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Abstract Accumulated evidence suggested that gut microbial dysbiosis interplayed with progressive chronic kidney disease (CKD). However, no available therapy is effective in suppressing progressive CKD. Here, using microbiomics in 480 participants including healthy controls and patients with stage 1–5 CKD, we identified an elongation taxonomic chain Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus-Lactobacillus johnsonii correlated with patients with CKD progression, whose abundance strongly correlated with clinical kidney markers. L. johnsonii abundance reduced with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation ameliorated kidney lesion. Serum indole-3-aldehyde (IAld), whose level strongly negatively correlated with creatinine level in CKD rats, decreased in serum of rats induced using unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (NX) as well as late CKD patients. Treatment with IAld dampened kidney lesion through suppressing aryl hydrocarbon receptor (AHR) signal in rats with CKD or UUO, and in cultured 1-hydroxypyrene-induced HK-2 cells. Renoprotective effect of IAld was partially diminished in AHR deficiency mice and HK-2 cells. Our further data showed that treatment with L. johnsonii attenuated kidney lesion by suppressing AHR signal via increasing serum IAld level. Taken together, targeting L. johnsonii might reverse patients with CKD. This study provides a deeper understanding of how microbial-produced tryptophan metabolism affects host disease and discovers potential pathways for prophylactic and therapeutic treatments for CKD patients.

Abstract Infertility affects approximately one-sixth of couples globally, with the incidence of male infertility steadily increasing. However, our understanding of the impact of viral infections on fertility remains limited. This review consolidates findings from previous studies, outlining 40 viruses identified in human semen and summarizing their key characteristics, modes of transmission, and their effects on both the reproductive and endocrine systems. Furthermore, it elucidates potential pathogenic mechanisms and treatment prospects of viruses strongly associated with male infertility. This synthesis will enhance our comprehension of how viral infections influence male reproductive health, offering valuable insights for future research as well as the diagnosis and treatment of infectious infertility. Graphical Abstract Abbreviated summary: Semen viral infections can damage the male reproductive system, further affecting semen quality and causing infertility, as well as sexually transmitted infections to partners and vertical transmission resulting in poor pregnancy outcomes.

Abstract The beveling process is an important process in the manufacturing of resonators, which has a significant impact on the frequency stability of resonators. Without understanding the frequency characteristics of the resonator after beveling, it is impossible to accurately design the beveled resonators. Thus, in order to investigate the vibration characteristics of AT-cut beveled resonators, we investigated the high-frequency vibration in this work by using the subregional geometric fitting method (SGFM) based on Mindlin’s plate theory. Quartz crystal plates with nonuniform thicknesses are partitioned into three regions and each region is fitted by using the polynomial functions based on the measured geometric morphology data. The governing equations are obtained based on Mindlin’s two-dimensional theory and the coupled vibrations are further solved using the partial differential equation module of COMSOL. In the numerical calculation, we compare the results obtained by the SGFM with those obtained by the global fitting method and the measured data. The accuracy and effectiveness of the SGFM are also verified. It is found that the frequencies obtained by the SGFM are slightly higher than the frequencies obtained by the global fitting method, and the results of SGFM are closer to the measured results. Meanwhile, as the beveling time increases, the frequency increases and the energy trapping effect becomes more significant. The proposed method can significantly improve the computational efficiency of thickness-shear vibration while ensuring accuracy. It is expected to provide a new geometric fitting method for the analysis of beveled crystal resonators.

Abstract Background The accelerated growth of older individuals worldwide has increased the number of patients presenting with fragility hip fractures. Having a hip fracture can cause excess mortality, and patients with hip fracture have a higher risk of death than those without hip fracture. Most studies have treated hip fracture as a single, homogeneous condition, but hip fracture includes two major anatomic types: intertrochanteric fracture and femoral neck fracture. Few studies have specifically evaluated 1-year mortality risk in older individuals with femoral intertrochanteric fracture. The aim of this study was to evaluate 1-year mortality and factors associated with mortality in older individuals with femoral intertrochanteric fracture. Methods A retrospective review was conducted of 563 patients ≥ 65 years old who underwent surgery for femoral intertrochanteric fractures at our institution between January 2010 and August 2018. Patient demographics, comorbidities, and treatment were collected by retrospective chart review. Age, sex, Body Mass Index (BMI), American Society of Anesthesiologists (ASA) classification, Charlson comorbidity index (CCI), Arbeitsgemeinschaft Für Osteosynthesefragen (AO) fracture classification, haemoglobin value at admission, time to surgery, operation time, and intraoperative blood loss were risk factors to be tested. Multivariable logistic regression was used to evaluate associations between variables and death. Results Among the 563 patients, 49 died within 1 year after surgery, and the 1-year mortality rate was 8.7%. Multivariate analysis identified age > 80 years (OR = 4.038, P = 0.011), haemoglobin 14 d (OR = 3.907, P = 0.030) as independent risk factors for 1-year mortality. Comorbidities such as myocardial infarction and chronic pulmonary disease were associated with 1-year mortality after adjusting for age > 80 years and time to surgery > 14 days. Conclusions Patients over 80 years old with haemoglobin

Abstract This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA (n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.

Abstract The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.

Objective To explore the feasibility, safety and efficacy of modified pharmacomechanical endovascular thrombolysis for chronic thrombosis of arteriovenous graft (AVG). Methods Between January 1, 2020 and December 31, 2022, retrospective analysis was performed for 81 patients on endovascular treatment for AVG thrombosis for more than 3 days. Based upon the duration of thrombosis formation, they were assigned into two groups of 3-7 d (n=66) and >7 d (n=15). Demographic profiles, fistula characteristics, thrombotic features, success rate of intracavitary treatment, incidence of complications and patency rate after pathway intervention were compared. Results Average thrombotic time was 4(3, 5) day in 3-7 d group and 14(10, 23) day in >7 d group. The success rate of intracavitary treatment was 98.77%(80/81) in both groups and clinical success rate 98.77%(80/81) without any serious complication. Technical success rate was 98.48%(65/66) in 3-7 d group and 100%(15/15) in >7 d group. Clinical success rate was 98.48%(65/66) in 3-7 d group and 100%(15/15) in >7 d group. There was no statistically significant inter-group difference. After a total follow-up period of 1 year, primary patency rates at Day 30/90/180/270/360 post-intervention were 89.39%(59/66), 69.70%(46/66), 50.00%(22/66), 33.33%(22/66) and 21.21%(12/66) in 3-7 d group and 86.67% (13/15), 80.00%(12/15), 46.67%(7/15), 26.67%(4/15) and 20.00%(3/15) in >7 d group. Both groups maintained decent 1-year cumulative patency rates. It was 78.79% in 3-7 d group and 80.00% in >7 d group. There was no significant inter-group statistical difference. Conclusions Modified pharmacomechanical endovascular thrombolysis is feasible, effective and safe for chronic AVG thrombosis. Capable of prolonging usage time of AVG, it is worthy of wider clinical promotions.

