Peripheral nerve-derived Sema3A promotes osteogenic differentiation of mesenchymal stem cells through the Wnt/ß-catenin/Nrp1 positive feedback loop.

Sensory nerves play a crucial role in maintaining bone homeostasis by releasing Semaphorin 3A (Sema3A). However, the specific mechanism of Sema3A in regulation of bone marrow mesenchymal stem cells (BMMSCs) during bone remodelling remains unclear. The tibial denervation model was used and the denervated tibia exhibited significantly lower mass as compared to sham operated bones. In vitro, BMMSCs cocultured with dorsal root ganglion cells (DRGs) or stimulated by Sema3A could promote osteogenic differentiation through the Wnt/ß-catenin/Nrp1 positive feedback loop, and the enhancement of osteogenic activity could be inhibited by SM345431 (Sema3A-specific inhibitor). In addition, Sema3A-stimulated BMMSCs or intravenous injection of Sema3A could promote new bone formation in vivo. To sum up, the coregulation of bone remodelling is due to the ageing of BMMSCs and increased osteoclast activity. Furthermore, the sensory neurotransmitter Sema3A promotes osteogenic differentiation of BMMSCs via Wnt/ß-catenin/Nrp1 positive feedback loop, thus promoting osteogenesis in vivo and in vitro.

Impact of pulmonary rehabilitation on patients with different chronic respiratory diseases during hospitalization.

The impact of pulmonary rehabilitation (PR) on patients with different chronic respiratory diseases (CRDs) during hospitalization has not been thoroughly evaluated before. The objectives of the current research were to assess the effect of comprehensive PR management on inpatients' self-management skills, exercise capacity, nutrition assessment and mental health issues and explore whether impacts of PR vary in different CRDs. This retrospective study analyzed the clinical data from 272 inpatients with CRDs receiving PR management during hospitalization between October 2020 and March 2022 in Beijing Chao-Yang Hospital. Significant improvements were found in the patients' ability of daily living (ADL), dyspnea (assessed by modified medical research council dyspnea scale (MMRC)), handgrip strength, maximal inspiratory and expiratory pressure, anxiety (using the 7-item generalized anxiety disorder scale (GAD-7)) and depression (the 9-item patient health questionnaire score (PHQ-9)). There was no significant change in nutrition assessment pre-post PR management during hospitalization. The subgroup analyses were conducted on hospitalized patients with chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, interstitial lung diseases (ILDs) and other CRDs (e.g., lung cancer, diaphragm hemiparesis, obesity, etc.). The results showed that ADL, MMRC score, MIP, MEP, PHQ-9 score improved in all subgroups with CRDs. Handgrip strength of left hand was increased in COPD inpatients and anxiety was improved in all subgroups except for ILDs. Comprehensive PR management was necessary and beneficial for patients with different CRDs during hospitalization.

Bacterial c-di-GMP signaling gene affects mussel larval metamorphosis through outer membrane vesicles and lipopolysaccharides.

Biofilms serve as crucial cues for settlement and metamorphosis in marine invertebrates. Within bacterial systems, c-di-GMP functions as a pivotal signaling molecule regulating both biofilm formation and dispersion. However, the molecular mechanism of how c-di-GMP modulates biofilm-induced larval metamorphosis remains elusive. Our study reveals that the deletion of a c-di-GMP related gene in Pseudoalteromonas marina led to an increase in the level of bacterial c-di-GMP by knockout technique, and the mutant strain had an enhanced ability to produce more outer membrane vesicles (OMVs) and lipopolysaccharides (LPS). The mutant biofilms had higher induction activity for larval metamorphosis in mussels Mytilus coruscus, and OMVs play a major role in the induction activity. We further explored the function of LPS in OMVs. Extracted LPS induced high larval metamorphosis rate, and LPS content were subject to c-di-GMP and LPS-biosynthesis gene. Thus, we postulate that the impact of c-di-GMP on biofilm-induced metamorphosis is mediated through OMVs and LPS.

Draft Genome Sequence of Candida saopaulonensis from a Very Premature Infant with Sepsis.

