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Abstract Hepatocellular carcinoma (HCC) is the primary malignant tumor of the liver. c-Myc is one of the most common oncogenes in clinical settings, and amplified levels of c-Myc are frequently found in HCC. Histone deacetylase inhibitors (HDACi), such as Trichostatin A (TSA), hold enormous promise for the treatment of HCC. However, the potential and mechanism of TSA in the treatment of c-Myc-induced HCC are unclear. In this study, we investigated the effects of TSA treatment on a c-Myc-induced HCC model in mice. TSA treatment delayed the development of HCC, and liver function indicators such as ALT, AST, liver weight ratio, and spleen weight ratio demonstrated the effectiveness of TSA treatment. Oil red staining further demonstrated that TSA attenuated lipid accumulation in the HCC tissues of mice. Through mRNA sequencing, we identified that TSA mainly affected cell cycle and fatty acid degradation genes, with alcohol dehydrogenase 4 (ADH4) potentially being the core molecular downstream target. QPCR, immunohistochemistry, and western blot analysis revealed that ADH4 expression was repressed by c-Myc and restored after TSA treatment both in vitro and in vivo. Furthermore, we observed that the levels of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration increased after c-Myc transfection in liver cells but decreased after TSA intervention. The levels of phosphorylated protein kinase B (p-AKT) and p-mTOR were identified as targets regulated by TSA, and they governed the ADH4 expression and the downstream regulation of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration. Overall, our study suggests that TSA has a therapeutic effect on c-Myc-induced HCC through the AKT-mTOR-ADH4 pathway. These findings provide valuable insights into the potential treatment of HCC using TSA and shed light on the underlying molecular mechanisms involved.

Abstract Background Although triglyceride-glucose (TyG) index is a reliable indicator of insulin resistance and cardiometabolic disease, its effectiveness in predicting mortality risk has not been adequately validated. We aimed to investigate the association between the TyG-related indices and all-cause and cause-specific mortality in the general population. Methods A total of 27,642 individuals were included from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. Three indicators were constructed, including the TyG index, TyG combined with waist-to-height ratio (TyG-WHtR), and TyG combined with waist circumference (TyG-WC). Mortality data was acquired through the linkage of NHANES data with National Death Index records. Weighted Cox proportional hazards models were used to estimate the independent association between the TyG-related indices and mortality. Nonlinear associations were explored using restricted cubic splines. Results Multivariable adjusted models showed a progressive increase in all-cause and cause-specific mortality across quartiles of the TyG-related indices. Compared with the lowest quartile of the TyG index, the highest quartile had adjusted hazard ratios of 1.26 (95% CI 1.04–1.52) for all-cause mortality, 1.38 (1.04–1.74) for cardiovascular mortality, and 1.23 (1.01–1.50) for non-cardiovascular mortality, respectively. For the TyG-WHtR index, the corresponding hazard ratios were 1.60 (1.25–2.05), 1.86 (1.26–2.50), and 1.48 (1.10–1.99), respectively. For the TyG-WC index, the corresponding hazard ratios were 1.42 (1.11–1.75), 1.48 (1.04–1.96), and 1.38 (1.05–1.72), respectively. The associations between the three TyG-related indices and all-cause, cardiovascular and non-cardiovascular mortality were J-shaped. Interaction tests revealed significant effect modification by age, low-density lipoprotein cholesterol (LDL-C) level, and statin use (all P values

Abstract Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications.

Abstract Whether small nucleolar RNAs (snoRNAs) are involved in the regulation of liver cancer stem cells (CSCs) self-renewal and serve as therapeutic targets remains largely unclear. Here we show that a functional snoRNA (SNORD88B) is robustly expressed in Hepatocellular carcinoma (HCC) tumors and liver CSCs. SNORD88B deficiency abolishes the self-renewal of liver CSCs and hepatocarcinogenesis. Mechanistically, SNORD88B anchors WRN in the nucleolus, promoting XRCC5 interacts with STK4 promoter to suppress its transcription, leading to inactivation of Hippo signaling. Moreover, low expression of STK4 and high expression of XRCC5 are positively correlated with HCC poor prognosis. Additionally, snord88b knockout suppresses mouse liver tumorigenesis. Notably, co-administration of SNORD88B antisense oligonucleotides (ASOs) with MST1 agonist adapalene (ADA) exert synergistic antitumor effects and increase overall murine survival. Our findings delineate that SNORD88B drives self-renewal of liver CSCs and accelerates HCC tumorigenesis via non-canonical mechanism, providing potential targets for liver cancer therapy by eliminating liver CSCs.

Abstract We aimed to assess the cumulative incidences of cancer-specific mortality (CSM) in non-metastatic patients with non‑muscle invasive urothelial bladder cancer (NMIUBC) and establish competing risk nomograms to predict CSM. Patient data was sourced from the Surveillance, Epidemiology, and End Results database, as well as the electronic medical record system in our institution to form the external validation cohort. Sub-distribution proportional hazards model was utilized to determine independent risk factors influencing CSM in non-metastatic NMIUBC patients. Competitive risk nomograms were constructed to predict 3-year, 5-year, and 8-year cancer-specific survival (CSS) in all patients group, TURBT group and cystectomy group, respectively. The discrimination and accuracy of the model were validated through the concordance index (C-index), the area under the receiver operating characteristic curve (AUC), and calibration curves. Decision curve analysis (DCA) and a risk stratification system was employed to evaluate the clinical utility of the model. Race, age, marital status, surgery in other sites, tumor size, histological type, histological grade, T stage and N stage were identified as independent risk factors to predict CSS in all patients group. The C-index for 3-year CSS was 0.771, 0.770 and 0.846 in the training, testing and external validation sets, respectively. The ROC curves showed well discrimination and the calibration plots were well fitted and consistent. Moreover, DCA demonstrated well clinical effectiveness. Altogether, the competing risk nomogram displayed excellent discrimination and accuracy for predicting CSS in non-metastatic NMIUBC patients, which can be applied in clinical practice to help tailor treatment plans and make clinical decisions.

Abstract Background Multiple epiphyseal dysplasia-4 (MED-4, MIM 226900) is a rare autosomal recessive disease characterized by disproportionate height and early onset osteoarthritis of the lower limbs. MED-4 is caused by homozygous or compound heterozygous pathogenic variants in the SLC26A2 gene. However, the underlying pathogenic mechanisms in chondrocytes remains unknown. This study aimed to identify the pathogenic variants within a MED-4 family and explore the molecular etiology of this condition in human primary chondrocyte cells. Methods Clinical data were recorded and peripheral blood samples were collected for analysis. Whole exome sequencing (WES) and bioinformatic analyses were performed to determine causative variants. Wild-type SLC26A2 and corresponding mutant expression plasmids were constructed and transfected into human primary chondrocytes. The expression and subcellular distribution of SLC26A2 protein in chondrocytes were detected by immunoblotting and immunofluorescence. Effects of these variants on chondrocytes viability and apoptosis were measured by Cell Counting Kit-8 (CCK-8) assay. Expression of genes related to cartilage homeostasis was subsequently analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Results We identified two compound heterozygous variants c.1020_1022delTGT(p.Val341del) and c.1262 T > C(p.Ile421Thr) in the SLC26A2 gene in the patients. Mutant SLC26A2Val341del and SLC26A2Ile421Thr proteins were distributed in relatively few cells and were observed only within the nucleus. The viability of chondrocytes with the SLC26A2 variant group was similar to the wild-type (WT) group. However, the protein expressions of SLC26A2Val341del and SLC26A2Ile421Thr were decreased compared with SLC26A2WT. Expression levels of matrix metallopeptidase 13 (MMP13), α-1 chain of type X collagen (COL10A1), and Runt-related transcription factor 2 (RUNX2) were significantly decreased in the variant group. However, aggrecan (ACAN) expression was higher in the variant group than the WT group. Conclusions Overall, our data demonstrate that the variants p.Val341del and p.Ile421Thr in SLC26A2 cause MED-4 and that these two variants promote chondrocyte proliferation while inhibiting chondrocyte differentiation.

