Spexin inhibits excessive autophagy-induced ferroptosis to alleviate doxorubicin-induced cardiotoxicity by upregulating Beclin 1.

BACKGROUND AND PURPOSE: Doxorubicin is widely used in the treatment of malignant tumours, but doxorubicin-induced cardiotoxicity severely limits its clinical application. Spexin is a neuropeptide that acts as a novel biomarker in cardiovascular disease. However, the effects of spexin on doxorubicin-induced cardiotoxicity is unclear. EXPERIMENTAL APPROACH: We established a model of doxorubicin-induced cardiotoxicity both in vivo and in vitro. Levels of cardiac damage in mice was assessed through cardiac function assessment, determination of serum cardiac troponin T and CKMB levels and histological examination. CCK8 and PI staining were used to assess the doxorubicin-induced toxicity in cultures of cardiomyocytes in vitro. Ferroptosis was assessed using FerroOrange staining, determination of MDA and 4-HNE content and ferroptosis-associated proteins SLC7A11 and GPX4. Mitochondrial membrane potential and lipid peroxidation levels were measured using TMRE and C11-BODIPY 581/591 probes, respectively. Myocardial autophagy was assessed by expression of P62 and Beclin1. KEY RESULTS: Spexin treatment improved heart function of mice with doxorubicin-induced cardiotoxicity, and attenuated doxorubicin-induced cardiotoxicity by decreasing iron accumulation, abnormal lipid metabolism and inhibiting ferroptosis. Interestingly, doxorubicin caused excessive autophagy in cardiomyocyte in culture, which could be alleviated by treatment with spexin. Knockdown of Beclin 1 eliminated the protective effects of spexin in mice with DIC. CONCLUSION AND IMPLICATIONS: Spexin ameliorated doxorubicin-induced cardiotoxicity by inhibiting excessive autophagy-induced ferroptosis, suggesting that spexin could be a drug candidate against doxorubicin-induced cardiotoxicity. Beclin 1 might be critical in mediating the protective effect of spexin against doxorubicin-induced cardiotoxicity.

Cognitive benefits of folic acid, docosahexaenoic acid and a combination of both nutrients in mild cognitive impairment; possible alterations though mitochondrial function and DNA damage.

INTRODUCTION: It is uncertain whether folic acid (FA) combined with docosahexaenoic acid (DHA) could improve cognitive performance. This study evaluated the effects of a 12-month FA and DHA supplementation, in combination or alone, on cognitive function, DNA oxidative damage, and mitochondrial function in participants with mild cognitive impairment (MCI). METHODS: This randomized, double-blind, placebo-controlled trial recruited MCI participants aged 60 years and older. Two hundred and eighty participants were randomly divided in equal proportion into four groups: FA+DHA (FA 800µg/d + DHA 800mg/d), FA (800µg/d), DHA (800mg/d), and placebo groups daily orally for 12 months. The primary outcome was cognitive function evaluated by the Wechsler Adult Intelligence Scale-Revised (WAIS-RC). Cognitive tests and blood mechanism-related biomarkers were determined at baseline and 12 months. RESULTS: During the 12-month follow, scores of full intelligence quotient (FIQ) (ßDHA: 1.302, 95%CI: 0.615, 1.990, p < 0.001; ßFA: 1.992, 95%CI: 1.304, 2.679, p < 0.001; ßFA+DHA: 2.777, 95%CI: 2.090, 3.465, p < 0.001), verbal intelligence quotient, and some subtests of the WAIS-RC were significantly improved in FA+DHA and single intervention groups compared to the placebo group. Moreover, the FA and DHA intervention combination was superior to either intervention alone (p < 0.001). Meanwhile, FA, DHA and their combined use significantly decreased 8-OHdG level and increased mitochondrial DNA copy number compared to the placebo (p < 0.05). CONCLUSIONS: Supplementation of FA and DHA, alone or combined, for 12 months can improve cognitive function in MCI participants, possibly through mitigating DNA oxidative damage and enhancing mitochondrial function. Combined supplementation may provide more cognitive benefit than supplementation alone. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000034351. Registered 3 July 2020 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=53345.

[Applications of chromatography in glycomics].

