Results In this study, the neural architecture search (NAS) algorithm was employed to automatically construct the network structures so as to capture the hidden features in protein sequences. In order to stably predict both the LDRs and SDRs, the model constructed by NAS was combined with length-dependent models for capturing the unique features of SDRs or LDRs and general models for capturing the common features between LDRs and SDRs. A new predictor called IDP-Fusion was proposed. Conclusions Experimental results showed that IDP-Fusion can achieve more stable performance than the other existing predictors on independent test sets with different ratios between SDRs and LDRs.

Abstract Schizophrenia is a chronic neuropsychiatric disorder that causes distinct structural alterations within the brain. We hypothesize that deep learning applied to a structural neuroimaging dataset could detect disease-related alteration and improve classification and diagnostic accuracy. We tested this hypothesis using a single, widely available, and conventional T1-weighted MRI scan, from which we extracted the 3D whole-brain structure using standard post-processing methods. A deep learning model was then developed, optimized, and evaluated on three open datasets with T1-weighted MRI scans of patients with schizophrenia. Our proposed model outperformed the benchmark model, which was also trained with structural MR images using a 3D CNN architecture. Our model is capable of almost perfectly (area under the ROC curve = 0.987) distinguishing schizophrenia patients from healthy controls on unseen structural MRI scans. Regional analysis localized subcortical regions and ventricles as the most predictive brain regions. Subcortical structures serve a pivotal role in cognitive, affective, and social functions in humans, and structural abnormalities of these regions have been associated with schizophrenia. Our finding corroborates that schizophrenia is associated with widespread alterations in subcortical brain structure and the subcortical structural information provides prominent features in diagnostic classification. Together, these results further demonstrate the potential of deep learning to improve schizophrenia diagnosis and identify its structural neuroimaging signatures from a single, standard T1-weighted brain MRI.

Air conditioning contributes a high percentage of energy consumption over the world. The efficient prediction of energy consumption can help to reduce energy consumption. Traditionally, multidimensional air conditioning energy consumption data could only be processed sequentially for each dimension, thus resulting in inefficient feature extraction. Furthermore, due to reasons such as implicit correlations between hyperparameters, automatic hyperparameter optimization (HPO) approaches can not be easily achieved. In this paper, we propose an auto-optimization parallel energy consumption prediction approach based on reinforcement learning. It can parallel process multidimensional time series data and achieve the automatic optimization of model hyperparameters, thus yielding an accurate prediction of air conditioning energy consumption. Extensive experiments on real air conditioning datasets from five factories have demonstrated that the proposed approach outperforms existing prediction solutions, with an increase in average accuracy by 11.48% and an average performance improvement of 32.48%.

The high-efficiency preparation of large-area microstructures of optical materials and precision graphic etching technology is one of the most important application directions in the atomic and near-atomic-scale manufacturing industry. Traditional focused ion beam (FIB) and reactive ion etching (RIE) methods have limitations in precision and efficiency, hindering their application in automated mass production. The pulsed ion beam (PIB) method addresses these issues by enhancing ion beam deflection to achieve high-resolution material removal on a macro scale, which can reach the equivalent removal resolution of 6.4 × 10−4 nm. Experiments were conducted on a quartz sample (10 × 10 × 1 mm) with a specific pattern mask using the custom PIB processing device. The surface morphology, etching depth, and roughness were measured post-process. The results demonstrated that precise control over cumulative sputtering time yielded well-defined patterns with expected average etching depths and surface roughness. This confirms the PIB technique’s potential for precise atomic depth image transfer and its suitability for industrial automation, offering a significant advancement in microfabrication technology.

The performance of corrosion-induced cracking of reinforced concrete members under transverse constraints was studied. Based on the theory of elastic-plastic mechanics and the hypothesis of uniform corrosion of a steel bar, a three-layer hollow cylinder model was established to predict the critical corrosion of the steel bar at the time of the cracking of the concrete cover. Taking the constraint of stirrups on surrounding concrete into consideration, it can be used to predict the corrosion rate of members with stirrups at the time of the cracking of the concrete cover, which further expands the application range of the corrosion-induced cracking models of concrete. On this basis, the critical corrosion rate of concrete under different stirrup ratios at the time of cracking was measured. The calculated results of the model are in accordance with experimental data. For corner steel bars, when the stirrup spacing is less than 100 mm, the existence of stirrups can effectively delay the occurrence of rust expansion cracks and enhance the durability of the structure. On the basis of this study, the problem of corrosion expansion and cracking of the concrete cover caused by non-uniform corrosion of steel bars along longitudinal and radial directions needs to be further studied in the future.