The diterpene ent-copalol is an important precursor to the synthesis of andrographolide and is found only in green chiretta (Andrographis paniculata). De novo biosynthesis of ent-copalol has not been reported, because the catalytic activity of ent-copalyl diphosphate synthase (CPS) is very low in microorganisms. In order to achieve the biosynthesis of ent-copalol, Saccharomyces cerevisiae was selected as the chassis strain, because its endogenous mevalonate pathway and dephosphorylases could provide natural promotion for the synthesis of ent-copalol. The strain capable of synthesizing diterpene geranylgeranyl pyrophosphate was constructed by strengthening the mevalonate pathway genes and weakening the competing pathway. Five full-length ApCPSs were screened by transcriptome sequencing of A. paniculata and ApCPS2 had the best activity and produced ent-CPP exclusively. The peak area of ent-copalol was increased after the ApCPS2 saturation mutation and its configuration was determined by NMR and ESI-MS detection. By appropriately optimizing acetyl-CoA supply and fusion-expressing key enzymes, 35.6 mg/L ent-copalol was generated. In this study, de novo biosynthesis and identification of ent-copalol were achieved and the highest titer ever reported. It provides a platform strain for the further pathway analysis of andrographolide and derivatives and provides a reference for the synthesis of other pharmaceutical intermediates.

Freeway work zone forms as a result of traffic crash or road rehabilitation. To ascertain the effects of work zone with lane II completely blocked on vehicular flow on ring freeways with a tunnel, a three-lane continuum model is put forward. The mandatory net lane-changing rate from lane II to lane I or III just upstream of the work zone is described by a random number model, with the random number being produced within a small range around a median based on a golden section analysis. The net-changing rate between adjacent lanes is described using a lane-changing time on the basis of an assumption: the time ratio to relaxation time equals infinity when the absolute value of traffic densities between the two adjacent lanes is less than 1 veh/km, implying that the net-changing rate is zero; otherwise, the time ratio is inversely proportional to the vehicular spatial headway, which is equal to unity for traffic flow at saturation state, but infinity when the traffic flow is completely jammed. It is assumed that the freeway is a three lane ring with a total length of 100 km, and has a tunnel with a speed limit of 60 km/h and a length of 1.6 km located downstream the work zone with a length of 0.16 km. The free flow speeds on lanes I, II, and III are 120 km/h, 100 km/h, and 85 km/h, respectively. For the vehicular flow on the ring freeway with a tunnel, numerical simulations based on the three-lane continuum model are carried out with a reliable numerical method of high accuracy. It is found that the vehicular flow has two thresholds of traffic jam formation, one depending upon the tunnel and the other upon the work zone. The tunnel triggers a traffic jam when the initial density normalized by jam density is equal to the first threshold 0.15, and the work zone originates another traffic jam when the normalized initial density equals the second threshold 0.19. The freeway tunnel plays a dominant role in the prediction of mean travel time as soon as the tunnel has generated a traffic jam at the tunnel entrance. For the vehicular flow at unsaturated state, the average speed through the tunnel is about 26.67 km/h. When the normalized initial density exceeds the second threshold 0.19, the mean travel time through every lane increases with the initial density linearly. Vehicle fuel consumption can be estimated by interpolation with the time averaged grid traffic speed and an assumed vehicle performance curve. It is found that the vehicle fuel consumption is lane number dependent, and distributes with the initial density concavely, as well as has a value in the range of 6.5 to 8.3 l.

Abstract Prevention of subsequent fracture is a major public health challenge in the field of osteoporosis prevention and treatment, and older women are at high risk for osteoporotic fractures. This study aimed to examine factors associated with subsequent fracture in older Chinese women with osteoporosis. We collected data on 9212 older female patients with osteoporotic fractures from 580 medical institutions in 31 provinces of China. Higher odds of subsequent fractures were associated with age of 70–79 years (OR 1.218, 95% CI 1.049–1.414), age ≥ 80 (OR 1.455, 95% CI 1.222–1.732), index fracture site was vertebrae (OR 1.472, 95% CI 1.194–1.815) and hip (OR 1.286, 95% CI 1.041–1.590), index fracture caused by fall (OR 1.822, 95% CI 1.281–2.591), strain (OR 1.587, 95% CI 1.178–2.139), no inducement (OR 1.541, 95% CI 1.043–2.277), and assessed as high risk of fracture (OR 1.865, 95% CI 1.439–2.416), BMD T-score ≤ −2.5 (OR 1.725, 95% CI 1.440–2.067), history of surgery (OR 3.941, 95% CI 3.475–4.471) and trauma (OR 8.075, 95% CI 6.941–9.395). Low risk of fall (OR 0.681, 95% CI 0.513–0.904), use of anti-osteoporosis medication (AOM, OR 0.801, 95% CI 0.693–0.926), and women who had received fall prevention health education (OR 0.583, 95% CI 0.465–0.730) associated with lower risk. The areas under the curve of the prediction model was 0.818. The sensitivity was 67.0% and the specificity was 82.0%. The prediction model showed a good ability to predict the risk of subsequent fracture in older women with osteoporotic fractures and are suitable for early self-measurement which may benefit post-fracture management.

Abstract Polymer-based circularly polarized luminescence (CPL) materials with the advantage of diversified structure, easy fabrication, high thermal stability, and tunable properties have garnered considerable attention. However, adequate and precise tuning over CPL in polymer-based materials remains challenging due to the difficulty in regulating chiral structures. Herein, visualized full-color CPL is achieved by doping red, green, and blue quantum dots (QDs) into reconfigurable blue phase liquid crystal elastomers (BPLCEs). In contrast to the CPL signal observed in cholesteric liquid crystal elastomers (CLCEs), the chiral 3D cubic superstructure of BPLCEs induces an opposite CPL signal. Notably, this effect is entirely independent of photonic bandgaps (PBGs) and results in a high g lum value, even without matching between PBGs and the emission bands of QDs. Meanwhile, the lattice structure of the BPLCEs can be reversibly switched via mechanical stretching force, inducing on-off switching of the CPL signals, and these variations can be further fixed using dynamic disulfide bonds in the BPLCEs. Moreover, the smart polymer-based CPL systems using the BPLCEs for anti-counterfeiting and information encryption have been demonstrated, suggesting the great potential of the BPLCEs-based CPL active materials.

Abstract Background Life’s Essential 8 (LE8), the recently updated construct for quantifying cardiovascular health, is related to the risks of cardiovascular events. The present study aimed to evaluate associations of LE8 score with the multi-territorial extent of atherosclerosis in a community-dwelling population. Methods Data were derived from the baseline cross-sectional survey of the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in Lishui City. The LE8 included overall, medical and behavior LE8 scores, and were categorized as low (

Water-soluble salt-based ceramic cores can be recycled and have excellent high-temperature chemical stability. In this work, vat photopolymerization was successfully applied to water-soluble salt-based ceramic cores for the first time. The powder raw materials of the printing suspension were sodium chloride and alumina. High-precision green bodies were manufactured by optimizing suspensions and parameters. In addition, the postprocessing method was optimized according to the microstructure and mechanical properties. The sintered part had a high bending strength and smooth surface. Finally, the dissolution rate and moisture resistance were compared under different dissolution and storage conditions. Compared to traditional manufacturing methods, vat photopolymerization enables the production of complex structures without molds and reduces production costs. This technology is suitable for the rapid iteration of complex structural parts and can be applied to precision parts in aerospace, military, and other technical fields with high cost-effectiveness and sustainability.