Glycomics, an emerging "omics" technology that was developed after genomics and proteomics, is a discipline that studies the composition, structure, and functions of glycomes in cells, tissues, and organisms. Glycomics plays key roles in understanding the laws of major life activities, disease prevention and treatment, and drug quality control and development. At present, the structural analysis of glycans relies mainly on mass spectrometry. However, glycans have low abundance in biological samples. In addition, factors such as variable monosaccharide compositions, differences in glycosidic bond positions and modes, diverse branching structures, contribute to the complexity of the compositions and structures of glycans, posing great challenges to glycomics research. Liquid chromatography can effectively remove matrix interferences and enhance glycan separation to improve the mass spectrometric response of glycans. Thus, liquid chromatography and liquid chromatography coupled with mass spectrometry are important technical tools that have been actively applied to solve these problems; these technologies play indispensable roles in glycomics research. Different studies have highlighted similarities and differences in the applications of various types of liquid chromatography, which also reflects the versatility and flexibility of this technology. In this review, we first discuss the enrichment methods for glycans and their applications in glycomics research from the perspective of chromatographic separation mechanisms. We then compare the advantages and disadvantages of these methods. Some glycan-enrichment modes include affinity, hydrophilic interactions, size exclusion, and porous graphitized carbon adsorption. A number of newly developed materials exhibit excellent glycan-enrichment ability. We enumerate the separation mechanisms of reversed-phase high performance liquid chromatography (RP-HPLC), high performance anion-exchange chromatography (HPAEC), hydrophilic interaction chromatography (HILIC), and porous graphitic carbon (PGC) chromatography in the separation and analysis of glycans, and describe the applications of these methods in the separation of glycans, glycoconjugates, and glyco-derivatives. Among these methods, HILIC and PGC chromatography are the most widely used, whereas HPAEC and RP-HPLC are less commonly used. The HILIC and RP-HPLC modes are often used for the separation of derived glycans. The ionization efficiency and detectability of glycans are significantly improved after derivatization. However, the derivatization process is relatively cumbersome, and byproducts inevitably affect the accuracy and completeness of the detection results. HPAEC and PGC chromatography exhibit good separation effects on nonderivative glycans, but issues related to the detection integrity of low-abundance glycans owing to their poor detection effect continue to persist. Therefore, the appropriate analytical method for a specific sample or target analyte or mutual verification must be selected. Finally, we highlight the research progress in various chromatographic methods coupled with mass spectrometry for glycomics analysis. Significant progress has been made in glycomics research in recent years owing to advancements in the development of chromatographic separation techniques. However, several significant challenges remain. As the development of novel separation materials and methods continues, chromatographic techniques may be expected to play a critical role in future glycomics research.

Machine-learning-aided decision-making model for the discontinuation of continuous renal replacement therapy.

BACKGROUND: Continuous renal replacement therapy (CRRT) is a primary form of renal support for patients with acute kidney injury in an intensive care unit. Making an accurate decision of discontinuation is crucial for the prognosis of patients. Previous research has mostly focused on the univariate and multivariate analysis of factors in CRRT, without the capacity to capture the complexity of the decision-making process. The present study thus developed a dynamic, interpretable decision model for CRRT discontinuation. METHODS: The study adopted a cohort of 1234 adult patients admitted to an intensive care unit in the MIMIC-IV database. We used the extreme gradient boosting (XGBoost) machine learning algorithm to construct dynamic discontinuation decision models across four time points. Shapley additive explanation (SHAP) analysis was conducted to show the contribution of an individual feature to the model output. RESULTS: Of the 1234 included patients with CRRT, 596 (48.3%) successfully discontinued CRRT. The dynamic prediction by the XGBoost model produced an area under the curve of 0.848 and accuracy, sensitivity, and specificity of 0.782, 0.786, and 0.776, respectively. The XGBoost model was thus far superior to other test models. SHAP demonstrated that the features that contributed most to the model results were the sequential organ failure assessment score, serum lactate level, and 24-hour urine output. CONCLUSIONS: Dynamic decision models supported by machine learning are capable of dealing with complex factors in CRRT and effectively predicting the outcome of discontinuation.