The rare fungus Candida saopaulonensis has never been reported to be associated with human infection. We report the draft genome sequence of the first clinical isolate of C. saopaulonensis, which was isolated from a very premature infant with sepsis. This is the first genome assembly reaching the near-complete chromosomal level with structural annotation for this species, opening up avenues for exploring evolutionary patterns and genetic mechanisms of pathogenesis.

Development and application of the physiologically-based toxicokinetic (PBTK) model for ochratoxin A (OTA) in rats and humans.

Ochratoxin A (OTA) is a common fungal toxin frequently detected in food and human plasma samples. Currently, the physiologically based toxicokinetic (PBTK) model plays an active role in dose translation and can improve and enhance the risk assessment of toxins. In this study, the PBTK model of OTA in rats and humans was established based on knowledge of OTA-specific absorption, distribution, metabolism, and excretion (ADME) in order to better explain the disposition of OTA in humans and the discrepancies with other species. The models were calibrated and optimized using the available kinetic and toxicokinetic (TK) data, and independent test datasets were used for model evaluation. Subsequently, sensitivity analyses and population simulations were performed to characterize the extent to which variations in physiological and specific chemical parameters affected the model output. Finally, the constructed models were used for dose extrapolation of OTA, including the rat-to-human dose adjustment factor (DAF) and the human exposure conversion factor (ECF). The results showed that the unbound fraction (Fup) of OTA in plasma of rat and human was 0.02-0.04% and 0.13-4.21%, respectively. In vitro experiments, the maximum enzyme velocity (Vmax) and Michaelis-Menten constant (Km) of OTA in rat and human liver microsomes were 3.86 and 78.17 µg/g min-1, 0.46 and 4.108 µg/mL, respectively. The predicted results of the model were in good agreement with the observed data, and the models in rats and humans were verified. The PBTK model derived a DAF of 0.1081 between rats and humans, whereas the ECF was 2.03. The established PBTK model can be used to estimate short- or long-term OTA exposure levels in rats and humans, with the capacity for dose translation of OTA to provide the underlying data for risk assessment of OTA.

Mulberry (Morus alba L.) leaf powder modified the processing of meat alternatives: Principal component analysis from apparent properties to chemical bonds.

For texture control in plant-meat alternatives, the interrelationship between apparent characteristics and chemical bonds in high-fiber formulations remains unclear. The influence of mulberry leaf powder on apparent characteristics and chemical bonds of raw materials, block and strip products at addition amounts of 0.5-25% was analyzed. The results showed that 8% addition significantly increased the chewiness of the block by 98.12%. The strips' texture shows a downward trend, and the processing produced more redness and color difference. Additives promoted the formation of voids, lamellar and filamentous structures, and the strip produced more striped structures. Disulfide bonds significantly increased in the block, and the ß-turn in the secondary structure enhanced by 12.20%. The ß-turn transformed into a ß-sheet in strips. Principal component analysis revealed that the texture improvement was associated with producing disulfide bonds and ß-turn, providing a basis for high-fiber components to improve products' apparent characteristics by chemical bonds.

SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors.

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

Endothelial lincRNA-p21 alleviates cerebral ischemia/reperfusion injury by maintaining blood-brain barrier integrity.

Blood-brain barrier (BBB) disruption is increasingly recognized as an early contributor to the pathophysiology of cerebral ischemia/reperfusion (I/R) injury, and is also a key event in triggering secondary damage to the central nervous system. Recently, long non-coding RNA (lncRNA) have been found to be associated with ischemic stroke. However, the roles of lncRNA in BBB homeostasis remain largely unknown. Here, we report that long intergenic non-coding RNA-p21 (lincRNA-p21) was the most significantly down-regulated lncRNA in human brain microvascular endothelial cells (HBMECs) after oxygen and glucose deprivation/reoxygenation (OGD/R) treatment among candidate lncRNA, which were both sensitive to hypoxia and involved in atherosclerosis. Exogenous brain-endothelium-specific overexpression of lincRNA-p21 could alleviate BBB disruption, diminish infarction volume and attenuate motor function deficits in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Further results showed that lincRNA-p21 was critical to maintain BBB integrity by inhibiting the degradation of junction proteins under MCAO/R and OGD/R conditions. Specifically, lincRNA-p21 could inhibit autophagy-dependent degradation of occludin by activating PI3K/AKT/mTOR signaling pathway. Besides, lincRNA-p21 could inhibit VE-cadherin degradation by binding with miR-101-3p. Together, we identify that lincRNA-p21 is critical for BBB integrity maintenance, and endothelial lincRNA-p21 overexpression could alleviate cerebral I/R injury in mice, pointing to a potential strategy to treat cerebral I/R injury.