Abstract Backgrounds Increased respiratory drive has been demonstrated to correlate with weaning failure, which could be quantified by electrical activity of the diaphragm (EAdi). We described the physiological process of EAdi-based parameters during the spontaneous breathing trial (SBT) and evaluated the change of EAdi-based parameters as potential predictors of weaning failure. Methods We conducted a prospective study in 35 mechanically ventilated patients who underwent a 2-hour SBT. EAdi and ventilatory parameters were continuously measured during the SBT. Diaphragm ultrasound was performed before the SBT and at the 30 min of the SBT. Three EAdi-based parameters were calculated: neuro-ventilatory efficiency, neuro-excursion efficiency and neuro-discharge per min. Results Of the thirty 35 patients studied, 25 patients were defined as SBT success, including 22 patients weaning successfully and 3 patients reintubated. Before the SBT, neuro-excursion efficiency differed significantly between two groups and had the highest predictive value for SBT failure (AUROC 0.875, p

Abstract Atrial fibrillation (AF) is the most common arrhythmia and its incidence increases with sepsis. However, data on new-onset AF during sepsis hospitalization remain limited in China. We aimed to evaluate the incidence, risk factors, and associated mortality of new-onset AF in sepsis patients in China. We conducted a retrospective study using the National Data Center for Medical Service system, from 1923 tertiary and 2363 secondary hospitals from 31 provinces in China from 2017 to 2019.In total we included 1,425,055 sepsis patients ≥ 18 years without prior AF. The incidence of new-onset AF was 1.49%. Older age, male sex, hypertension, heart failure, coronary disease, valvular disease, and mechanical ventilation were independent risk factor. New-onset AF was associated with a slight increased risk of mortality (adjusted RR 1.03, 95% CI 1.01–1.06). Population attributable fraction suggested AF accounted for 0.2% of sepsis deaths. In this large nationwide cohort, new-onset AF occurred in 1.49% of sepsis admissions and was associated with a small mortality increase. Further research should examine whether optimized AF management can improve sepsis outcomes in China.

Abstract The protection of the replication fork structure under stress conditions is essential for genome maintenance and cancer prevention. A key signaling pathway for fork protection involves TRPV2-mediated Ca2+ release from the ER, which is triggered after the generation of cytosolic DNA and the activation of cGAS/STING. This results in CaMKK2/AMPK activation and subsequent Exo1 phosphorylation, which prevent aberrant fork processing, thereby ensuring genome stability. However, it remains poorly understood how the TRPV2 channel is activated by the presence of cytosolic DNA. Here, through a genome-wide CRISPR-based screen, we identify TRPM8 channel-associated factor 1 (TCAF1) as a key factor promoting TRPV2-mediated Ca2+ release under replication stress or other conditions that activate cGAS/STING. Mechanistically, TCAF1 assists Ca2+ release by facilitating the dissociation of STING from TRPV2, thereby relieving TRPV2 repression. Consistent with this function, TCAF1 is required for fork protection, chromosomal stability, and cell survival after replication stress.

Abstract Background Emerging evidences have demonstrated that gut microbiota composition is associated with pulmonary arterial hypertension (PAH). However, the underlying causality between intestinal dysbiosis and PAH remains unresolved. Method An analysis using the two-sample Mendelian randomization (MR) approach was conducted to examine the potential causal relationship between gut microbiota and PAH. To assess exposure data, genetic variants associated with 196 bacterial traits were extracted from the MiBioGen consortium, which included a sample size of 18,340 individuals. As for the outcomes, summary statistics for PAH were obtained from the NHGRI-EBI GWAS Catalog, which conducted a meta-analysis of four independent studies comprising a total of 11,744 samples. Causal effects were estimated employing various methods, including inverse variance weighted (IVW), MR-Egger, weighted median, weight mode and simple mode, with sensitivity analyses also being implemented with Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots. Results Following false discovery rate (FDR) correction, the genetically predicted genus Eubacterium fissicatena group (odds ratio (OR) 1.471, 95% confidence interval (CI) 1.178–1.837, q = 0.076) exhibited a causal association with PAH. In addition, the genus LachnospiraceaeUCG004 (OR 1.511, 95% CI 1.048–2.177) and genus RuminococcaceaeUCG002 (OR 1.407, 95% CI 1.040–1.905) showed a suggestive increased risk of PAH, while genus Eubacterium eligens group (OR 0.563, 95% CI 0.344–0.922), genus Phascolarctobacterium (OR 0.692, 95% CI 0.487–0.982), genus Erysipelatoclostridium (OR 0.757, 95% CI 0.579–0.989) and genus T–yzzerella3 (OR 0.768, 95% CI 0.624–0.945) were found to have nominal protective effect against PAH. Conclusion The findings from our MR study have revealed a potential causal relationship between gut microbiota and PAH. Specifically, we have identified four types of gut microbiota that exhibit a protective effect on PAH, as well as three types that have a detrimental impact on PAH, thereby offering valuable insights for future mechanistic and clinical investigations in the field of PAH.

Abstract Emotions play a crucial role in the learning process, yet there is a scarcity of studies examining emotion dynamics in problem-solving with fine-grained data and advanced tools. This study addresses this gap by investigating the emotional trajectories during self-regulated learning (SRL) phases (i.e., forethought, performance, and self-reflection) among 47 medical students utilizing an intelligent tutoring system. Real-time facial expressions were analyzed through recurrence quantification analysis alongside an examination of electrodermal activities (EDA) across the SRL phases. The findings reveal that emotion stability varied across SRL phases, with students exhibiting more stable emotions during the performance phase. Compared to the forethought and self-reflection phases, students had less frequent and lower intensity of emotional arousal in the performance phase. Moreover, we found that students with better performance demonstrated more stable emotions in the forethought phase, less stable emotions in the self-reflection phase, and a higher level of emotional arousal in the self-reflection phase. These insights highlight the temporal and dynamic nature of emotions in SRL, offering methodological and educational implications for leveraging facial expressions and EDA to monitor and enhance students’ emotional experience during problem-solving.

Abstract In mines, tunnel ventilation is monitored using wind speed sensors to measure the stability of the mine ventilation system. However, opening and closing the air door will cause violent fluctuations in the monitoring data of the wind speed sensors. When false alarms are triggered, the staff can diagnose only the mine ventilation system based on their experience. A numerical simulation method is adopted to explore the changes in the flow field during the opening and closing of the air door to address this issue. In addition, a method that is based on the wind speed data of a single sensor is proposed to identify the time and divide the stages of air door opening and closing. The experimental results showed that the proposed method can successfully identify the air door opening and closing time and apply stage division when needed.

Abstract Background Small nucleolar RNAs (snoRNAs) play key roles in ribosome biosynthesis. However, the mechanism by which snoRNAs regulate cancer stemness remains to be fully elucidated. Methods SNORA68 expression was evaluated in breast cancer tissues by in situ hybridization and qRT‒PCR. Proliferation, migration, apoptosis and stemness analyses were used to determine the role of SNORA68 in carcinogenesis and stemness maintenance. Mechanistically, RNA pull-down, RNA immunoprecipitation (RIP), cell fractionation and coimmunoprecipitation assays were conducted. Results SNORA68 exhibited high expression in triple-negative breast cancer (TNBC) and was significantly correlated with tumor size (P = 0.048), ki-67 level (P = 0.037), and TNM stage (P = 0.015). The plasma SNORA68 concentration was significantly lower in patients who achieved clinical benefit. The SNORA68-high patients had significantly shorter disease-free survival (DFS) (P = 0.036). Functionally, SNORA68 was found to promote the cell stemness and carcinogenesis of TNBC in vitro and in vivo. Furthermore, elevated SNORA68 expression led to increased nucleolar RPL23 expression and retained RPL23 in the nucleolus by binding U2AF2. RPL23 in the nucleolus subsequently upregulated c-Myc expression. This pathway was validated using a xenograft model. Conclusion U2AF2-SNORA68 promotes TNBC stemness by retaining RPL23 in the nucleolus and increasing c-Myc expression, which provides new insight into the regulatory mechanism of stemness.