Characteristics and Controlling Factors of Methane Adsorption of the Longmaxi Shale in Northeastern Chongqing: Implications for Shale Gas Occurrence in Complex Structural Areas.

Accurately determining the adsorption capacity of Longmaxi shale in complex structural areas is crucial for evaluating the shale gas resources in northeastern Chongqing. However, studies on the pore characteristics and methane adsorption capacity of these Longmaxi shales are currently limited. In this paper, we collected core samples from the YDB-1 well in northeastern Chongqing and determined the pore structure and adsorption capacity of the Longmaxi shale using low-pressure gas adsorption and high-temperature, high-pressure methane adsorption experiments, respectively. The results indicate that the adsorption capacity of shale in complex structural areas is significantly positively correlated with the organic matter (OM) content, weakly positively correlated with the quartz content, and weakly negatively correlated with clay minerals. Meanwhile, gas-in-place content is simultaneously controlled by the pressure and temperature of the reservoir, and with increasing depth, the adsorbed gas rapidly increases to a maximum value (at 0.8 km) and then slowly decreases, whereas the free gas continuously increases. Compared with the shale in the stable structural areas, the Longmaxi shale in complex structural areas usually develops OM-hosted pores and intergranular pores of OM and minerals and contains more micropores due to tectonic compression, resulting in a relatively larger specific surface area and adsorption capacity. This is the reason shale in complex structural areas has high development potential. The final result can provide an important basis for the evaluation of the gas content and the optimization of dessert areas in the Lower Paleozoic shale gas in southern China.

Socioeconomic disparities and green space associated with myopia among Chinese school-aged students: A population-based cohort study.

Background: There is increasing evidence on the link between environmental factors and myopia in children and adolescents, yet with inconsistent conclusions. We investigated the associations between socioeconomic inequalities and green space with myopia in school-aged students participating in the Tianjin Child and Adolescent Research of Eye (TCARE) study. Methods: We obtained data from a population-based dynamic cohort study conducted in Tianjin, China, in 2021 and followed up in 2022. We included 1 245 271 participants from 16 districts with an average age of 11.6 years (standard deviation = 3.3) in our analysis. We synthesized their area-level SES through a prediction model that combined economic, educational, and health care variables and assessed the greenness levels surrounding the school using the Normalized Difference Vegetation Index (NDVI) based on data obtained through satellite remote sensing. We performed generalised linear mixed effects analyses for each myopia outcome separately, with adjustments for students' sex, years of education completed, and the school's geographical location. Results: We observed that students living in low SES areas had the highest prevalence of myopia (60.7%) in the last screening in 2022, as well as a higher incidence of one-year myopia (26.4%) compared to those residing in middle SES areas (22.7%). With a 0.1 increase in the 250, 500, and 1000 m buffer NDVI, the prevalence of myopia dropped by 6.3% (odds ratio (OR) = 0.937; 95% confidence interval (CI) = 0.915, 0.960), 7.7% (OR = 0.923; 95% CI = 0.900, 0.946), and 8.7% (OR = 0.913; 95% CI = 0.889, 0.937), respectively. The interaction analysis showed that low SES and low greenness exacerbate the prevalence of myopia. Findings from longitudinal analyses consistently demonstrated a correlation between higher values of NDVI and a slower progression of myopia. These findings remained robust across sensitivity analyses, including for variables on parental myopia and students' behaviors. Conclusions: Exposure to green spaces could play a crucial role in slowing the progression of myopia among school-aged students. Myopia control policies should prioritise young populations residing in low SES areas with limited access to green spaces, as they face the highest potential risks.

Bearing Rigidity-Based Flocking Control of AUVs via Semi-Supervised Incremental Broad Learning.