Tislelizumab plus chemotherapy is an optimal option for second-line treatment for advanced gastroesophageal junction adenocarcinoma.

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab (P = 0.015 and P = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it.

Antibacterial Activity of Plants in Cirsium: A Comprehensive Review.

As ethnic medicine, the whole grass of plants in Cirsium was used as antimicrobial. This review focuses on the antimicrobial activity of plants in Cirsium, including antimicrobial components, against different types of microbes and bacteriostatic mechanism. The results showed that the main antimicrobial activity components in Cirsium plants were flavonoids, triterpenoids and phenolic acids, and the antimicrobial ability varied according to the species and the content of chemicals. Among them, phenolic acids showed a strong antibacterial ability against Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium. The antibacterial mechanisms include: (1) damaging the cell membrane, cell walls, mitochondria and nucleus of bacteria; (2) inhibiting the synthesis of proteins and nucleic acids; (3) suppressing the synthesis of enzymes for tricarboxylic acid cycle pathways and glycolysis, and then killing the bacteria via inhibition of energy production. Totally, most research results on antimicrobial activity of Cirsium plants are reported based on in vitro assays. The evidence from clinical data and comprehensive evaluation are needed.

Ambient Air Pollution and Vision Disorder: A Systematic Review and Meta-Analysis.

The effects of air pollution on physical health are well recognized, with many studies revealing air pollution's effects on vision disorder, yet no relationship has been established. Therefore, a meta-analysis was carried out in this study to investigate the connection between vision disorder and ambient particles (diameter ≤ 2.5 µm (PM2.5), diameter ≤ 10 µm (PM10)) and gaseous pollutants (nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), Ozone (O3)). Twelve relevant studies published by 26 February 2024 were identified in three databases. A pooled odds ratios (ORs) of 95% confidence intervals (CIs) were obtained using random-effects meta-analysis models. Meta-analysis results revealed that for every 10 µg/m3 increase in PM2.5 and NO2 exposure, a substantially higher incidence of vision disorder was observed (OR = 1.10; 95% CI: 1.01, 1.19; OR = 1.08, 95% CI: 1.00, 1.16). No significant correlation existed between exposure to PM10, SO2 and CO and vision disorder. However, O3 exposure was negatively associated with vision disorder. In addition, subgroup analyses revealed that PM2.5 exposure was significantly correlated with the risk of glaucoma and age-related macular degeneration and that children and adolescents were more susceptible to NO2 and PM2.5 than adults. Overall, exposure to air pollutants, especially PM2.5 and NO2, may increase the incidence of vision disorder.

Ultrahigh Bifunctional Photocatalytic CO2 Reduction and H2 Evolution by Synergistic Interaction of Heteroatomic Pt-Ru Dimerization Sites.

Diatomic-site catalysts (DASCs) inherit the excellent performance of single-atom catalysts (SACs) by utilizing two adjacent atomic metal species to achieve functional complementarity and synergistic effects that improve the carbon dioxide reduction reaction (CO2RR) and H2 evolution reaction (HER) kinetics. Herein, we report a method to further improve the catalytic efficiency of Pt by using Pt and Ru single atoms randomly anchored on a g-C3N4 surface, yielding partial Pt-Ru dimers. The synthesized catalyst exhibits extraordinary photocatalytic activity and stability in both the CO2RR and HER processes. In-depth experimentation, the pH-dependent chemical exchange saturation transfer (CEST) imaging nuclear magnetic resonance (NMR) method, and theoretical analyses reveal that the excellent performance is attributed to orbital coupling between the Pt atoms and the neighboring Ru atoms (mainly dxy and dxz), which decreases the orbital energy levels and weakens the bond strength with intermediates, resulting in improved CO2RR and HER performance. This study successfully applies the pH-dependent CEST imaging NMR method to catalytic reactions, and CO2 adsorption is directly observed using CEST 2D imaging maps. This work presents significant potential for a variety of catalytic reaction applications by systematically designing bimetallic dimers with higher activity and stability.