Solid-contact ion-selective electrodes (SC-ISEs) have the advantages of easy miniaturization, even chip integration, easy carrying, strong stability, and more favorable detection in complex environments. They have been widely used in conjunction with portable, wearable, and intelligent detection devices, as well as in on-site analysis and timely monitoring in the fields of environment, industry, and medicine. This article provides a comprehensive review of the composition of sensors based on redox capacitive and double-layer capacitive SC-ISEs, as well as the ion–electron transduction mechanisms in the solid-contact (SC) layer, particularly focusing on strategies proposed in the past three years (since 2021) for optimizing the performance of SC-ISEs. These strategies include the construction of ion-selective membranes, SC layer, and conductive substrates. Finally, the future research direction and possibilities in this field are discussed and prospected.

Curved grid stiffeners, compared to straight stiffeners, offer greater flexibility in adjusting the force transmission paths and give better structural performance. In this paper, a level-set-based density method is employed to generate layouts of curved grid stiffeners so that the critical buckling load factor (BLF) of the stiffened structures is improved. During the optimization process, volume constraint is incorporated to control material utilization, and gradient constraints are employed to maintain uniformity in the width of the stiffeners. Finally, the proposed method is demonstrated through several numerical examples.

The integration of Synthetic Aperture Radar (SAR) imaging technology with deep neural networks has experienced significant advancements in recent years. Yet, the scarcity of high-quality samples and the difficulty of extracting prior information from SAR data have experienced limited progress in this domain. This study introduces an innovative sparse SAR imaging approach using a self-supervised non-local asymmetric pixel-shuffle blind spot network. This strategy enables the network to be trained without labeled samples, thus solving the problem of the scarcity of high-quality samples. Through asymmetric pixel-shuffle downsampling (AP) operation, the spatial correlation between pixels is broken so that the blind spot network can adapt to the actual scene. The network also incorporates a non-local module (NLM) into its blind spot architecture, enhancing its capability to analyze a broader range of information and extract more comprehensive prior knowledge from SAR data. Subsequently, Plug and Play (PnP) technology is used to integrate the trained network into the sparse SAR imaging model to solve the regularization term problem. The optimization of the inverse problem is achieved through the Alternating Direction Method of Multipliers (ADMM) algorithm. The experimental results of the unlabeled samples demonstrate that our method significantly outperforms traditional techniques in reconstructing images across various regions.

Objectives Radiofrequency catheter ablation is the first-line treatment for idiopathic premature ventricular complexes (PVCs) and ventricular tachycardias (VTs). However, the outcomes were less compared among the categories. The study aims to assess the effectiveness and safety of catheter ablation for idiopathic PVC/VTs in a single high-volume centre, using the right ventricular outflow tract (RVOT) as a reference.Design Retrospective cohort study.Setting Patient data were collected from a tertiary hospital in Guizhou, China.Participants Between September 2013 and September 2022, 1028 patients (male: 41.3%; age: 46.5±15.6 years) who underwent the first catheter ablation for idiopathic monomorphic PVC/VTs were enrolled.Outcome measures Acute success, procedure-related complications, and long-term recurrence were assessed. Antiarrhythmic drugs (AADs) were not administrated after procedures unless recurrence was identified.Results The overall acute success rate was 90.3%, with 368 patients (35.8%) experiencing left ventricular PVC/VTs. No cases of third-degree atrioventricular block or death were reported. Complications were more common in patients with left ventricular PVC/VTs than those with right-sided ones (4.6% vs 0.1%, p

Drought stress is one of the main threats to poplar plant growth and has a negative impact on plant yield. Currently, high-throughput plant phenotyping has been widely studied as a rapid and nondestructive tool for analyzing the growth status of plants, such as water and nutrient content. In this study, a combination of computer vision and deep learning was used for drought-stressed poplar sapling phenotyping. Four varieties of poplar saplings were cultivated, and 5 different irrigation treatments were applied. Color images of the plant samples were captured for analysis. Two tasks, including leaf posture calculation and drought stress identification, were conducted. First, instance segmentation was used to extract the regions of the leaf, petiole, and midvein. A dataset augmentation method was created for reducing manual annotation costs. The horizontal angles of the fitted lines of the petiole and midvein were calculated for leaf posture digitization. Second, multitask learning models were proposed for simultaneously determining the stress level and poplar variety. The mean absolute errors of the angle calculations were 10.7° and 8.2° for the petiole and midvein, respectively. Drought stress increased the horizontal angle of leaves. Moreover, using raw images as the input, the multitask MobileNet achieved the highest accuracy (99% for variety identification and 76% for stress level classification), outperforming widely used single-task deep learning models (stress level classification accuracies of