Abstract Oxidative stress induced endothelial dysfunction plays a particularly important role in promoting the development of cardiovascular diseases (CVDs). Salvianolic acid A (SalA) is a water-soluble component of traditional Chinese medicine Salvia miltiorrhiza Bunge with anti-oxidant potency. This study aims to explore the regulatory effect of SalA on oxidative injury using an in vitro model of H2O2-induced injury in human umbilical vein endothelial cells (HUVECs). In the study, we determined cell viability, the activities of Lactate dehydrogenase (LDH) and Superoxide dismutase (SOD), cell proliferation rate and intracellular reactive oxygen species (ROS). Flow cytometry was used to detect cell apoptosis. Western-blotting was used to evaluate the expression of cell senescence, apoptosis, autophagy and pyroptosis protein factors. The expression level of miRNA was determined by qRT-PCR. Compared with H2O2-induced HUVECs, SalA promoted cell viability and cell proliferation rate; decreased LDH and ROS levels; and increased SOD activity. SalA also significantly attenuated endothelial senescence, inhibited cell apoptosis, reversed the increase of LC3 II/I ratio and NLRP3 accumulation. Furthermore, miR-204-5p was regulated by SalA. Importantly, miR-204-5p inhibitor had similar effect to that of SalA on H2O2-induced HUVECs. Our results indicated that SalA could alleviate H2O2-induced oxidative injury by downregulating miR-204-5p in HUVECs.

Abstract Background Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, this study aims to determine the 90% effective dose (ED90) of remimazolam to inhibit responses to insertion of a duodenoscope during endoscopic retrograde cholangiopancreatography (ERCP). Methods A dose-response study was carried out undergoing ERCP who received remimazolam-alfentanil anesthesia using 10 µg/kg of alfentanil between September 2021 and November 2021. The initial dose of remimazolam was 0.2 mg/kg. The dose was then decided based on the responses of earlier patients by exploiting the sequential ascend and descend according to a 9: 1 biased coin design. Upon failure, the dose of remimazolam was increased by 0.025 mg/kg in the next patient. When the insertion was successful, the succeeding patient was randomized to an identical dose or a dose that was lower by 0.025 mg/kg.The ED90 of remimazolam for inhibiting responses to the insertion of a duodenoscope during ERCP was calculated. Adverse events and complications of remimazolam were recorded. Results A total of 55 elderly patients (age > 65) were included in the study. 45 successfully anesthetized patients, and 10 unsuccessfully. The ED90 of remimazolam was 0.300 mg/kg (95% CI = 0.287–0.320). ED95 was 0.315 (95% CI = 0.312–0.323) and ED99 was 0.323 (95% CI = 0.323–0.325). Among the patients, 9 patients developed hypotension, 2 patients developed bradycardia and 1 patient developed tachycardia, and hypoxia occurred in 2 patients. Conclusions A loading dose of 0.300 mg / kg of remimazolam for elderly patients undergoing ERCP can safely, effectively, and quickly induce patients to fall asleep and inhibit responses to the insertion of a duodenoscope. Trial registration The study protocol was registered at the website ClinicalTrials.gov on 22/09/2021(NCT05053763).

Abstract Objectives To develop and validate radiomics model based on computed tomography (CT) for preoperative prediction of CN0 status in patients with papillary thyroid carcinoma (PTC). Methods A total of 548 pathologically confirmed LNs (243 non-metastatic and 305 metastatic) two distinct hospitals were retrospectively assessed. A total of 396 radiomics features were extracted from arterial-phase CT images, where the strongest features containing the most predictive potential were further selected using the least absolute shrinkage and selection operator (LASSO) regression method. Delong test was used to compare the AUC values of training set, test sets and cN0 group. Results The Rad-score showed good discriminating performance with Area Under the ROC Curve (AUC) of 0.917(95% CI, 0.884 to 0.950), 0.892 (95% CI, 0.833 to 0.950) and 0.921 (95% CI, 868 to 0.973) in the training, internal validation cohort and external validation cohort, respectively. The test group of CN0 with a AUC of 0.892 (95% CI, 0.805 to 0.979). The accuracy was 85.4% (sensitivity = 81.3%; specificity = 88.9%) in the training cohort, 82.9% (sensitivity = 79.0%; specificity = 88.7%) in the internal validation cohort, 85.4% (sensitivity = 89.7%; specificity = 83.8%) in the external validation cohort, 86.7% (sensitivity = 83.8%; specificity = 91.3%) in the CN0 test group.The calibration curve demonstrated a significant Rad-score (P-value in H-L test > 0.05). The decision curve analysis indicated that the rad-score was clinically useful. Conclusions Radiomics has shown great diagnostic potential to preoperatively predict the status of cN0 in PTC.

Background: Filamin A (FLNA) is a member of the filamin family and has been found to be critical for the progression of several cancers. However, its biological function in papillary thyroid cancer (PTC) remains largely unexplored. Methods: Data from The Cancer Genome Atlas (TCGA) databases were utilized to analyze the FLNA expression level and its influence on the clinical implications of patients with PTC. Gene Expression Omnibus (GEO) and qRT-PCR was used to verify the expression levels of FLNA in PTC. Kaplan–Meier survival analysis was conducted to evaluate the prognostic value of FLNA in PTC. Transwell assays and wound healing were performed to examine the biological function of FLNA knockdown in PTC cells. Gene set enrichment analysis (GSEA) and Western blotting were conducted to investigate the potential mechanisms underlying the role of FLNA in PTC progression. In addition, the relationship between FLNA expression and the tumor immune microenvironment (TME) in PTC was explored. Results: FLNA was significantly upregulated in PTC tissues. High expression levels of FLNA was correlated with advanced TNM stage, T stage, and N stage, as well as poor disease-free interval (DFI) and progression-free interval (PFI) time in PTC patients. Moreover, we found that FLNA knockdown inhibited the migration and invasion of PTC cells. Mechanistically, FLNA knockdown inhibited epithelial–mesenchymal transition (EMT) in PTC and affected the activation of the FAK/AKT signaling pathway. In addition, FLNA expression was associated with TME in PTC. Conclusion: FLNA may be regarded as a new therapeutic target for PTC patients.

Objective To explore the distribution of serological markers related to samples whose serological test results were inconsistent with HBV DNA test results among voluntary blood donors in Xi′an. Methods A total of 71 HBsAg ELISA positive and NAT non-reactive (ELISA+ /NAT-)blood samples were collected from Shaanxi Blood Center from November 1, 2022 to April 30, 2023. The serological markers of hepatitis B were detected by electrochemiluminescence method, and the HBV S region and C region gene fragments were amplified by nested-PCR. Results The positive rate of nested-PCR in double ELISA+ /NAT- group(n=30) was statistically higher than that of ELISA+ /NAT- group(n=41)(60% vs 24.4%, P