Abstract Objective Previous studies have shown that the obesity paradox exists in a variety of clinical settings, whereby obese individuals have lower mortality than their normal-weight counterparts. It remains unclear whether the association between obesity and mortality risk varies by anthropometric measures. The purpose of this study is to examine the association between various anthropometric measures and all-cause and cause-specific mortality in US adults. Methods This cohort study included data from the National Health and Nutrition Examination Survey between 2009 and 2018, with a sample size of 28,353 individuals weighted to represent 231 million US adults. Anthropometric measurements were obtained by trained technicians using standardized methods. Mortality data were collected from the date of enrollment through December 31, 2019. Weighted Cox proportional hazards models, restricted cubic spline curves, and cumulative incidence analyses were performed. Results A total of 2091 all-cause deaths, 606 cardiovascular deaths, 519 cancer deaths, and 966 other-cause deaths occurred during a median follow-up of 5.9 years. The association between body mass index (BMI) and mortality risk was inversely J-shaped, whereas the association between waist-to-height ratio (WHtR) and mortality risk was positively J-shaped. There was a progressive increase in the association between the WHtR category and mortality risk. Compared with the reference category of WHtR

In order to improve the efficiency of emergency repair for multiple faults in distribution networks, a method for allocating emergency repair resources for multiple faults in distribution networks based on parallel convolutional neural network (CNN) algorithm is studied. This method uses a matrix operation based multiple fault detection method for distribution networks. After determining the location of multiple faults based on the direction of fault power, the principle is to allocate emergency repair resources nearby for multiple faults, with the goal of minimizing economic losses caused by the fault point and minimizing fault repair time. The objective function for allocating emergency repair resources nearby is constructed, and parallel CNN algorithm is used to solve the problem by classification, to find the feasible solution with the minimum mean square error between the objective function and the feasible solution set for nearby allocation of emergency repair resources, and it is used as the optimal solution for nearby allocation of repair resources. The experimental results show that when the proposed method is used to allocate emergency repair resources for multiple faults in the distribution network, the optimal time for setting the repair plan is 0.53 and 0.96 s, respectively, with an average allocation accuracy of 91%. It has been confirmed that this method can achieve the optimal decision of resource allocation plan in a short period of time, improving the efficiency of emergency repair.

Osteoarthritis (OA) is a prevalent chronic degenerative disease that affects the bones and joints, particularly in middle-aged and elderly individuals. It is characterized by progressive joint pain, swelling, stiffness, and deformity. Notably, treatment with a heat shock protein 90 (HSP90) inhibitor has significantly curtailed cartilage destruction in a rat model of OA. Although the monoclonal antibody 9B8 against HSP90 is recognized for its anti-tumor properties, its potential therapeutic impact on OA remains uncertain. This study investigated the effects of 9B8 on OA and its associated signaling pathways in interleukin-1β (IL-1β)−stimulated human chondrocytes and a rat anterior cruciate ligament transection (ACLT) model. A specific concentration of 9B8 preserved cell viability against IL-1β−induced reduction. In vitro, 9B8 significantly reduced the expression of extracellular matrix-degrading enzyme such as disintegrin and metallopeptidase-4 (ADAMTS4) of thrombospondin motifs, matrix metalloproteinase-13 (MMP-13), as well as cellular inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which were upregulated by IL-1β.In vivo, 9B8 effectively protected the articular cartilage and subchondral bone of the rat tibial plateau from ACLT-induced damage. Additionally, gene microarray analysis revealed that IL-1β substantially increased the expression of SLC2A1, PFKP, and ENO2 within the HIF-1 signaling pathway, whereas 9B8 suppressed the expression of these genes. Thus, 9B8 effectively mitigates ACLT-induced osteoarthritis in rats by modulating the HIF-1 signaling pathway, thereby inhibiting overexpression involved in glycolysis.These results collectively indicate that 9B8 is a promising novel drug for the prevention and treatment of OA.

Background: Osteoarthritis (OA) is a common chronic joint disease. This study aimed to investigate possible OA diagnostic biomarkers and to verify their significance in clinical samples. Methods: We exploited three datasets from the Gene Expression Omnibus (GEO) database, serving as the training set. We first determined differentially expressed genes and screened candidate diagnostic biomarkers by applying three machine learning algorithms (Random Forest, Least Absolute Shrinkage and Selection Operator logistic regression, Support Vector Machine-Recursive Feature Elimination). Another GEO dataset was used as the validation set. The test set consisted of RNA-sequenced peripheral blood samples collected from patients and healthy donors. Blood samples and chondrocytes were collected for quantitative real-time PCR to confirm expression levels. Receiver operating characteristic curves were generated for individual and combined biomarkers. Results: In total, 251 DEGs were screened, where B3GALNT1, SCRG1 and ZNF423 were screened by all three algorithms. The area under the curve (AUC) of various biomarkers in our test set did not reach as high as that in public datasets. GRB10 exhibited highest AUC of 0.947 in the training set but 0.691 in our test set, while the favorable combined model comprising B3GALNT1, GRB10, KLF9 and SCRG1 demonstrated an AUC of 0.986 in the training set, 1.000 in the validation set and 0.836 in our test set. Conclusion: We identified a combined model for early diagnosis of OA that includes B3GALNT1, GRB10, KLF9 and SCRG1. This finding offers new avenues for further exploration of mechanisms underlying OA.

Abstract Introduction The impact of immunosuppression on prognosis of carbapenem-resistant organism (CRO) bloodstream infection (BSI) remains unclear. The aim of this study was to clarify the relationship between immunosuppression and mortality of CRO-BSI and to identify the risk factors associated with mortality in immunosuppressed patients. Methods This retrospective study included 279 patients with CRO-BSI from January 2018 to March 2023. Clinical characteristics and outcomes were compared between the immunosuppressed and immunocompetent patients. The relationship between immunosuppression and 30-day mortality after BSI onset was assessed through logistic-regression analysis, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Factors associated with mortality in immunosuppressed patients were analyzed using multivariable logistic regression analysis. Results A total of 88 immunocompetent and 191 immunosuppressed patients were included, with 30-day all-cause mortality of 58.8%. Although the 30-day mortality in immunosuppressed patients was significantly higher than in immunocompetent patients (46.6% vs. 64.4%, P = 0.007), immunosuppression was not an independent risk factor for mortality in multivariate logistic regression analysis (odds ratio [OR] 3.53, 95% confidence interval [CI] 0.74–18.89; P = 0.123), PSM (OR 1.38, 95% CI 0.60–3.18; P = 0.449,) or IPTW (OR 1.40, 95% CI 0.58–3.36; P = 0.447). For patients with CRO-BSI, regardless of immune status, appropriate antibiotic therapy was associated with decreased 30-day mortality, while Charlson comorbidity index (CCI), intensive care unit (ICU)-acquired infection and thrombocytopenia at CRO-BSI onset were associated with increased mortality. Conclusion Despite the high mortality rate of CRO-BSI, immunosuppression did not affect the mortality. Appropriate antibiotic therapy is crucial for improving the prognosis of CRO-BSI, regardless of the immune status.