Enhancing Clinical Utility: Utilization of International Standards and Guidelines for Metagenomic Sequencing in Infectious Disease Diagnosis.

Metagenomic sequencing has emerged as a transformative tool in infectious disease diagnosis, offering a comprehensive and unbiased approach to pathogen detection. Leveraging international standards and guidelines is essential for ensuring the quality and reliability of metagenomic sequencing in clinical practice. This review explores the implications of international standards and guidelines for the application of metagenomic sequencing in infectious disease diagnosis. By adhering to established standards, such as those outlined by regulatory bodies and expert consensus, healthcare providers can enhance the accuracy and clinical utility of metagenomic sequencing. The integration of international standards and guidelines into metagenomic sequencing workflows can streamline diagnostic processes, improve pathogen identification, and optimize patient care. Strategies in implementing these standards for infectious disease diagnosis using metagenomic sequencing are discussed, highlighting the importance of standardized approaches in advancing precision infectious disease diagnosis initiatives.

Toxicity of three microcystin variants on the histology, physiological and metabolism of hepatopancreas and intestinal microbiota of Litopenaeus vannamei.

Microcystins (MCs) are prevalent harmful contaminants within shrimp aquaculture systems, exhibiting a diverse array of variants. Gut microbiota can engage in mutual interactions with the host through the gut-liver axis. In this study, the shrimp Litopenaeus vannamei were subjected to three different variants of MCs (LR, YR, RR) at a concentration of 1 µg/L each, and elucidated the alterations in both intestinal microbiota and hepatopancreas physiological homeostasis. The results showed that all three variants of MCs prompted histological alterations in the hepatopancreas, induced elevated levels of oxidative stress biomarkers (H2O2, T-SOD, and CAT), disturbed the transcription levels of immune-related genes (Crus, ALF, and Lys), along with an increase in apoptotic genes (Casp-3 and P53). Furthermore, the metabolic profiles of the hepatopancreas were perturbed, particularly in amino acid metabolism such as "lysine degradation" and "ß-alanine metabolism"; the mTOR and FoxO signaling were also influenced, encompassing alterations in the transcription levels of related genes. Additionally, the alterations were observed in the intestinal microbiota's diversity and composition, particularly potential beneficial bacteria (Alloprevotella, Bacteroides, Collinsella, Faecalibacterium, and Prevotellaceae UCG-001), which exhibited a positive correlation with the metabolite berberine. These findings reveal that the three MCs variants can impact the health of the shrimp by interfering with the homeostasis of intestinal microbial and hepatopancreas physiology.

Multimedia distribution, dynamics, and seasonal variation of PAHs in Songhua wetland: Implications for ice-influenced conditions.

The knowledge of polycyclic aromatic hydrocarbons (PAHs) in wetlands remains limited. There is a research need for the dynamics between interfaces of multimedia when ice is present in this fragile ecosystem. In this study, sediment, open-water, sub-ice water, and ice samples were collected from the Songhua wetland to study the behaviors of PAHs with and without influences from ice. The concentration of all individual PAHs in sub-ice water (370-1100 ng/L) were higher than the open-water collected from non-ice-covered seasons (50-250 ng/L). Enrichment of PAHs in the ice of wetland was found, particularly for high-molecular-weight PAHs (HMW). This could be attributed to the relatively lower polarity of hydrocarbons compounds, making them more likely to remain in the ice layer during freezing. Source assessments reveal common sources for sub-ice water and ice, which differ from those in the open water in non-ice-covered seasons. This difference is primarily attributed to heating activities in the Harbin during winter. The average percentage contributions were 79% for sub-ice water and 36% for ice related to vehicle exhausts and coal combustion. Additionally, wood burning contributed 25% to sub-ice water and 62% to ice. Sediment in the wetland was found to serve as a final deposit particularly for heavier PAHs, especially those with 6 rings. Sediment also has the potential to act as a source for the secondary emission of low-molecular-weight PAHs (LMW) congeners into the water. PAHs in wetland displayed low ecological risk, while HMW PAHs with relative higher ecological risk is recommended to be further monitored.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study.