In recent years, to liberate coal resources from high pressure limestone water on the coal seam floor, North China Coalfields have generally adopted surface directional drilling technology to carry out regional grouting reinforcement and transformation (commonly known as “floor regional treatment”) on the thin-layer limestone of the Taiyuan Formation in order to comprehensively seal karst cracks in limestone and block vertical guide water channels. In this technology, the design of the spacing between “horizontal branching holes” closely related to the diffusion range (radius) of the slurry has been widely studied by academia and industry. There is a large amount of grouting work in the bottom plate area of the Anhui North mining area, especially in the mining of deep resources, which will cost billions of yuan. It is necessary to verify the true data of the diffusion range of the grout. Therefore, based on the Hengyuan Coal Mine in the northern Anhui mining area as the research base, relying on the II63 mining area floor area treatment project, the slurry diffusion range tracing test was designed and implemented. The fluorescent agent (tracer) was added to the horizontal branch hole (Z8-7) in the middle, and the rock debris samples were taken from the horizontal branch holes (Z8-6, Z8-8) and cross branch detection holes (Z8JC) on both sides to identify fluorescent cement and obtain the diffusion range of the slurry. Furthermore, based on the analysis of the influencing factors of slurry diffusion, a formula for calculating the diffusion range of slurry in the grouting treatment of the bottom plate area of the Hengyuan Coal Mine was constructed. The results show that: ① Based on the analysis of on-site and indoor identification results of rock debris, the diffusion range of grouting slurry under the coal seam floor area of the Hengyuan Coal Mine II63 mining area was 38.3−44.0 m, and the cement distribution was dense within the diffusion range of horizontal branch hole slurry within 30 meters. The grouting effect was the best in this area. ② Through a rapid identification of on-site rock cuttings and precise identification of indoor rock cuttings, the diffusion range of the slurry obtained was basically consistent, proving the effectiveness of fluorescence tracing of the diffusion range of the slurry. ③ Through comparative analysis, it was believed that under actual grouting conditions such as calculation parameters and boundary constraints, the theoretical calculation and numerical simulation results of the slurry diffusion range were close to the measured results of on-site tracing experiments. ④ Using the data from water pressure tests, grouting parameters, drilling structures, and hydrogeological responses during the tracer test process, taking into account the factors such as gravity, structure, and groundwater runoff, and using SPSS nonlinear fitting software, a formula for calculating the diffusion range of grouting slurry in the bottom plate area of the Hengyuan Coal Mine II63 mining area was obtained. ⑤ Based on the actual geological and hydrogeological conditions of the injection layer in the Hengyuan Coal Mine, using the fitted slurry diffusion range calculation formula, the slurry diffusion range of Z8 site in the II63 mining area was obtained to be 37.8−42.9 m, which was similar to the measured results of the slurry diffusion range tracer test. The calculation formula could be promoted and applied under similar conditions. The on-site tracing engineering test of the diffusion range of grouting slurry in the coal mine floor area not only obtained real data on the diffusion range of slurry, but also clarified the inherent relationship between slurry diffusion and various geological and hydrogeological factors. The diffusion mechanism of grouting slurry for ultra deep and ultra long directional drilling was revealed, and a formula for calculating the diffusion range of slurry was constructed, providing a reference basis for the reasonable design of horizontal branch hole spacing in bottom plate area treatment projects under similar conditions.

Abstract Background Laser-assisted hatching (LAH) stands as the predominant technique for removing the zona pellucida (ZP) in embryos, primarily consisting of two methods: drilling laser-assisted hatching (D-LAH) and thinning laser-assisted hatching (T-LAH). Presently, both methods have limitations, and their comparative efficacy for embryo implantation and clinical pregnancy remains uncertain. Aim Evaluate the impact of D-LAH and T-LAH on clinical pregnancy rates within assisted reproductive technology (ART). Methods We systematically searched electronic databases including PubMed, Web of Science, and Cochrane Library until July 20, 2022. This study encompassed observational studies and randomized controlled trials (RCTs). A 95% confidence interval (CI) was utilized for assessing the risk ratio (RR) of pregnancy outcomes. The level of heterogeneity was measured using I2 statistics, considering a value exceeding 50% as indicative of substantial heterogeneity. Results The meta-analysis scrutinized 9 studies involving 2405 clinical pregnancies from D-LAH and 2239 from T-LAH. Findings suggested no considerable variation in the clinical pregnancy rates between the two techniques (RR = 0.93, 95% CI: 0.79–1.10, I2 = 71%, P = 0.41). Subgroup analyses also revealed no substantial differences. However, D-LAH exhibited a notably higher occurrence of singleton pregnancies compared to T-LAH (RR = 2.28, 95% CI: 1.08–4.82, I2 = 89%, P = 0.03). There were no noteworthy distinctions observed in other secondary outcomes encompassing implantation rate, multiple pregnancies, ongoing pregnancy, miscarriage, premature birth, and live birth. Conclusion Both the primary findings and subgroup analyses showed no marked variance in clinical pregnancy rates between D-LAH and T-LAH. Therefore, patients with varying conditions should select their preferred LAH technique after assessing their individual situation. However, due to the restricted number of studies involved, accurately gauging the influence of these laser techniques on clinical outcomes is challenging, necessitating further RCTs and high-quality studies to enhance the success rate of ART. Trial registration PROSPERO: CRD42022347066.

Abstract Background Flexible hybrid teaching has become the new normal of basic medical education in the postepidemic era. Identifying ways to improve the quality of curriculum teaching and achieve high-level talent training is a complex problem that urgently needs to be solved. Over the course of the past several semesters, the research team has integrated design thinking (DT) into undergraduate teaching to identify, redesign and solve complex problems in achieving curriculum teaching and professional talent training objectives. Methods This study is an observational research. A total of 156 undergraduate stomatology students from Jining Medical University in 2021 were selected to participate in two rounds of online flipped teaching using the design thinking EDIPT (empathy, definition, idea, prototype, and test) method. This approach was applied specifically to the chapters on the respiratory system and female reproductive system. Data collection included student questionnaires, teacher-student interviews, and exam scores. GraphPad Prism software was used for data analysis, and the statistical method was conducted by multiple or unpaired t test. Results According to the questionnaire results, the flipped classroom teaching design developed using design thinking methods received strong support from the majority of students, with nearly 80% of students providing feedback that they developed multiple abilities during the study process. The interview results indicated that teachers generally believed that using design thinking methods to understand students' real needs, define teaching problems, and devise instructional design solutions, along with testing and promptly adjusting the effectiveness through teaching practices, played a highly positive role in improving teaching and student learning outcomes. A comparison of exam scores showed a significant improvement in the exam scores of the class of 2021 stomatology students in the flipped teaching chapters compared to the class of 2020 stomatology students, and this difference was statistically significant. However, due to the limitation of the experimental chapter scope, there was no significant difference in the overall course grades. Conclusion The study explores the application of design thinking in histology and embryology teaching, revealing its positive impact on innovative teaching strategies and students' learning experience in medical education. Online flipped teaching, developed through design thinking, proves to be an effective and flexible method that enhances student engagement and fosters autonomous learning abilities.

Abstract It is known that titanium (Ti) implant surfaces exhibit poor antibacterial properties and osteogenesis. In this study, chitosan particles loaded with aspirin, amoxicillin or aspirin + amoxicillin were synthesized and coated onto implant surfaces. In addition to analysing the surface characteristics of the modified Ti surfaces, the effects of the modified Ti surfaces on the adhesion and viability of rat bone marrow-derived stem cells (rBMSCs) were evaluated. The metabolic activities of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) biofilms on the modified Ti surfaces were also measured in vitro. Moreover, S. aureus was tested for its antibacterial effect by coating it in vivo. Using water as the droplet medium, the contact angles of the modified Ti surfaces increased from 44.12 ± 1.75° to 58.37 ± 4.15°. In comparison to those of the other groups tested, significant increases in rBMSC adhesion and proliferation were observed in the presence of aspirin + amoxicillin-loaded microspheres, whereas a significant reduction in the metabolic level of biofilms was observed in the presence of aspirin + amoxicillin-loaded microspheres both in vitro and in vivo. Aspirin and amoxicillin could be used in combination to coat implant surfaces to mitigate bacterial activities and promote osteogenesis.

Abstract Flash floods can carry substantial sediment, posing significant sedimentation hazards in hilly cities. The sedimentation hazard map can reproduce the sediment thickness and extent of an extreme events scenario, playing an important role in sediment risk management. However, current research primarily focuses on modeling the inundation area and depth of floods, while studying sedimentation hazard caused by flash floods in urban areas remains insufficient. This paper aims to address this gap by utilizing a numerical model that simulates hyperconcentrated flow in hilly urban areas using the two‐dimensional hydro‐sediment‐morphological model to compile the cumulative sedimentation hazard map. The model, built upon the open‐source TELEMAC‐MASCARET framework, incorporates Zhang Hongwu's formula to simulate sediment‐carrying capacity, particularly suitable for hyper‐sediment concentration near the riverbed. This paper uses the data of extreme flash flood events in the Wuding River basin in 2017 to simulate and compile the cumulative sedimentation hazard map. The hazard map delineates the sedimentation hazard extent and level attributable to overbank floodplain sedimentation. Notably, the sediment thickness is highest in areas near the levees on both sides of the Dali River. Moreover, the map illustrates the extent of channel erosion resulting from hyperconcentrated floods, which could jeopardize bank stability.