Exercise rehabilitation has been proven as a promising intervention for recovery of patients after percutaneous coronary intervention for acute myocardial infarction. Based on the analysis of individual’s condition, early exercise rehabilitation plan should be designed systematically and logically to reduce the mortality due to acute myocardial infarction, prevent complications, promote the early rehabilitation and improve the exercise tolerance and quality of life of the patient. This paper summarized the status quo of exercise rehabilitation and its research status, potential problems and clinical practice in patients with acute myocardial infarction after percutaneous coronary intervention, and provided reference for the establishment of exercise rehabilitation plan after percutaneous coronary intervention. (运动康复是急性心肌梗死患者经皮冠状动脉介入(PCI)术恢复行之有效的方法。早期运动康复应该基于个体的特殊状况, 有层次有逻辑设计并推进活动方案, 降低因急性心肌梗死而造成的死亡率, 规避其他症状并发, 压缩患者的治疗康复周期, 优化患者的运动耐量与生活水平。本研究针对运动康复疗法在国内外的发展、研究应用、存在的问题及其用于急性心肌梗死PCI术后的展望进行综述, 旨在为制定更完善的PCI术后运动康复方案提高可靠参考。)

Abstract Investigating the impact of train-induced vibration loads on soil hydraulic properties, this study conducted experiments using a self-designed indoor soil seepage platform that incorporates vibration loads. The experiments were complemented with scanning electron microscopy to analyze the influence of train-induced vibration loads on soil hydraulic conductivity and its evolutionary characteristics under different vibration frequencies. The experimental results indicated that as the vibration frequency increases from no vibration (0 Hz) to 20 Hz, the time required for the soil volumetric moisture content to reach its peak and stabilize decreases rapidly. However, after the vibration frequency exceeds 20 Hz, the rate at which the time required for the volumetric moisture content to reach its peak and stabilize decreases slows down. Furthermore, the soil pore water pressure increases with the increase in vibration frequency. At a vibration frequency of 80 Hz, the peak value of pore water pressure increases by 105% compared to the non-vibration state, suggesting that higher vibration frequencies promote the development and acceleration of soil pore moisture migration. Additionally, as the vibration frequency increases, the soil hydraulic conductivity initially experiences a rapid increase, with a growth rate ranging from 40.1 to 47.4%. However, after the frequency exceeds 20 Hz, this growth rate significantly decreases, settling to only 18.6% to 7.8%. When the soil was subjected to a vibration load, the scanning electron microscopy test revealed alterations in its pore structure. Micropores and small pores transformed into macropores and mesopores. Additionally, the microstructural parameters indicated that vibration load decreased the complexity of soil pores, thereby speeding up the hydraulic conduction process. This, in turn, affected the hydraulic properties of the soil and established a relationship between pore structure complexity and soil hydraulic properties.

Abstract Background The recently identified methylation patterns specific to cell type allows the tracing of cell death dynamics at the cellular level in health and diseases. This study used COVID-19 as a disease model to investigate the efficacy of cell-specific cell-free DNA (cfDNA) methylation markers in reflecting or predicting disease severity or outcome. Methods Whole genome methylation sequencing of cfDNA was performed for 20 healthy individuals, 20 cases with non-hospitalized COVID-19 and 12 cases with severe COVID-19 admitted to intensive care unit (ICU). Differentially methylated regions (DMRs) and gene ontology pathway enrichment analyses were performed to explore the locus-specific methylation difference between cohorts. The proportion of cfDNA derived from lung and immune cells to a given sample (i.e. tissue fraction) at cell-type resolution was estimated using a novel algorithm, which reflects lung injuries and immune response in COVID-19 patients and was further used to evaluate clinical severity and patient outcome. Results COVID‑19 patients had globally reduced cfDNA methylation level compared with healthy controls. Compared with non-hospitalized COVID-19 patients, the cfDNA methylation pattern was significantly altered in severe patients with the identification of 11,156 DMRs, which were mainly enriched in pathways related to immune response. Markedly elevated levels of cfDNA derived from lung and more specifically alveolar epithelial cells, bronchial epithelial cells, and lung endothelial cells were observed in COVID-19 patients compared with healthy controls. Compared with non-hospitalized patients or healthy controls, severe COVID-19 had significantly higher cfDNA derived from B cells, T cells and granulocytes and lower cfDNA from natural killer cells. Moreover, cfDNA derived from alveolar epithelial cells had the optimal performance to differentiate COVID-19 with different severities, lung injury levels, SOFA scores and in-hospital deaths, with the area under the receiver operating characteristic curve of 0.958, 0.941, 0.919 and 0.955, respectively. Conclusion Severe COVID-19 has a distinct cfDNA methylation signature compared with non-hospitalized COVID-19 and healthy controls. Cell type-specific cfDNA methylation signature enables the tracing of COVID-19 related cell deaths in lung and immune cells at cell-type resolution, which is correlated with clinical severities and outcomes, and has extensive application prospects to evaluate tissue injuries in diseases with multi-organ dysfunction.

Abstract Background We aimed to identify some potential biomarkers for elderly osteoporosis (OP) by integral analysis of lncRNA and mRNA expression data. Methods A total of 8 OP cases and 5 healthy participants were included in the study. Fasting peripheral venous blood samples were collected from individuals, and total RNA was extracted. RNA-seq library was prepared and sequenced on the Illumina HiSeq platform. Differential gene expression analysis was performed using “DESeq2” package in R language. Functional enrichment analysis was conducted using the “clusterProfiler” package, and the cis- and trans-regulatory relationships between lncRNA and target mRNA were analyzed by the lncTar software. A protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified through the MCODE plugin in Cytoscape. Results We identified 897 differentially expressed lncRNAs (DELs) and 1366 differentially expressed genes (DEGs) between normal and OP samples. After co-expression network analysis and cis-trans regulatory genes analysis, we identified 69 candidate genes regulated by lncRNAs. Then we further screened 7 genes after PPI analysis. The target gene DOCK4, trans-regulated by two lncRNAs, was found to be significantly upregulated in OP samples. Additionally, 4 miRNAs were identified as potential regulators of DOCK4. The potential diagnostic value of DOCK4 and its two trans-regulatory lncRNAs was supported by ROC analysis, indicating their potential as biomarkers for OP. Conclusion DOCK4 is a potential biomarker for elderly osteoporosis diagnostic. It is identified to be regulated by two lncRNAs and four miRNAs.

Abstract Rheumatoid arthritis (RA) is a common inflammatory arthritis in women. The effects of RA on the reproductive system are usually overlooked, as RA is not diagnosed until later in reproductive age. Whether RA itself or its related rheumatoid antibodies have an impact on female reproductive function has long been a thought-provoking issue. In brief, relevant epidemiological evidence has shown that women affected by RA are more likely to have coexisting reproductive disorders, including infertility, endometriosis, and premature ovarian insufficiency (POI), or to subsequently develop them. Furthermore, linkage between RA and pregnancy loss (PL) as well as polycystic ovary syndrome (PCOS) is also well known, albeit controversial in available evidence. RA and reproductive disorders appear to share a similar inflammatory immune response and genetic background. The stress experienced by patients with RA may affect their reproductive choices to some extent. Notably, few studies have explored the impact of rheumatoid antibodies such as rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPAs) on reproductive disorders. Although it has been mentioned that the rate of RF and/or ACPA positivity is higher in women with a history of PL and POI, the clinical relevance of this relationship and underlying mechanisms still need to be further clarified.