As an effective tool for refining local gravity data with mGal accuracy, vehicle gravimetry system usually consists of Strapdown Inertial Navigation System (SINS) and Global Navigation Satellite System (GNSS). However, the traditional system is unable to achieve gravimetry in an environment without GNSS signal dues to heavy dependence on GNSS signal. To solve this problem, this study proposed a gravimetry method specifically for the environment without GNSS signal, which consists of the high-precision Strapdown Inertial Navigation System (SINS) and Laser Doppler Velocimeter (LDV) developed by our unit. Based on the error analysis, the system index requirements were proposed, and the relevant indexes of the LDV are verified through simulation and vehicle experiment. The simulation results for different velocimeter accuracies show that the internal accord accuracy of the system is within 1mGal when the velocimeter accuracy is 1 ‰, and the internal accord accuracies of the system are more than 1mGal when the velocimeter accuracies are 5 ‰ and 10‰. The results of the vehicle experiment for different dimensional velocimeters show that when the spatial resolution is 1.7 km, the SINS/LDV (2D) and SINS/GNSS integrated systems have an internal accord accuracy of 0.68 mGal and 0.54 mGal, respectively, while the SINS/LDV (1D) integrated system has an internal accord accuracy of 1.50 mGal. The feasibility of the SINS/LDV system and the necessity of the SINS/LDV system for the dimension and accuracy of the velocimeter are illustrated.

IntroductionEarly postoperative seizures has been the most common clinical expression in gliomas; however, the incidence and risk factors for early postoperative seizures in gliomas are more controversial. This protocol describes a systematic review and meta-analysis to clarify the prevalence and risk factors of early postoperative seizures in patients with glioma.Methods and analysisSearches will be conducted on CNKI, WanFang, VIP, PubMed, Embase, Cochrane Library databases and Web of Science for the period from database inception to December 31st, 2023. Case-control and cohort studies of the incidence and risk factors for early postoperative seizures in all gliomas will be included. The primary outcome will be incidence, risk factors. Newcastle-Ottawa Scale was used for quality evaluation. Review of article screening, extracting data and risk of bias assessment will be repeated by two independent reviewers.ResultThis study will provide evidence for the risk factors and incidence of early postoperative seizures in patients with glioma.ConclusionOur study will provide evidence for the prevention of early postoperative seizures in glioma patients.Trail registrationThis protocol was registered in PROSPERO and registration number is CRD42023415658.

Objective Cardiac CT (CCT) is an emerging non-invasive modality for assessing left atrial appendage (LAA) thrombus, but the results were conflicting. Our study aims to evaluate the accuracy of CCT for detecting LAA thrombus in patients undergoing catheter ablation of atrial fibrillation, using trans-oesophageal echocardiography (TEE) as the reference standard.Design Case-control study.Setting Patient data were collected from a tertiary hospital in China between 2017 and 2022.Participants The study enrolled 726 patients (male: 60.2%, age: 61±11 years) who had both TEE and CCT before catheter ablation of atrial fibrillation.Measures The CCT protocol consisted of one angiographic phase and one delayed scan 30 s later. LAA thrombi were defined as solid masses on TEE or persistent defects on CCT. The thrombus dimension and location, the LAA filling and emptying flow velocity were assessed by TEE.Results Of the 57 (7.9%) patients with LAA thrombi identified by TEE, 29 (50.9%) were located at the LAA ostium, and 28 (49.1%) were in the LAA. The former showed higher motility following blood flow and heartbeats than the latter. The CCT detected 14 (48.3%) of the LAA-ostium thrombi but 25 (89.3%) of those in the LAA (p=0.001). The LAA-ostium thrombi with the LAA mean flow velocity >0.35 m/s and maximum diameters