ABSTRACT: Semen quality is an important indicator that can directly affect fertility. In mammals, miRNAs in seminal plasma extracellular vesicles (SPEVs) and sperms can regulate semen quality. However, relevant regulatory mechanism in duck sperms remains largely unclear. In this study, duck SPEVs were isolated and characterized by transmission electron microscopy (TEM), western blot (WB), and nanoparticle tracking analysis (NTA). To identify the important molecules affecting semen quality, we analysed the miRNA expression in sperms and SPEVs of male ducks in high semen quality group ((DHS, DHSE) and low semen quality group (DLS, DLSE). We identified 94 differentially expressed (DE) miRNAs in the comparison of DHS vs. DLS, and 21 DE miRNAs in DHSE vs. DLSE. Target genes of SPEVs DE miRNAs were enriched in ErbB signaling pathway, glycometabolism, and ECM-receptor interaction pathways (P < 0.05), while the target genes of sperm DE miRNAs were enriched in ribosome (P < 0.05). The miRNA-target-pathway interaction network analyses indicated that 5 DE miRNAs (miR-34c-5p, miR-34b-3p, miR-449a, miR-31-5p, and miR-128-1-5p) targeted the largest number of target genes enriched in MAPK, Wnt and calcium signaling pathways, of which FZD9 and ANAPC11 were involved in multiple biological processes related to sperm functions, indicating their regulatory effects on sperm quality. The comparison of DE miRNAs of SPEVs and sperms found that mir-31-5p and novel-273 could potentially serve as biomarkers for semen quality detection. Our findings enhance the insight into the crucial role of SPEV and sperm miRNAs in regulating semen quality and provide a new perspective for subsequent studies.

Estimating bioavailable heavy metals in seawater is closely related to the indication of ecological risk. This study combined a CadR-regulated vioABE expression module and a MerR-regulated VioC expression module to generate a novel dual-colored bacterial cell-based biosensor. After genetic optimization, the preferred biosensor could detect as low as 9.7 nM Cd(II), 24.4 nM Pb(II), and 0.5 nM Hg(II). Increased grey-green intensities were observed in Cd(II) (4.9 nM to 40 μM) and Pb(II) (24.4 nM to 200 μM) exposure groups. Interestingly, increased purple intensity was observed in the Hg(II) exposure group (3.7 to 468.8 nM) in a dose-dependent manner. A low-cost and mini-equipment biosensing process was established for detecting pollutant heavy metals in seawater, with the added advantage of providing information on the bioavailability and cytotoxicity of heavy metals. High salinity weakly interferes with the biosensing response to Hg(II). This study shows that novel colorimetric biosensors have the potential to simultaneously report various toxic metals in environmental water samples, contributing to protecting marine ecology.

BackgroundAltitude illness has serious effects on individuals who are not adequately acclimatized to high-altitude areas and may even lead to death. However, the individualized mechanisms of onset and preventive measures are not fully elucidated at present, especially the relationship between altitude illness and elements, which requires further in-depth research.MethodsFresh serum samples were collected from individuals who underwent health examinations at the two hospitals in Xining and Sanya between November 2021 and December 2021. The blood zinc (Zn), iron (Fe), and calcium (Ca) concentrations, as well as hypoxia-inducible factor 1-alpha (HIF-1α) concentrations, were measured. This study conducted effective sample size estimation, repeated experiments, and used GraphPad Prism 9.0 and IBM SPSS version 19.0 software for comparative analysis of differences in the expression of elements and HIF-1α among different ethnic groups, altitudes, and concentration groups. Linear regression and multiple linear regression were employed to explore the relationships among elements and their correlation with HIF-1α.ResultsThis study included a total of 400 participants. The results from the repeated measurements indicated that the consistency of the laboratory test results was satisfactory. In terms of altitude differences, except for Fe (p = 0.767), which did not show significant variance between low and high altitude regions, Zn, Ca, and HIF-1α elements all exhibited notable differences between these areas (p

IntroductionThis study aims to investigate whether the transrectal ultrasound-guided combined biopsy (CB) improves the detection rates of prostate cancer (PCa) and clinically significant PCa (csPCa) in biopsy-naïve patients. We also aimed to compare the Prostate Imaging Reporting and Data System (PI-RADS v2.1) score, ADC values, and PSA density (PSAd) in predicting csPCa by the combined prostate biopsy.MethodsThis retrospective and single-center study included 389 biopsy-naïve patients with PSA level 4~20 ng/ml, of whom 197 underwent prebiopsy mpMRI of the prostate. The mpMRI-based scores (PI-RADS v2.1 scores and ADC values) and clinical parameters were collected and evaluated by logistic regression analyses. Multivariable models based on the mpMRI-based scores and clinical parameters were developed by the logistic regression analyses to forecast biopsy outcomes of CB in biopsy-naïve patients. The ROC curves measured by the AUC values, calibration plots, and DCA were performed to assess multivariable models.ResultsThe CB can detect more csPCa compared with TRUSB (32.0% vs. 53%). The Spearman correlation revealed that Gleason scores of the prostate biopsy significantly correlated with PI-RADS scores and ADC values. The multivariate logistic regression confirmed that PI-RADS scores 4, 5, and prostate volume were important predictors of csPCa. The PI-RADS+ADC+PSAd (PAP) model had the highest AUCs of 0.913 for predicting csPCa in biopsy-naïve patients with PSA level 4~20 ng/ml. When the biopsy risk threshold of the PAP model was greater than or equal to 0.10, 51% of patients could avoid an unnecessary biopsy, and only 5% of patients with csPCa were missed.ConclusionThe prebiopsy mpMRI and the combined prostate biopsy have a high CDR of csPCa in biopsy-naïve patients. A multivariable model based on the mpMRI-based scores and PSAd could provide a reference for clinicians in forecasting biopsy outcomes in biopsy-naïve patients with PSA 4~20 ng/ml and make a more comprehensive assessment during the decision-making of the prostate biopsy.

Background: Male breast cancer (MBC) is a rare malignancy with a worse prognosis than female breast cancer (FBC). Current MBC treatment strategies are based on those for FBC. However, molecular differences between MBC and FBC with respect to prognosis and drug responses remain unclear. Methods: After controlling for confounding factors with propensity score matching (PSM), differences between MBC and FBC were comprehensively analyzed using many types of data: survival, immune microenvironments, sex hormone responses, drug sensitivity, transcriptomes, genomes, epigenomes, and proteomes. Results: Overall survival (OS) and cancer-specific survival (CSS) were both worse for MBC than for FBC. Differentially expressed mRNAs were enriched in numerous cancer-related functions and pathways, with SPAG16 and STOX1 being as the most important prognosis-related mRNAs for MBC. Competing endogenous RNA (ceRNA) and transcription factor (TF)-mRNA regulatory networks contain potential prognostic genes. Nine genes had higher mutation frequencies in MBC than in FBC. MBC shows a comparatively poor response to immunotherapy, with five proteins that promote breast cancer progression being highly expressed in MBC. MBC may be more responsive than FBC to estrogen. We detected six United States Food and Drug Administration (FDA)-approved therapeutic target genes as being differentially expressed between MBC and FBC. Conclusion: The poor prognosis of MBC compared to FBC is due to numerous molecular differences and resulting drug responses.