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6-7.6), 8.6 % (95 % CI: 5.3-21.9) and 40.5 % (95 % CI: 24.9-55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65-0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Long-term air pollutants exposure and respiratory mortality: A large prospective cohort study.

Ambient air pollution is a major global health concern. Yet, no study has thoroughly assessed its link to respiratory mortality. Our research evaluated the combined and individual effects of air pollutants on respiratory mortality risks based on the UK Biobank. A total of 366,478 participants were studied. A Cox proportional hazards model was used to estimate the respiratory mortality risk from combined long-term exposure to five pollutants, summarized as a weighted air pollution score. During a median of 13.6 years of follow-up, 6113 deaths due to respiratory diseases were recorded. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of respiratory diseases were 2.64 (2.05-3.39), 1.62 (1.23-2.12), 2.06 (1.73-2.45), 1.20 (1.16-1.25), and 1.07 (1.05-1.08) per 10 µg/m3 increase in PM2.5, PM2.5-10, PM10, NO2, and NOx, respectively. The air pollution score showed a dose-response association with an elevated respiratory mortality risk. The highest versus lowest quartile air pollution score was linked to a 44% increase in respiratory mortality risk (HR 1.44, 95% CI: 1.33-1.57), with consistent findings in subgroup and sensitivity analyses. Long-term individual and joint air-pollutant exposure showed a dose-response association with an increased respiratory mortality risk, highlighting the importance of a comprehensive air-pollutant assessment to protect public health.

Methylated ctDNA predicts early recurrence risk in patients undergoing resection of initially unresectable colorectal cancer liver metastases.

Background: Patients with initially unresectable colorectal cancer liver metastases (IU-CRLM) might benefit from using an effective systemic treatment followed by resection of liver metastases but the curative success rate is quite low. Indeed, nearly one-third of patients exhibit early recurrence within the first 6 months after surgery, and these individuals often have poor overall survival. Objectives: This study aims to clarify the application value of serial circulating tumor DNA (ctDNA) analysis in predicting the clinical outcome of IU-CRLM patients following liver metastasectomy. Design: A retrospective study was conducted on a cohort of patients with IU-CRLM between February 2018 and April 2021. Methods: Plasma samples at different time points during CRLM treatment [baseline (BL), preoperation (PRE), postoperation (POST), end-of-treatment (EOT), and progressive disease (PD)] were retrospectively collected from patients with initially unresectable CRLM enrolled at the Sun Yat-sen University Cancer Center. Dynamic changes of SEPTIN 9 (SEPT9) and Neuropeptide Y (NPY) methylated circulating tumor DNA (MetctDNA) levels in serial plasma samples were detected using droplet-digital PCR (ddPCR). Results: SEPT9 and NPY genes were hypermethylated in colon cancer cell lines and tissues while no difference was observed between primary and metastatic tumors. Patients with MetctDNA positive at POST or EOT had significantly lower recurrence-free survival (RFS) compared to patients with MetctDNA negative at these time points [POST: Hazard ratio (HR) 9.44, 95% confidence interval (CI) 5.15-17.30, p < 0.001; EOT: HR 11.48, 95% CI 3.27-40.31, p < 0.001]. Multivariate analysis demonstrated that POST (OR 33.96, 95% CI 4.03-286.10, p = 0.001) and EOT (OR 18.36, 95% CI 1.14-295.71, p = 0.04) MetctDNA was an independent risk factor for early recurrence. Time-dependent receiver operating characteristic curve (T-ROC) analysis revealed that area under the curve (AUC) value was greatest at the relapse time point of 6 months post-intervention, with POST-AUC and EOT-AUC values of 0.74 (95% CI 0.66-0.81) and 0.73 (95% CI 0.53-0.94), respectively. Serial MetctDNA analysis showed that RFS was significantly lower in patients with no MetctDNA clearance compared with those with MetctDNA clearance (HR 26.05, 95% CI 4.92-137.81, p < 0.001). Conclusion: Our study confirmed that serial ctDNA analysis of NPY and SEPT9 gene methylation could effectively predict early recurrence in IU-CRLM patients, especially at POST and EOT.