The electromyography(EMG) signal is the biocurrent associated with muscle contraction and can be used as the input signal to a myoelectric intelligent bionic hand to control different gestures of the hand. Increasing the number of myoelectric-signal channels can yield richer information of motion intention and improve the accuracy of gesture recognition. However, as the number of acquisition channels increases, its effect on the improvement of the accuracy of gesture recognition gradually diminishes, resulting in the improvement of the control effect reaching a plateau. To address these problems, this paper presents a proposed method to improve gesture recognition accuracy by virtually increasing the number of EMG signal channels. This method is able to improve the recognition accuracy of various gestures by virtually increasing the number of EMG signal channels and enriching the motion intention information extracted from data collected from a certain number of physical channels, ultimately providing a solution to the issue of the recognition accuracy plateau caused by saturation of information from physical recordings. Meanwhile, based on the idea of the filtered feature selection method, a quantitative measure of sample sets (separability of feature vectors [SFV]) derived from the divergence and correlation of the extracted features is introduced. The SFV value can predict the classification effect before performing the classification, and the effectiveness of the virtual-dimension increase strategy is verified from the perspective of feature set differentiability change. Compared to the statistical motion intention recognition success rate, SFV is a more representative and faster measure of classification effectiveness and is also suitable for small sample sets.

BackgroundPrevious studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases.MethodsSummary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR–Egger regression, weighted median, weight mode, Cochran’s Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results.ResultsThe IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p

Purpose: Heavy biomechanical loadings at workplaces may lead to high risks of work-related musculoskeletal disorders. This study aimed to explore the efficacy of an Omaha System-based remote ergonomic intervention program on self-reported work-related musculoskeletal disorders among frontline nurses. Materials and methods: From July to October 2020, 94 nurses with self-reported pain in one of the three body parts, i.e., neck, shoulder, and low back, were selected and were randomly divided into two groups. The intervention group received a newly developed remote program, where the control group received general information and guidance on health and life. Program outcome was evaluated by a quick exposure check approach. Results: After 6 weeks, the intervention group exhibited significantly less stress in the low back, neck, and shoulder/forearms, compared to the control group (p

Aconitine (AC), which is the primary bioactive diterpene alkaloid derived from Aconitum L plants, have attracted considerable interest due to its unique structural feature. Additionally, AC demonstrates a range of biological activities, such as its ability to enhance cardiac function, inhibit tumor growth, reduce inflammation, and provide analgesic effects. However, the structure-activity relationships of AC are remain unclear. A clear understanding of these relationships is indeed critical in developing effective biomedical applications with AC. In line with these challenges, this paper summarized the structural characteristics of AC and relevant functional and bioactive properties and the structure-activity relationships presented in biomedical applications. The primary temporal scope of this review was established as the period spanning from 2010 to 2023. Subsequently, the objective of this review was to provide a comprehensive understanding of the specific action mechanism of AC, while also exploring potential novel applications of AC derivatives in the biomedical field, drawing upon their structural characteristics. In conclusion, this review has provided a comprehensive analysis of the challenges and prospects associated with AC in the elucidation of structure-bioactivity relationships. Furthermore, the importance of exploring modern biotechnology approaches to enhance the potential biomedical applications of AC has been emphasized.

Background: The aim of this study was to investigate the potential role of lipid metabolism-associated genes (LMAGs) in neoadjuvant chemoradiotherapy (nCRT) and immunotherapy for rectal cancer. Methods: Differential LMAGs were characterized and functional enrichment analysis was performed. Multiple machine learning algorithms were combined to explore candidate LMAGs. ROC analysis was performed to evaluate the predicting accuracy of candidate LMAGs. The expression patterns, prognostic value, genetic alterations, and immune cell infiltration of the top-ranked LMAGs were investigated. Results: We identified 45 LMAGs that were differentially expressed in tumor samples of nCRT responders and non-responders. These LMAGs were closely associated with lipid metabolism-related biological processes and pathways. ROC analysis revealed that the SREBF2 gene, an important transcription factor in regulating lipid metabolism, was the highest predictor of nCRT in rectal cancer. SREBF2 was highly expressed in rectal cancer tissues and high expression of SREBF2 was associated with favorable prognosis. Multivariate analysis showed that SREBF2 was an independent prognostic factor, and we integrated it with other clinical factors to establish an effective prognostic nomogram. SREBF2 also played a synergistic role with its co-expressed genes in the prognostic process of rectal cancer. Furthermore, SREBF2 was demonstrated to be closely associated with multiple immune infiltrating cells, and immunotherapy-related genes and may be used to predict the response to immunotherapy. Conclusion: Our study suggests that LMAGs may serve as promising biomarkers in nCRT combined with immunotherapy for rectal cancer. However, large-scale clinical trials and biological experiments are necessary to demonstrate the efficacy and underlying mechanisms.