In recent years, shale logging has played a crucial role in the grouting reinforcement engineering of the floor limestone strata in “North China-type”coalfields. However, existing shale logging techniques are limited to the recognition of physical indicators such as color, particle size, and morphology. This limitation makes an accurate stratification challenging, and the “along-stratum rate” in borehole design is difficult to be ensured. These constraints hinder the effectiveness of water damage control in the floor limestone strata areas. This study, based on the elemental geochemical differences in the Carboniferous Taiyuan Formation thin-layered limestone and its clastic interlayers, selected the Taoyuan Coal Mine in the Huaibei Coalfield as the research area. Some vertical core samples were obtained from drill holes in the upper part of the Taiyuan Formation, including L1 limestone to L4 limestone (with L3 limestone as the grouting control target layer). Using the X-ray fluorescence spectrometry (XRF), the major elemental background values of thin-layered limestone and its interlayers were quantitatively determined. Also, a major elemental geochemical identification model was established for thin-layered limestone using mathematical statistical methods such as cluster analysis and factor analysis. Simultaneously, major elemental testing was conducted on shale samples from directional drilling horizontal branch holes. The identification pattern validation was completed through shale stratigraphic source analysis based on the established geochemical identification model. The results showed that high CaO content and Loss on Ignition (LOI) value could serve as characteristic indicators for the target layer L3 limestone in grouting and reinforcement. Abundances of MgO (0.5%±), MnO (0.03%±), and P2O5 (0.08%±) could be used as recognition indicators for the overlying marker layer J3. The cluster analysis identification model effectively distinguished the Taiyuan Formation L1 to L3 limestone. The model established using element factor scores effectively differentiated clastic interlayers from thin-layered limestone in the Taiyuan Formation. The Fisher discriminant equation obtained by running the model with rock geochemical background values achieved an accuracy rate of 100% in the source analysis of cuttings from grouting target layer L3 limestone. Based on the above findings, the feasibility of applying the elemental geochemical source analysis method, aimed at ensuring the “in-layer rate” in horizontal branch hole cuttings, was demonstrated. This, in turn, led to the proposal of a ground directional drilling “in-layer rate” control technology scheme. This study, grounded in elemental geochemical theory, identified the target layer stratification through characteristic geochemical information carried by cuttings from directional drilling. With the support of on-site rapid quantitative testing techniques, the technology offers new insights into addressing the challenge of grouting and modification at bottom limestone water hazard areas in the North China-type coalfields.

Abstract The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition. We identify 4765 independent primary and 616 secondary cis-expression quantitative trait loci (cis-eQTLs) in the synovium and find that the eQTLs with multiple independent signals have stronger effects and heritability than single independent eQTLs. Integration of genome-wide association studies (GWASs) and eQTLs identifies 84 arthritis related genes, revealing 38 novel genes which have not been reported by previous studies using eQTL data from the GTEx project or immune cells. We further develop a method called eQTac to identify variants that could affect gene expression by affecting chromatin accessibility and identify 1517 regions with potential regulatory function of chromatin accessibility. Altogether, our study provides a comprehensive synovium multi-omics resource for arthritic diseases and gains new insights into the regulation of gene expression.

Abstract The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits, and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways. Here, we identified that DOK6, a member of the Dok (downstream of tyrosine kinases) family, is required for the maintenance of peripheral axons, and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice, manifested as impaired sensory, abnormal posture, paw deformities, blocked nerve conduction, and dysmyelination. Furthermore, Dok6 is highly expressed in peripheral neurons but not in Schwann cells, and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding, axon destruction, and hindered retrograde axonal transport. Specifically, DOK6 acts as an adaptor protein for selectivity-mediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB. DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation, including MAP1B, Tau and Dynein for axonal transport, and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis. This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.

To study the molecular mechanism of baicalein interrupting the programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) pathway, molecular docking, molecular dynamics simulation, binding free energy calculation and principal component analysis were first performed to predict the inhibition effect of baicalein on this pathway, which was verified by enzyme-linked immunosorbent assay (ELISA) subsequently. Binding free energy calculations showed that the affinity of baicalein to the PD-L1 dimer was −32.41±0.31 kcal/mol. Free energy decomposition, contact numbers and nonbonded interaction results revealed that baicalein mainly interacted with the C-, C'-, F- and G-sheet domains of the PD-L1 dimer. Importantly, nonpolar interactions between the key residues Tyr56, Met115, Ala121, Asp122 and baicalein were dominant factors during the binding process. Cross-correlation matrixes and secondary structure results further demonstrated that baicalein could stably interact with the sheet domains of the PD-L1 dimer. The result of ELISA showed that the IC50 value of baicalein for inhibiting the PD-1/PD-L1 interaction was 79.47 µg/L. In conclusion, this study revealed that baicalein could directly bind to the PD-L1 dimer, thus blocking the PD-1/PD-L1 interaction, would provide basis for discovering natural small-molecule inhibitors of this pathway.

With the rise of social networks, various types of information have emerged in the vision field in a complex manner, making it crucial to analyze the propagation patters of online public opinion to effectively guide information dissemination. To elucidate the dynamics of information dissemination, this paper proposes a directed network information based on self-organized network information dissemination scenario. This model takes into account the influence of networks formed by users spontaneously and distinguishes the dissemination population based on the in- and out-degree of user nodes in the network. To assess the model’s performance, it is evaluated using real retweets from Chinese Sina Weibo, considering the impact of user interactions on information dissemination. Comparing real data with model-fitted data, the proposed model-based evaluation and numerical analysis demonstrate that the forwarding and transfer probabilities align with actual information dissemination. Furthermore, the evaluation sensitivity analyses describe the key factors influencing information dissemination, aiding decision-making in formulating strategies to guide public opinion. To quantify the importance of these factors, assessment metrics are introduced, such as the propagation regeneration number.

Abstract Information regarding regional arterial stiffness assessment in osteoarthritis (OA) was scarce and sometimes contradictory. We aimed to investigate the aortic, lower limb peripheral arterial stiffness and their associations with knee OA. Patients with primary knee OA and matched non-OA controls were prospectively enrolled from two medical centers in China. The carotid-femoral pulse wave velocity (cfPWV) and femoral-ankle pulse wave velocity (faPWV) were measured using a novel ultrasound technique. A total of 238 participants (including 128 patients with knee OA and 110 controls) were included. In OA patients, cfPWV was significantly higher than that of non-OA controls (9.40 ± 1.92 vs 8.25 ± 1.26 m/s, P

Abstract Rapid mass transfer in solid-solid reactions is crucial for catalysis. Although phoretic nanoparticles offer potential for increased collision efficiency between solids, their implementation is hindered by limited interaction ranges. Here, we present a self-driven long-range electrophoresis of organic nanocrystals facilitated by a rationally designed photogenerated outer electric field (OEF) on their surface. Employing perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) molecular nanocrystals as a model, we demonstrate that a directional OEF with an intensity of 13.6-0.4 kV m−1 across a range of 25–200 μm. This OEF-driven targeted electrophoresis of PTCDA nanocrystals onto the microplastic surface enhances the activity for subsequent decomposition of microplastics (196.8 mg h−1) into CO2 by solid-solid catalysis. As supported by operando characterizations and theoretical calculations, the OEF surrounds PTCDA nanocrystals initially, directing from the electron-rich (0 1 1) to the hole-rich $$(11\bar{2})$$ ( 11 2 ¯ ) surface. Upon surface charge modulation, the direction of OEF changes toward the solid substrate. The OEF-driven electrophoretic effect in organic nanocrystals with anisotropic charge enrichment characteristics indicates potential advancements in realizing effective solid-solid photocatalysis.