Abstract The PD-1/PD-L1 pathway in mucosal immunity is currently actively explored and considered as a target for inflammatory bowel disease (IBD) treatment. However, systemic PD-L1 administration may cause unpredictable adverse effects due to immunosuppression. Here we show that reactive oxygen species (ROS)-responsive nanoparticles enhance the efficacy and safety of PD-L1 in a mouse colitis model. The nanoparticles control the accumulation and release of PD-L1 fused to Fc (PD-L1-Fc) at inflammatory sites in the colon. The nanotherapeutics shows superiority in alleviating inflammatory symptoms over systemic PD-L1-Fc administration and mitigates the adverse effects of PD-L1-Fc administration. The nanoparticles-formulated PD-L1-Fc affects production of proinflammatory and anti-inflammatory cytokines, attenuates the infiltration of macrophages, neutrophils, and dendritic cells, increases the frequencies of Treg, Th1 and Tfh cells, reshapes the gut microbiota composition; and increases short-chain fatty acid production. In summary, PD-L1-Fc-decorated nanoparticles may provide an effective and safe strategy for the targeted treatment of IBD.

In order to enhance the stability of anthocyanins and broaden its application in the fields of food health care and medicine, carboxymethyl chitosan (CMCS), L-histidine (L-His) and stearic acid (SA) were used as carrier materials, and Lonicera edulis pomace anthocyanins were used as core materials. The preparation process of acid-responsive Lonicera edulis pomace anthocyanins micelles was optimized by response surface method. The stability of Lonicera edulis pomace anthocyanins under different conditions such as light, temperature and pH and their cytotoxicity to liver cancer cells were evaluated. The results showed that the optimal preparation process was as follows: Water bath time 10 min, ultrasonic time 15 min, ultrasonic temperature 60 °C, and the encapsulation efficiency was 85.3%±0.31%. The storage stability analysis showed that under various conditions of temperature, pH, light, oxidant and reducing agent, the preservation rate of anthocyanins in the micelles were 1.33, 1.26, 1.16, 1.11 and 2.41 times that of anthocyanins, respectively. In the in vitro liver cancer cell killing experiment, after 24 h, the inhibition rate of anthocyanin-loaded micelles on liver cancer cells was 1.34 times that of anthocyanin. In this study, a novel amphiphilic carboxymethyl chitosan derivative was synthesized, which could significantly improve the stability of anthocyanins and was suitable as a potential nanomicelle carrier for anthocyanins and other food active ingredients.

Ga2O3-based heterojunction features the capability of self-driven detection, which is reckoned as a promising candidate for the next-generation deep-ultraviolet (DUV) sensing scenarios. Heterojunction consisting of fully ultra-wide bandgap (UWB) semiconductors would prevent additional response in the near-ultraviolet band. In this work, a $\beta $ -Ga2O3/AlN heterojunction photodetector is constructed and its operating mechanisms are investigated. By measuring its static current-voltage (I-V) and dynamic current-time (I-t) characteristics, the detection performance, including a photo-to-dark current ratio of $8.6\times 10\,\,^{\mathrm{ 5}}$ , a responsivity of 0.41 mA/W, a specific detectivity of $3.4\times 10\,\,^{\mathrm{ 12}}$ Jones, and an external quantum efficiency of 0.2% were achieved under 0 V bias, indicating that the proposed device realized high-performance self-driven detection. Moreover, this work demonstrated the impact of Fermi-level splitting introduced by the enhanced photo illumination on the carrier recombination and the sensing performance. With the increase of light intensity, Fermi levels are separated and available recombination centers are increased, leading to the enhancement of the recombination process and the variation of detection properties. Consequently, this work highlights the potential of the fully UWB heterojunction and provides further optimization guidelines.

The operation and maintenance of railway signal systems create a significant and complex quantity of text data about faults. Aiming at the problems of fuzzy entity boundaries and low accuracy of entity recognition in the field of railway signal equipment faults, this paper provides a method for entity recognition of railway signal equipment fault information based on RoBERTa-wwm and deep learning integration. First, the model utilizes the RoBERTa-wwm pretrained language model to get the word vector of text sequences. Second, a parallel network consisting of a BiLSTM and a CNN is constructed to obtain the context feature information and the local attention information, respectively. Third, the feature vectors output from BiLSTM and CNN are combined and fed into MHA, focusing on extracting key feature information and mining the connection between different features. Finally, the label sequences with constraint relationships are outputted in CRF to complete the entity recognition task. The experimental analysis is carried out with fault text of railway signal equipment in the past ten years, and the experimental results show that the model has a higher evaluation index compared with the traditional model on this dataset, in which the precision, recall and F1 value are 93.25%, 92.45%, and 92.85%, respectively.

A new pixel circuit consisting of eleven n-type IGZO transistors (TFTs) and four capacitors is proposed and applied for micro light emitting diode (MLED) displays. The circuit is driven by pulse hybrid modulation (PHM), combining pulse amplitude modulation (PAM) and pulse width modulation (PWM). In purpose, high grayscales are achieved by PAM mode and low grayscales are achieved by PWM mode, which keep the driving current of LED out of the small value range so as to avoid unstable luminance performance. It is conducted that the MLED display driven by PHM demonstrate a stable luminance at low grayscale with well suppressed luminance errors of over 30% decrease, in comparison with the display driven by PAM. Moreover, both threshold voltage (VTH) shifts of driving TFTs for PAM mode and PWM mode could be well compensated in this circuit. As revealed by simulations, the driving current variations of LED could be retained within 10% when VTH shifts in the ranges from −1 to 2 V for PAM driving TFT and from −1 to 1.5 V for PWM driving TFT, respectively. In practice, a good brightness uniformity over 90% after 240-hours aging of the MLED display could be realized.

Abstract Background China is experiencing an aging population, leading to a significant demand for “Internet + nursing services” tailored for elderly individuals. However, there are many risk problems in the process of nurse service, which hinder the development of the service, and a scale is needed to assess the risk problems faced by nurses in “Internet + nursing services” for the elderly. Objective The purpose of this study is to develop an assessment scale for risk factors and outcomes related to nurses’ involvement in the “Internet + Nursing Service” for the elderly and to assess its reliability and validity. Methods Based on literature analysis, focus group, the Delphi method, and a presurvey, we designed an initial scale. The initial scale comprised two sections: risk factors and risk outcomes for nurses. In January and February of 2023, nurses engaged in “Internet + nursing services” for the elderly in Shanxi Province were chosen through a convenience sampling technique for a questionnaire survey. Subsequently, item analysis and exploratory factor analysis were employed to refine and develop a test version of the scale further. A follow-up questionnaire survey was carried out in March and April 2023 using a similar approach. The reliability and validity of the scale were assessed through confirmatory factor analysis, culminating in the formation of the final scale. Results The initial survey yielded 244 valid responses. The cumulative variance contributions of the two segments from the exploratory factor analysis were 84.584% and 90.089%, respectively. A subsequent survey garnered 220 valid responses. The confirmatory factor analysis results indicated: χ2/df = 2.086, comparative fit index (CFI) = 0.918, normative fit index (NLI) = 0.855, root mean square of residuals (RMR) = 0.045, and root mean square of error of approximation (RMSEA) = 0.070. These results demonstrate good structural, convergent, and discriminant validity. The content validity index at the item level (I-CVI) ranged between 0.875 and 1.000, while the content validity index at the scale level (S-CVI/Ave) was 0.941. Cronbach’s alpha coefficient for the entire scale stood at 0.970. Moreover, the scale exhibited a split-half reliability of 0.876 and a retest reliability of 0.980 (p

Aims: cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect. Methods: CREB1 activity and expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) in cells and tissues were measured by immunoblotting and immunohistochemical (IHC) staining. The effect of 666-15 on chondrocyte viability and apoptosis was examined by cell counting kit-8 (CCK-8) assay, JC-10, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. The effect of 666-15 on the microstructure of subchondral bone, and the synthesis and catabolism of cartilage, in anterior cruciate ligament transection mice were detected by micro-CT, safranin O and fast green (S/F), immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Results: CREB1 was hyperactive in osteoarthritic articular cartilage, interleukin (IL)-1β-treated cartilage explants, and IL-1β- or carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-treated chondrocytes. 666-15 enhanced cell viability of OA-like chondrocytes and alleviated IL-1β- or CCCP-induced chondrocyte injury through inhibition of mitochondrial dysfunction-associated apoptosis. Moreover, inhibition of CREB1 by 666-15 suppressed expression of ADAMTS4. Additionally, 666-15 alleviated joint degeneration in an ACLT mouse model. Conclusion: Hyperactive CREB1 played a critical role in OA development, and 666-15 exerted anti-IL-1β or anti-CCCP effects in vitro as well as joint-protective effects in vivo. 666-15 may therefore be used as a promising anti-OA drug. Cite this article: Bone Joint Res 2024;13(1):4–18.