Background Neurosurgical patients are at an increased risk of deep venous thrombosis (DVT), which, if not properly managed, can lead to pulmonary embolism. This study aimed to investigate the accuracy of age-adjusted D-dimer thresholds combined with the modified Wells score as a predictor for lower extremity DVT diagnosis. Methods We conducted a study among patients aged >50 years with suspected lower extremity DVT in the neurosurgery intensive care unit between December 2019 and December 2020. Receiver operating characteristic curve analysis was performed to examine the diagnostic capacity of age-adjusted D-dimer combined with the modified Wells score. Results A total of 233 participants, with an average age of 71.81 ± 12.59 years, were enrolled in the study. The mean D-dimer levels were 0.73 ± 0.39 mg/L. Among the participants, 57 (57.9%, 33 males) were diagnosed with DVT. The age-adjusted D-dimer combined with the modified Wells score had the highest area under the curve for diagnosing lower extremity DVT compared to D-dimer and age-adjusted D-dimer alone, with an AUC of 0.858. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the age-adjusted D-dimer combined with the modified Wells score for DVT diagnosis were 78.95%, 80.68%, 57%, 92.2%, and 80.26%, respectively. When analyzing subgroups, the accuracy was 79.55% for participants with cerebral hemorrhage, 81.69% for those with craniocerebral injury, 74.99% for participants with intracranial infection, and 88.89% for those with craniocerebral tumor. Conclusion The combination of the age-adjusted D-dimer thresholds with the modified Wells score might effectively predict lower extremity DVT.

IntroductionDementia and musculoskeletal disorders (MSDs) are major public health problems. We aimed to investigate the genetic causality of common MSDs and dementia.MethodsTwo-sample Mendelian randomization (MR) was used in this study. MR analysis based on gene-wide association study (GWAS) data on osteoarthritis (OA), dementia with Lewy bodies, and other MSDs and dementia types were obtained from the Genetics of Osteoarthritis consortium, IEU-open GWAS project, GWAS catalog, and FinnGen consortium. Rigorously selected single-nucleotide polymorphisms were regarded as instrumental variables for further MR analysis. Inverse-variance weighted, MR–Egger regression, weight median, simple mode, and weight mode methods were used to obtain the MR estimates. Cochran’s Q test, MR–Egger and MR-Pleiotropy Residual Sum and Outlier analysis, and the leave-one-out test were applied for sensitivity testing.ResultsThe inverse-variance weighted method showed that hip OA was genetically associated with a lower risk of dementia, unspecified dementia, dementia in Alzheimer’s disease, and vascular dementia. Kneehip OA was inversely associated with unspecified dementia and vascular dementia. Rheumatoid arthritis, juvenile idiopathic arthritis and seronegative rheumatoid arthritis were inversely associated with frontotemporal dementia, and rheumatoid arthritis was inversely associated with unspecified dementia. Simultaneously, ankylosing spondylitis was an independent risk factor for dementia, dementia with Lewy bodies, and dementia in Alzheimer’s disease. Sensitivity tests showed that heterogeneity and horizontal pleiotropy did not exist in these associations. The leave-one-out test showed that these associations were stable.ConclusionWe found that some MSDs were associated with the risk of dementia and provide evidence for the early detection of dementia in patients with MSDs and for the impact of inflammation on the central nervous system.