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function. In the present study we investigated the contribution of megakaryocytic leukemia 1 (MKL1), a transcriptional modulator, to liver regeneration. We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients. Mice with MKL1 deletion exhibited defective regenerative response in the liver. Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription. MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1. Of interest, phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid (PA). PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure. Finally, PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients. In conclusion, our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration. Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

Background Few studies have examined how multi-level social factors interact and affect developmental patterns of sexual risk among middle-to-late adolescents who are at risk of experiencing sexual risk behaviors. We examined developmental trajectories of sexual risk behaviors of boys and girls in middle-to-late adolescence and the effects of exposure to three social risk factors (poor parental monitoring, peer risk, and neighborhood risk).Methods We followed 2,332 Bahamian adolescents every six months from Grades 10–12. We used group-based trajectory modeling to identify distinct trajectories of sexual risk behaviors for boys and girls.Results We identified three trajectories each for boys and girls. Peer risk and neighborhood risk predicted a high sexual-risk trajectory for boys, and peer risk (alone or combined with other risk factors) had the greatest impact on the membership of moderate-to-high-risk trajectory for girls. Parental monitoring had a relatively small effect on adolescents’ sexual risk behavior.Conclusion Our results underscore the importance of early identification of adolescents with sexual risk behavior and development of targeted prevention interventions to improve adolescent health outcomes.

Ceftazidime-avibactam resistance attributable to the blaKPC-2 gene mutation is increasingly documented in clinical settings. In this study, we characterized the mechanisms leading to the development of ceftazidime-avibactam resistance in ST11-K47 hypervirulent Klebsiella pneumoniae that harboured the blaKPC-135 gene. This strain possessed fimbriae and biofilm, demonstrating pathogenicity. Compared with the wild-type KPC-2 carbapenemase, the novel KPC-135 enzyme exhibited a deletion of Glu168 and Leu169 and a 15-amino acid tandem repeat between Val262 and Ala276. The blaKPC-135 gene was located within the Tn6296 transposon truncated by IS26 and carried on an IncFII/IncR-type plasmid. Compared to the blaKPC-2-positive cloned strain, only the MIC of ceftazidime increased against blaKPC-135-positive K. pneumoniae and wasn’t inhibited by avibactam (MIC 32 μg/mL), while clavulanic acid and vaborbactam demonstrated some inhibition. Kinetic parameters revealed that KPC-135 exhibited a lower Km and kcat/Km with ceftazidime and carbapenems, and a higher (∼26-fold) 50% inhibitory concentration with avibactam compared to KPC-2. The KPC-135 enzyme exerted a detrimental effect on fitness relative to the wild-type strain. Furthermore, this strain possessed hypervirulent determinants, which included the IncHI1B/FIB plasmid with rmpA2 and expression of type 1 and 3 fimbriae. In conclusion, we reported a novel KPC variant, KPC-135, in a clinical ST11-K47 hypervirulent K. pneumoniae strain, which conferred ceftazidime-avibactam resistance, possibly through increased ceftazidime affinity and decreased avibactam susceptibility. This strain simultaneously harboured resistance and virulence genes, posing an elevated challenge in clinical treatment.

Ceftazidime-avibactam (CZA) is employed for the treatment of infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). Resistance to CZA is frequently linked to point mutations in the blaKPC. We conducted in vitro simulations of in vivo blaKPC mutations using CZA. Four pre-therapy KPC-KP isolates (K1, K2, K3, and K4) were evaluated, all initially exhibited susceptibility to CZA and produced KPC-2. The crucial distinction was that following CZA treatment, the blaKPC-2 mutated in K1, K2, and K3, rendering them resistant to CZA, while K4 achieved microbiological clearance, and blaKPC-2 remained unaltered. The induction assay identified various blaKPC-2 variants, including blaKPC-25, blaKPC-127, blaKPC-100, blaKPC-128, blaKPC-137, blaKPC-138, blaKPC-144 and blaKPC-180. Our findings suggest that the resistance of KPC-KP to CZA primarily results from the emergence of KPC variants, complemented by increased blaKPC expression. A close correlation exists between avibactam concentration and the rate of increased CZA minimum Inhibitory concentration, as well as blaKPC mutation. Inadequate avibactam concentration is more likely to induce resistance in strains against CZA, there is also a higher likelihood of mutation in the blaKPC-2 and the optimal avibactam ratio remains to be determined. Simultaneously, we selected a blaKPC-33-producing K. pneumoniae strain (mutated from blaKPC-2) and induced it with imipenem and meropenem, respectively. The blaKPC-2 was detected during the process, indicating that the mutation is reversible. Clinical use of carbapenems to treat KPC variant strains increases the risk of infection, as the gene can mutate back to blaKPC-2, rendering the strain even more cross-resistant to carbapenems and CZA.

ABSTRACT Introduction Community‐based cohort studies of HIV seroconversion can identify important avenues for enhancing HIV prevention efforts in the era of pre‐exposure prophylaxis (PrEP). Within individuals, one can assess exposure and outcome variables repeatedly and with increased certainty regarding temporal ordering. This cohort study examined the association of several risk factors with subsequent HIV seroconversion. Methods We report data from a 4‐year study (2017−2022) of 6059 HIV seronegative sexual and gender minority individuals who have sex with men who had indications for‐, but were not using‐, PrEP at enrolment. Participants completed repeat exposure assessments and self‐collection of biospecimens for HIV testing. We examined the roles of race and ethnicity, socio‐economic status, methamphetamine use and PrEP uptake over the course of follow‐up in relation to HIV seroconversion. Results Over 4 years, 303 of the participants seroconverted across 18,421 person‐years (incidence rate = 1.64 [95% CI: 1.59−1.70] per 100 person‐years). In multivariable discrete‐time survival analysis, factors independently associated with elevated HIV seroconversion risk included being Black/African American (adjusted risk ratio [aRR]: 2.44, 1.79−3.28), Hispanic/Latinx (1.53, 1.19−1.96), housing instability (1.58, 1.22−2.05) and past year methamphetamine use (3.82, 2.74−5.33). Conversely, time since study enrolment (24 vs. 12 months, 0.67, 0.51−0.87; 36 months, 0.60, 0.45−0.80; 48 months, 0.48, 0.35−0.66) and higher education (master's degree or higher vs. less than or equal to high school, 0.36, 0.17−0.66) were associated with reduced seroconversion risk. Compared to non‐PrEP users in the past 2 years without a current clinical indication, those who started PrEP but then discontinued had higher seroconversion risk, irrespective of clinical indication (3.23, 1.74−6.46) or lack thereof (4.30, 1.85−9.88). However, those who initiated PrEP in the past year (0.14, 0.04−0.39) or persistently used PrEP in the past 2 years (0.33, 0.14−0.74) had a lower risk of seroconversion. Of all HIV seroconversions observed during follow‐up assessments (12, 24, 36 and 48 months), methamphetamine was reported in the 12 months prior 128 (42.2%) times (overall). Conclusions Interventions that acknowledge race and ethnicity, economic variables such as education and housing instability, and methamphetamine use are critically needed. Not only are interventions to engage individuals in PrEP care needed, but those that retain them, and re‐engage those who may fall out of care are essential, given the exceptionally high risk of seroconversion in these groups.