Abstract Background The management of small gastric submucosal tumors (SMTs) originating from the muscularis propria layer (SMT-MPs) remains a subject of debate. Endoscopic submucosal dissection (ESD) is currently considered the optimal treatment for resection. However, high expenses, complex procedures, and the risk of complications have limited its application. Our previously proposed novel operation, precutting endoscopic band ligation (precutting EBL), has been demonstrated in a long-term, single-arm study to be an effective and safe technique for removing small gastric SMTs. However, the absence of a pathological examination and the potential for delayed perforation have raised concerns. Thus, we modified the precutting EBL by adding endoscopic resection to the snare after ligation and closure, yielding the precutting endoscopic band ligation-assisted resection (precutting EBLR). Moreover, the initial pilot study confirmed the safety and efficacy of the proposed approach and we planned a randomized controlled trial (RCT) to further validate its clinical feasibility. Methods This was a prospective, single-center, open-label, parallel group, and randomized controlled trial. Approximately 40 patients with SMT-MPs will be included in this trial. The patients included were allocated to two groups: ESD and precutting EBLR. The basic clinical data of the patients were collected in detail. To better quantify the difference between ESD and precutting EBLR, the primary outcome was set as the operation duration. The secondary outcomes included total operation cost and hospitalization, intraoperative adverse events, and postoperative recurrence. The primary outcome was tested for superiority, while the secondary outcomes were tested for noninferiority. SPSS is commonly used for statistical analysis. Discussion This study was designed to validate the feasibility of a novel operation for removing gastric SMT-MPs. To intuitively assess this phenomenon, the operation durations of precutting EBLR and ESD were compared, and other outcomes were also recorded comprehensively. Trial registration Chinese Clinical Trial Registry ChiCTR2200065473 . Registered on November 5, 2022.

Drought and salinity are two abiotic stresses that affect plant productivity. We exposed 2-year-old Platycladus orientalis saplings to single and combined stress of drought and salinity. Subsequently, the responses of physiological traits and soil properties were investigated. Biochemical traits such as leaf and root phytohormone content significantly increased under most stress conditions. Single drought stress resulted in significantly decreased nonstructural carbohydrate (NSC) content in stems and roots, while single salt stress and combined stress resulted in diverse response of NSC content. Xylem water potential of P. orientalis decreased significantly under both single drought and single salt stress, as well as the combined stress. Under the combined stress of drought and severe salt, xylem hydraulic conductivity significantly decreased while NSC content was unaffected, demonstrating that the risk of xylem hydraulic failure may be greater than carbon starvation. The tracheid lumen diameter and the tracheid double wall thickness of root and stem xylem was hardly affected by any stress, except for the stem tracheid lumen diameter, which was significantly increased under the combined stress. Soil ammonium nitrogen, nitrate nitrogen and available potassium content was only significantly affected by single salt stress, while soil available phosphorus content was not affected by any stress. Single drought stress had a stronger effect on the alpha diversity of rhizobacteria communities, and single salt stress had a stronger effect on soil nutrient availability, while combined stress showed relatively limited effect on these soil properties. Regarding physiological traits, responses of P. orientalis saplings under single and combined stress of drought and salt were diverse, and effects of combined stress could not be directly extrapolated from any single stress. Compared to single stress, the effect of combined stress on phytohormone content and hydraulic traits was negative to P. orientalis saplings, while the combined stress offset the negative effects of single drought stress on NSC content. Our study provided more comprehensive information on the response of the physiological traits and soil properties of P. orientalis saplings under single and combined stress of drought and salt, which would be helpful to understand the adapting mechanism of woody plants to abiotic stress.

ObjectiveThis study aims to evaluate the effectiveness of non-pharmacological interventions in improving cognitive function in patients with ischemic stroke through network meta-analysis.MethodsWe searched databases including the Cochrane Library, PubMed, EmBase, and Web of Science for randomized controlled trials (RCTs) on non-pharmacological treatments to improve cognitive impairment following ischemic stroke. The publication date was up to 15 March 2023. Due to the insufficiency of included studies, supplementary searches for high-quality Chinese literature were performed in databases such as CNKI, WanFang Data, and VIP Chinese Science Journals Database. Two reviewers independently went through the literature, extracted data, and assessed the risk of bias in the included studies using the risk of bias assessment tool recommended by the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. By utilizing R 4.2.3 RStudio software and the GeMTC package, a Bayesian network meta-analysis was conducted to assess the improvement in Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores under a variety of non-pharmacological interventions.ResultsA total of 22 RCTs involving 2,111 patients and 14 different non-pharmacological treatments were included. These interventions were transcranial direct current stimulation (tDCS), reminiscence therapy (RT), remote ischemic conditioning (RIC), physical fitness training (PFT), intensive patient care program (IPCP), moderate-intensity continuous training + high-intensity interval training (MICT + HIIT), medium intensity continuous training (MICT), grip training (GT), acupuncture, cognitive behavioral therapy (CBT), cognitive rehabilitation training (CRT), high pressure oxygen (HPO), moxibustion, and repetitive transcranial magnetic stimulation (rTMS). The results of the network meta-analysis indicated that rTMS had the highest likelihood of being the most effective intervention for improving MMSE and MoCA scores.ConclusionThe evidence from this study suggests that rTMS holds promise for improving MMSE and MoCA scores in patients with cognitive impairment following ischemic stroke. However, further high-quality research is needed to confirm and validate this finding.

Liver cancer is a heterogeneous disease characterized by poor responses to standard therapies and therefore unfavourable clinical outcomes. Understanding the characteristics of liver cancer and developing novel therapeutic strategies are imperative. Ferroptosis, a type of programmed cell death induced by lipid peroxidation, has emerged as a potential target for treatment. Naringenin, a natural compound that modulates lipid metabolism by targeting AMPK, shows promise in enhancing the efficacy of ferroptosis inducers. In this study, we utilized liver cancer cell lines and xenograft mice to explore the synergistic effects of naringenin in combination with ferroptosis inducers, examining both phenotypic outcomes and molecular mechanisms. Our study results indicate that the use of naringenin at non-toxic doses to hepatocytes can significantly enhance the anticancer effects of ferroptosis inducers (erastin, RSL3, and sorafenib). The combination index method confirmed a synergistic effect between naringenin and ferroptosis inducers. In comparison to naringenin or ferroptosis inducers alone, the combined therapy caused more robust lipid peroxidation and hence more severe ferroptotic damage to cancer cells. The inhibition of aerobic glycolysis mediated by the AMPK-PGC1α signalling axis is the key to naringenin's effect on reducing ferroptosis resistance in liver cancer, and the synergistic cytotoxic effect of naringenin and ferroptosis inducers on cancer cells was reversed after pretreatment with an AMPK inhibitor or a PGC1α inhibitor. Taken together, these findings suggest that naringenin could boost cancer cell sensitivity to ferroptosis inducers, which has potential clinical translational value.