Drought and heat stresses cause yield losses in alfalfa, a forage crop cultivated worldwide. Improving its drought and heat tolerance is desirable for maintaining alfalfa productivity in hot, arid regions. Cuticular wax forms a protective barrier on aerial surfaces of land plants against environmental stresses. ABCG11 encodes an ATP binding cassette (ABC) transporter that functions in the cuticular wax transport pathway. In this study, ZxABCG11 from the xerophyte Zygophyllum xanthoxylum was introduced into alfalfa by Agrobacterium tumefaciens-mediated transformation. Compared to the wild type (WT), transgenic alfalfa displayed faster growth, higher wax crystal density, and thicker cuticle on leaves under normal condition. Under either drought or heat treatment in greenhouse conditions, the plant height and shoot biomass of transgenic lines were significantly higher than those of the WT. Transgenic alfalfa showed excellent growth and 50% greater hay yield than WT under field conditions in a hot, arid region. Overexpression of ZxABCG11 up-regulated wax-related genes and resulted in more cuticular wax deposition, which contributed to reduction of cuticle permeability and thus increased water retention and photosynthesis capacity of transgenic alfalfa. Thus, overexpression of ZxABCG11 can simultaneously improve biomass yield, drought and heat tolerance in alfalfa by increasing cuticular wax deposition. Our study provides a promising avenue for developing novel forage cultivars suitable for planting in hot, arid, marginal lands.

Abstract Background N6-methyladenosine (m6A) modification is the most abundant reversible methylation modification in eukaryotes, and it is reportedly closely associated with a variety of cancers progression, including colorectal cancer (CRC). This study showed that activated lipid metabolism and glycolysis play vital roles in the occurrence and development of CRC. However, only a few studies have reported the biological mechanisms underlying this connection. Methods Protein and mRNA levels of FTO and ALKBH5 were measured using western blot and qRT-PCR. The effects of FTO and ALKBH5 on cell proliferation were examined using CCK-8, colony formation, and EdU assays, and the effects on cell migration and invasion were tested using a transwell assay. m6A RNA immunoprecipitation (MeRIP) and RNA-seq was used to explore downstream target gene. RIP was performed to verify the interaction between m6A and HK2. The function of FTO and ALKBH5 in vivo was determined by xenograft in nude mice. Results In this study, FTO and ALKBH5 were significantly down-regulated in CRC patients and cells both in vivo and in vitro in a high-fat environment. Moreover, FTO and ALKBH5 over-expression hampered cell proliferation both in vitro and in vivo. Conversely, FTO and ALKBH5 knockdown accelerated the malignant biological behaviors of CRC cells. The mechanism of action of FTO and ALKBH5 involves joint regulation of HK2, a key enzyme in glycolysis, which was identified by RNA sequencing and MeRIP-seq. Furthermore, reduced expression of FTO and ALKBH5 jointly activated the FOXO signaling pathway, which led to enhanced proliferation ability in CRC cells. IGF2BP2, as a m6A reader, positively regulated HK2 mRNA in m6A dependent manner. Additionally, down-regulation of FTO/ALKBH5 increased METTL3 and decreased METTL14 levels, further promoting CRC progression. Conclusion In conclusion, our study revealed the FTO-ALKBH5/IGF2BP2/HK2/FOXO1 axis as a mechanism of aberrant m6A modification and glycolysis regulation in CRC.

Abstract Objective The prognosis for patients presenting with a large ischemic core (LIC) following endovascular thrombectomy is relatively poor. This study aimed to construct and validate a nomogram for predicting 3‐month unfavorable outcome in patients with anterior circulation occlusion‐related LIC who underwent endovascular thrombectomy. Methods A retrospective training cohort and a prospective validation cohort of patients with a large ischemic core were studied. The diffusion weighted imaging related radiomic features and pre‐thrombectomy clinical features were collected. After the selection of relevant features, a nomogram predicting modified Rankin Scale score of 3–6 as an unfavorable outcome was established. The discriminatory value of the nomogram was evaluated with a receiver operating characteristic curve. Results A total of 140 patients (mean age 66.3 ± 13.4 years, 35% female) were included in this study, consisting of a training cohort (n = 95) and a validation cohort (n = 45). The percentage of patients with an mRS scores of 0–2 was 30%, 0–3 was 40.7%, and 32.9% were dead. Age, National Institute of Health Stroke Scale (NIHSS) score, and two radiomic features, Maximum2DDiameterColumn and Maximum2DDiameterSlice, were identified as factors associated with unfavorable outcome in the nomogram. The nomogram demonstrated an area under the curve of 0.892 (95% confidence interval [CI], 0.812–0.947) in the training dataset and 0.872 (95% CI, 0.739–0.953) in the validation dataset. Interpretation This nomogram, which includes age, NIHSS score, Maximum2DDiameterColumn, and Maximum2DDiameterSlice, may predict the risk of unfavorable outcome in patients with LIC caused by anterior circulation occlusion.