BackgroundIn spite of its high mortality rate and poor prognosis, the pathogenesis of sepsis is still incompletely understood. This study established a cuproptosis-based risk model to diagnose and predict the risk of sepsis. In addition, the cuproptosis-related genes were identified for targeted therapy.MethodsSingle-cell sequencing analyses were used to characterize the cuproptosis activity score (CuAS) and intercellular communications in sepsis. Differential cuproptosis-related genes (CRGs) were identified in conjunction with single-cell and bulk RNA sequencing. LASSO and Cox regression analyses were employed to develop a risk model. Three external cohorts were conducted to assess the model’s accuracy. Differences in immune infiltration, immune cell subtypes, pathway enrichment, and the expression of immunomodulators were further evaluated in distinct groups. Finally, various in-vitro experiments, such as flow cytometry, Western blot, and ELISA, were used to explore the role of LST1 in sepsis.ResultsScRNA-seq analysis demonstrated that CuAS was highly enriched in monocytes and was closely related to the poor prognosis of sepsis patients. Patients with higher CuAS exhibited prominent strength and numbers of cell–cell interactions. A total of five CRGs were identified based on the LASSO and Cox regression analyses, and a CRG-based risk model was established. The lower riskScore cohort exhibited enhanced immune cell infiltration, elevated immune scores, and increased expression of immune modulators, indicating the activation of an antibacterial response. Ultimately, in-vitro experiments demonstrated that LST1, a key gene in the risk model, was enhanced in the macrophage in response to LPS, which was closely related to the decrease of macrophage survival rate, the enhancement of apoptosis and oxidative stress injury, and the imbalance of the M1/M2 phenotype.ConclusionsThis study constructed a cuproptosis-related risk model to accurately predict the prognosis of sepsis. We further characterized the cuproptosis-related gene LST1 to provide a theoretical framework for sepsis therapy.

Summary: Cholesterol efflux capacity (CEC) dysfunction in macrophages is important in atherosclerosis. However, the mechanism underlying CEC dysfunction remains unclear. We described the characteristics of ATF4 and inflammasome activation in macrophages during atherosclerosis through scRNA sequencing analysis. Then model of hyperlipemia was established in ApoE−/− mice; some were treated with tauroursodeoxycholic acid (TUDCA). TUDCA decreased the ATF4, Hspa, and inflammasome activation, reduced plaque area of the artery, and promoted CEC in macrophages. Furthermore, TUDCA abolished oxLDL-induced foam cell formation by inhibiting activation of the PERK/eIF2α/ATF4 and AIM2 inflammasome in macrophages. Further assays revealed ATF4 binding to AIM2 promoter, promoting its transcriptional activity significantly. Then we discovered that ATF4 affected AIM2-mediated foam cell formation by targeting ABCA1, which could be blocked by TUDCA. Our study demonstrated that TUDCA alleviates atherosclerosis by inhibiting AIM2 inflammasome and enhancing CEC of macrophage, which provided possibilities for the development of therapies.

Venous Thromboembolism (VTE) is a complex disease that can be classified into two subtypes: Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE. The MR results identified that fatty acid (FA) unsaturation traits (Ratio of bis-allylic bonds to double bonds in lipids, and Ratio of bis-allylic bonds to total fatty acids in lipids) were associated with VTE (OR [95% CI]: 1.21 [1.15-1.27]; 1.21 [1.13-1.30]), DVT (OR [95%CI]: 1.24 [1.16-1.33]; 1.26 [1.16-1.36]) and PE (OR [95%CI]: 1.18 [1.08-1.29]; 1.18 [1.09-1.27]). Phosphatidylcholines exhibit potential causal effects on VTE and PE. Phosphatidylcholine acyl-alkyl C40:4 (PC ae C40:4) was negatively associated with VTE (OR [95% CI]: 0.79 [0.73-0.86]), while phosphatidylcholine diacyl C42:6 (PC aa C42:6) and phosphatidylcholine acyl-alkyl C36:4 (PC ae C36:4) were positively associated with PE (OR [95%CI]: 1.44 [1.20-1.72]; 1.22 [1.10-1.35]). Additionally, we found that medium LDL had a protective effect on VTE. Our study indicates that higher FA unsaturation may increase the risk of VTE, DVT, and PE. Different types of phosphatidylcholine have either promotive or inhibitory effects on VTE and PE, contributing to a better understanding of the risk factors for VTE.

Abstract Background Some solitary pulmonary nodules (SPNs) as early manifestations of lung cancer, it is difficult to determine its nature, which brings great trouble to clinical diagnosis and treatment. Radiomics can deeply explore the essence of images and provide clinical decision support for clinicians. The purpose of our study was to explore the effect of positron emission tomography (PET) with 2‐deoxy‐2‐[fluorine‐18] fluoro‐d‐glucose integrated with computed tomography (CT; 18F‐FDG‐PET/CT) combined with radiomics for predicting probability of malignancy of SPNs. Methods We retrospectively enrolled 190 patients with SPNs confirmed by pathology from January 2013 to December 2019 in our hospital. SPNs were benign in 69 patients and malignant in 121 patients. Patients were randomly divided into a training or testing group at a ratio of 7:3. Three‐dimensional regions of interest (ROIs) were manually outlined on PET and CT images, and radiomics features were extracted. Synthetic minority oversampling technique (SMOTE) method was used to balance benign and malignant samples to a ratio of 1:1. In the training group, least absolute shrinkage and selection operator (LASSO) regression analyses and Spearman correlation analyses were used to select the strongest radiomics features. Three models including PET model, CT model, and joint model were constructed using multivariate logistic regression analysis. Receiver operating characteristic (ROC) curves, calibration curves, and decision curves were plotted to evaluate diagnostic efficiency, calibration degree, and clinical usefulness of all models in training and testing groups. Results The estimative effectiveness of the joint model was superior to the CT or PET model alone in the training and testing groups. For the joint model, CT model, and PET model, area under the ROC curve was 0.929, 0.819, 0.833 in the training group, and 0.844, 0.759, 0.748 in the testing group, respectively. Calibration and decision curves showed good fit and clinical usefulness for the joint model in both training and testing groups. Conclusion Radiomics models constructed by combining PET and CT radiomics features are valuable for distinguishing benign and malignant SPNs. The combined effect is superior to qualitative diagnoses with CT or PET radiomics models alone.

ObjectiveAmong adolescents with depression, the occurrence of non-suicidal self-injury (NSSI) behavior is prevalent, constituting a high-risk factor for suicide. However, there has been limited research on the neuroimaging mechanisms underlying adolescent depression and NSSI behavior, and the potential association between the two remains unclear. Therefore, this study aims to investigate the alterations in functional connectivity (FC) of the regions in the prefrontal cortex with the whole brain, and elucidates the relationship between these alterations and NSSI behavior in adolescents with depression.MethodsA total of 68 participants were included in this study, including 35 adolescents with depression and 33 healthy controls. All participants underwent assessments using the 17-item Hamilton Depression Rating Scale (17-HAMD) and the Ottawa Self-Harm Inventory. In addition, functional magnetic resonance imaging (fMRI) data of the participants’ brains were collected. Subsequently, the FCs of the regions in the prefrontal cortex with the whole brain was calculated. The FCs showing significant differences were then subjected to correlation analyses with 17-HAMD scores and NSSI behavior scores.ResultCompared to the healthy control group, the adolescent depression group exhibited decreased FCs in several regions, including the right frontal eye field, left dorsolateral prefrontal cortex, right orbitofrontal cortex, left insula and right anterior cingulate coetex. The 17-HAMD score was positively correlated with the frequency of NSSI behavior within 1 year (rs = 0.461, p = 0.005). The FC between the right anterior cingulate cortex and the right precuneus showed a negative correlation with the 17-HAMD scores (rs = −0.401, p = 0.023). Additionally, the FC between the right orbitofrontal cortex and the right insula, demonstrated a negative correlation with the frequency of NSSI behavior within 1 year (rs = −0.438, p = 0.012, respectively).ConclusionAdolescents with depression showed decreased FCs of the prefrontal cortex with multiple brain regions, and some of these FCs were associated with the NSSI frequency within 1 year. This study provided neuroimaging evidence for the neurophysiological mechanisms underlying adolescent depression and its comorbidity with NSSI behavior.