Abstract BackgroundVentilator-associated pneumonia (VAP) is a serious complication of mechanical ventilation therapy that affects patients’ treatments and prognoses. Owing to its excellent data mining capabilities, artificial intelligence (AI) has been increasingly used to predict VAP. ObjectiveThis paper reviews VAP prediction models that are based on AI, providing a reference for the early identification of high-risk groups in future clinical practice. MethodsA scoping review was conducted in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The Wanfang database, the Chinese Biomedical Literature Database, Cochrane Library, Web of Science, PubMed, MEDLINE, and Embase were searched to identify relevant articles. Study selection and data extraction were independently conducted by 2 reviewers. The data extracted from the included studies were synthesized narratively. ResultsOf the 137 publications retrieved, 11 were included in this scoping review. The included studies reported the use of AI for predicting VAP. All 11 studies predicted VAP occurrence, and studies on VAP prognosis were excluded. Further, these studies used text data, and none of them involved imaging data. Public databases were the primary sources of data for model building (studies: 6/11, 55%), and 5 studies had sample sizes of

ObjectiveSoluble suppression of tumorigenicity 2 (sST2) is associated with the prognosis of some cardiac diseases, but studies on sST2 and the prognosis of patients with myocarditis are rare. This study investigated the relationship between major adverse cardiovascular events (MACEs) and sST2 during hospitalization in pediatric patients with myocarditis.MethodsThis was a single-center retrospective cohort study. A total of 252 patients aged ≤14 years diagnosed with myocarditis were enrolled. Events during the hospitalization were defined as MACEs (all-cause death > new heart failure > ventricular arrhythmia).ResultsA total of 25 people had MACEs during their hospital stay. The mortality during hospitalization was 6/23 (26%) in patients with heart failure and 3/10 (30%) in patients with ventricular arrhythmias. After including these risk factors in a multivariate logistic regression analysis, NT-proBNP (OR 4.323; 95% CI, 2.433–7.679; p

BackgroundAnisakis are globally distributed, marine parasitic nematodes that can cause human health problems, including symptoms such as vomiting, acute diarrhea, and allergic reactions. As parasitic nematodes that primarily affect the patient’s digestive tract, intestinal helminths can interact directly with the host microbiota through physical contact, chemicals, or nutrient competition. It is widely accepted that the host microbiota plays a crucial role in the regulation of immunity.Materials and methodsNematodes collected from the abdominal cavity of marine fish were identified by molecular biology and live worms were artificially infected in rats. Infection was determined by indirect ELISA based on rat serum and worm extraction. Feces were collected for 16S rDNA-based analysis of microbiota diversity.ResultsMolecular biology identification based on ITS sequences identified the collected nematodes as A. pegreffii. The success of the artificial infection was determined by indirect ELISA based on serum and worm extraction from artificially infected rats. Microbiota diversity analysis showed that a total of 773 ASVs were generated, and PCoA showed that the infected group was differentiated from the control group. The control group contained five characterized genera (Prevotellaceae NK3B31 group, Turicibacter, Clostridium sensu stricto 1, Candidatus Stoquefichus, Lachnospira) and the infected group contained nine characterized genera (Rodentibacter, Christensenella, Dubosiella, Streptococcus, Anaeroplasma, Lactococcus, Papillibacter, Desulfovibrio, Roseburia). Based on the Wilcoxon test, four processes were found to be significant: bacterial secretion system, bacterial invasion of epithelial cells, bacterial chemotaxis, and ABC transporters.ConclusionThis study is the first to analyze the diversity of the intestinal microbiota of rats infected with A. pegreffii and to determine the damage and regulation of metabolism and immunity caused by the infection in the rat gut. The findings provide a basis for further research on host-helminth-microbe correlationships.

Summary: Background: The use of mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for many diseases including perianal fistulizing Crohn’s disease (CD). Whether hUC-MSCs can promote the healing of luminal ulcer in CD has not been studied so far. Methods: The model of TNBS-induced colitis in rats was used to confirm the efficacy of hUC-MSCs in the treatment of CD. Then, seventeen CD patients refractory to or unsuitable for currently available therapies were enrolled and received once submucosal local injection through colonoscopy combined with once intravenous drip on the next day. All patients received a 24-week follow-up. Clinical and laboratory assessments were monitored at baseline, week 4, 8, 12, and 24. Endoscopic evaluations were conducted at baseline and week 12. Mucosal specimens were obtained at the margin of lesions by endoscopy biopsies and used for RNA sequencing. Two hUC-MSCs co-culture systems were established in vitro, one with the mucosa specimens and the other with M1 macrophages induced from THP1. The expressions of genes representing inflammation (TNFα, IL-6, and IL-1β) and intestinal barrier function (ZO1, CLAUDIN1, and CDH1) were tested by RT-PCR. Findings: hUC-MSCs treatment increased body weight and decreased disease activity index (DAI), colon macroscopic damage index (CMDI), and histopathological score (HPS) of rats with TNBS-induced colitis. The results of the clinical study also showed that this mode of hUC-MSCs application was associated with regression of intestinal ulceration. Eight patients (47%) got endoscopic responses (SES-CD improvement of ≥50% from baseline) and three patients (17.65%) got mucosal healing (SES-CD is zero), with a parallel improvement of clinical and laboratory parameters without serious adverse events. RNA sequencing showed hUC-MSCs therapy was associated with an upregulation of transcripts linked to intestinal epithelial barrier integrity and a downregulation of inflammatory signaling pathways in the intestinal mucosa, especially the TNF signaling pathway, IL-17 signaling pathway, and TLR signaling pathway. RNA expression of intestinal epithelial tight junction protein (ZO1, CLAUDIN1, and CDH1), and the RNA expression of major intestinal inflammatory factors in CD (IL-1β, IL-6, and TNFα, p

The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic PLAA variants were reported with progressive neurodegeneration, consequences of monoallelic PLAA variants have not been elucidated. Using exome or genome sequencing we identified PLAA de-novo missense variants, affecting conserved residues within the PUL domain, in children affected with neurodevelopmental disorders (NDDs), including psychomotor regression, intellectual disability (ID) and autism spectrum disorders (ASDs). Computational and in-vitro studies of the identified variants revealed abnormal chain arrangements at C-terminal and reduced PLAA-p97/VCP interaction, respectively. These findings expand both allelic and phenotypic heterogeneity associated to PLAA-related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA.

Abstract Exercise is an effective non-pharmacological strategy for ameliorating nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism needs further investigation. Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) decreases basal metabolic rate of the mice and impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) increases basal metabolic rate of the mice and synergizes with exercise to ameliorate NAFLD. Mechanistically, Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD.

With the rapid growth of science and technology, the Internet of Things (IoT) technology has matured and attracted the attention of many researchers. The development of agricultural modernization leads to the gradual emergence of intelligent management gradually taking root in agricultural production. Among many technologies in the IoT technologies, low-power Wide Area Network (WAN) technology has the characteristics of reliable and stable transmission with long distance and low power consumption. This is very useful for data transmission in special environments, especially for orchards in mountainous areas. This paper proposed a new agricultural Internet of Things in orchard management based on multi-sensors, such as DHT11 for temperature/humidity and GY-30 for illumination, the Long Range (LoRa) technology for transmitting the collected data or control command between the terminal and data cloud center, etc. Setting a low-power IoT sensor network in the orchard can remotely measure the parameters in the orchard. LoRa WAN is used to transmit data to the central node. In order to reduce power consumption and cost, a single monitoring node selects two power supplies, a solar power supply and a power supply, and the power supply can be turned on remotely by users in special circumstances. Experiments in different environments in the peach orchard show that the monitoring system has enough reliability and accuracy, and is suitable for environmental monitoring in orchards in remote areas or areas with complex terrain.