Gastric cancer (GC) is one of the most prominent malignancies that originate in the epithelial cells of the gastric mucosa and is one of the main causes of cancer-related mortality worldwide. New circulating biomarkers of exosomal RNA might have great potential for non-invasive early prognosis of GC. Sijunzi Decoction (SJZD) is a typical representative formula of the method of benefiting Qi and strengthening the spleen in Traditional Chinese Medicine (TCM). However, the effects and mechanism of SJZD in treating GC remain unclear. This study looked for biomarkers of exosomal RNA for early prognosis of GC, and explored the mechanism of SJZD in treating GC. A gastric cancer model with spleen deficiency syndrome was established in nude mice, and the curative effects of SJZD were investigated. Differentially expressed miRNAs in plasma and saliva exosomes were sequenced and analyzed. Potential target genes of these miRNAs were predicted and applied for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment annotation. Overlapping miRNAs in saliva and plasma samples were analyzed, and qRT-PCR was performed for verification. miR-151a-3p was selected, and qRT-PCR further determined that miR-151a-3p was downregulated in saliva and plasma exosomes from the SJZD group. The intersected miR-151a-3p target genes were predicted and enriched in the extrinsic apoptotic signaling pathways. SJZD significantly ameliorates gastric cancer with spleen deficiency syndrome in mouse models, and exosomal miRNAs, particularly miR-151-3p, might be modulated by SJZD in plasma and saliva. The exosomal miR-151-3p in saliva may serve as a non-invasive potential marker for gastric cancer diagnosis and prognosis.

Abstract Primary health care (PHC) is the most effective way to improve people's health and well-being, and primary care services should act as the cornerstone of a resilient health system and the foundation of universal health coverage. To promote high quality development of PHC, an International Symposium on Quality Primary Health Care Development was held on December 4–5, 2023 in Beijing, China, and the participants have proposed and advocated the Beijing Initiative on Quality Primary Health Care Development. The Beijing Initiative calls on all countries to carry out and strengthen 11 actions: fulfill political commitment and accountability; achieve “health in all policies” through multisectoral coordination; establish sustainable financing; empower communities and individuals; provide community-based integrated care; promote the connection and integration of health services and social services through good governance; enhance training, allocation and motivation of health workforce, and medical education; expand application of traditional and alternative medicine for disease prevention and illness healing; empower PHC with digital technology; ensure access to medicinal products and appropriate technologies; and last, strengthen global partnership and international health cooperation. The Initiative will enrich the content of quality development of PHC, build consensus, and put forward policies for quality development of PHC in China in the new era, which are expected to make contributions in accelerating global actions.

Abstract Background Epithelial ovarian cancer (OC) is the fourth leading cause of cancer-related deaths in women, with a 5-year survival rate of 30%-50%. Platinum resistance is the chief culprit for the high recurrence and mortality rates. Several studies confirm that the metabolic regulation of ubiquitinating enzymes plays a vital role in platinum resistance in OC. Methods In this study, we selected ubiquitin-conjugating enzyme E2S (UBE2S) as the candidate gene for validation. The levels of UBE2S expression were investigated using TCGA, GTEx, UALCAN, and HPA databases. In addition, the correlation between UBE2S and platinum resistance in OC was analyzed using data from TCGA. Cisplatin-resistant OC cell lines were generated and UBE2S was knocked down; the transfection efficiency was verified. Subsequently, the effects of knockdown of UBE2S on the proliferation and migration of cisplatin-resistant OC cells were examined through the CCK8, Ki-67 immunofluorescence, clone formation, wound healing, and transwell assays. In addition, the UBE2S gene was also validated in vivo by xenograft models in nude mice. Finally, the relationship between the UBE2S gene and autophagy and the possible underlying regulatory mechanism was preliminarily investigated through MDC and GFP-LC3-B autophagy detection and western blotting experiments. Most importantly, experimental validation of mTOR agonist reversion (the rescuse experiments) was also performed. Results UBE2S was highly expressed in OC at both nucleic acid and protein levels. The results of immunohistochemistry showed that the level of UBE2S expression in platinum-resistant samples was significantly higher relative to the platinum-sensitive samples. By cell transfection experiments, knocking down of the UBE2S gene was found to inhibit the proliferation and migration of cisplatin-resistant OC cells. Moreover, the UBE2S gene could inhibit autophagy by activating the PI3K/AKT/mTOR signaling pathway to induce cisplatin resistance in OC in vivo and in vitro. Conclusion In conclusion, we discovered a novel oncogene, UBE2S, which was associated with platinum response in OC, and examined its key role through bioinformatics and preliminary experiments. The findings may open up a new avenue for the evaluation and treatment of OC patients at high risk of cisplatin resistance.

Abstract Arsenic enhances the carcinogenicity of ultraviolet radiation (UVR). However, the mechanisms of arsenic-driven oncogenesis are not well understood. Here, we utilize experimental systems to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR. In vitro and in vivo exposures indicate that, by itself, arsenic is not mutagenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis and to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, is observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13, to the best of our knowledge, the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing skin cancer genomics data reveals that only a subset of cancers harbor ID13 and these exhibit an elevated UVR mutagenesis. Our results report a unique mutational signature caused by a co-exposure to two environmental carcinogens and provide comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR.

Abstract Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Myofibroblasts, derived primarily from hepatic stellate cells (HSCs), are the effector of liver fibrosis. In the present study we investigated the mechanism by which Brahma-related gene 1 (BRG1, encoded by Smarca4) regulates HSC-myofibroblast transition and the implication in intervention against liver fibrosis. We report that BRG1 expression was elevated during HSC maturation in cell culture, in animal models, and in human cirrhotic liver biopsy specimens. HSC-specific deletion of BRG1 attenuated liver fibrosis in several different animal models. In addition, BRG1 ablation in myofibroblasts ameliorated liver fibrosis. RNA-seq identified IGFBP5 as a novel target for BRG1. Over-expression of IGFBP5 partially rescued the deficiency in myofibroblast activation when BRG1 was depleted. On the contrary, IGFBP5 knockdown suppressed HSC-myofibroblast transition in vitro and mollified liver fibrosis in mice. Mechanistically, IGFBP5 interacted with Bat3 to stabilize the Bat3-TβR complex and sustain TGF-β signaling. In conclusion, our data provide compelling evidence that BRG1 is a pivotal regulator of liver fibrosis by programming HSC-myofibroblast transition.

Abstract Prior research has shown that the deconvolution of cell-free RNA can uncover the tissue origin. The conventional deconvolution approaches rely on constructing a reference tissue-specific gene panel, which cannot capture the inherent variation present in actual data. To address this, we have developed a novel method that utilizes a neural network framework to leverage the entire training dataset. Our approach involved training a model that incorporated 15 distinct tissue types. Through one semi-independent and two complete independent validations, including deconvolution using a semi in silico dataset, deconvolution with a custom normal tissue mixture RNA-seq data, and deconvolution of longitudinal circulating tumor cell RNA-seq (ctcRNA) data from a cancer patient with metastatic tumors, we demonstrate the efficacy and advantages of the deep-learning approach which were exerted by effectively capturing the inherent variability present in the dataset, thus leading to enhanced accuracy. Sensitivity analyses reveal that neural network models are less susceptible to the presence of missing data, making them more suitable for real-world applications. Moreover, by leveraging the concept of organotropism, we applied our approach to trace the migration of circulating tumor cell-derived RNA (ctcRNA) in a cancer patient with metastatic tumors, thereby highlighting the potential clinical significance of early detection of cancer metastasis.