Flocking control of autonomous underwater vehicles (AUVs) has been regarded as the basis of many sophisticated marine coordination missions. However, there is still a research gap on the flocking of AUVs in weak communication and complex marine environment. This article attempts to fill up the above research gap from graph theory and intelligent learning perspectives. We first employ the bearing rigidity graph to describe the topology relationships of AUVs, through which an iterative gradient decent-based localization estimator is provided to obtain the position information. In order to improve the localization accuracy and energy efficiency, a min-weighted bearing rigidity graph generation strategy is developed. Along with this, we adopt the semi-supervised broad learning system (BLS) to design the model-free flocking controllers for AUVs in obstacle environment. The innovations of this article are summarized as follows: 1) the min-weighted bearing rigidity-based localization strategy can balance the localization accuracy and communication consumption as compared to the neighboring rule-based solutions and 2) the semi-supervised broad learning-based flocking controller can decrease the training time and solve the label limit over the supervised learning-based controllers. Finally, simulation and experimental studies are provided to verify the effectiveness.

Mediation effect of sleep time on the association between outdoor activity and myopia in Chinese children and adolescents: a cross-sectional study.

BACKGROUND: This study aimed to assess the association between outdoor activity and myopia among children and adolescents and investigate whether sleep time could mediate this relationship. METHODS: This cross-sectional study was performed on students aged 4-16 years in China, from August 2021 to January 2022. Outdoor activity was assessed by the Assessment Questionnaire of Exposure to Sunlight Activities for Students (AQESAS). Binary logistic regression combined with the mediation analysis was used to analyze the association of AQESAS with myopia and the mediating effect of sleep time on this relationship. RESULTS: The prevalence of myopia was 53.51% (N = 1609). Multivariate logistic regression analysis showed that more sleep time (OR = 0.794, 95%CI: 0.707-0.893) and a higher score of AQESAS (OR = 0.989, 95%CI: 0.981-0.996) were significantly associated with a decreased risk of myopia. Mediation analysis revealed that sleep time plays a mediating role in the association between outdoor activity and myopia (ACME = -0.0006, P < 0.001), and the mediation proportion was 19.7%. CONCLUSION: Outdoor activity affects myopia directly and indirectly through sleep time. The result suggested that children may be able to reduce the risk of myopia by promoting sleep through increased awareness of outdoor activity and exposure to sunlight.

The effect of narrative nursing on improving the negative emotions and quality of life of patients with moderate to severe cancer pain.

OBJECTIVE: This study aimed to explore the effect of narrative nursing on improving the negative emotions, sleep quality, and quality of life of patients with moderate to severe cancer pain. METHODS: A total of 80 patients with moderate to severe cancer pain who had been hospitalized in the lymphoma oncology department in our hospital from March 2019 to September 2021 were selected as the study subjects and randomly divided into the conventional nursing and narrative nursing groups, with 40 cases in each group. A conventional nursing intervention was conducted for one group, and narrative nursing was provided for the second group in addition to the conventional nursing. The anxiety and depression, sleep quality, quality of life, and satisfaction with pain management of the patients in the two groups were compared before and after the intervention. RESULTS: In the narrative nursing group, the self-rating anxiety scale and self-rating depression scale scores were significantly lower than those in the conventional nursing group after the intervention (P < 0.05). The scores for sleep quality, sleep duration, sleep efficiency, and daytime dysfunction and the total Pittsburgh Sleep Quality Index scores were significantly lower in the narrative nursing group compared with the conventional care group (P < 0.05). The scores for the physical function, living ability, social adaptation, and psychological status items in the Quality of Life Questionnaire Core 30 were significantly higher in the narrative nursing group than in the conventional care group (P < 0.05). The patients' satisfaction with pain management was higher in the narrative nursing group than in the conventional care group (P < 0.05). CONCLUSION: Narrative nursing can alleviate the negative emotions of anxiety and depression in patients with moderate to severe cancer pain and improve their sleep quality, quality of life, and pain management satisfaction.

Graphene/ chitosan tubes inoculated with dental pulp stem cells promotes repair of facial nerve injury.

Introduction: Facial nerve injury significantly impacts both the physical and psychological] wellbeing of patients. Despite advancements, there are still limitations associated with autografts transplantation. Consequently, there is an urgent need for effective artificial grafts to address these limitations and repair injuries. Recent years have witnessed the recognition of the beneficial effects of chitosan (CS) and graphene in the realm of nerve repair. Dental pulp stem cells (DPSCs) hold great promise due to their high proliferative and multi-directional differentiation capabilities. Methods: In this study, Graphene/CS (G/CST) composite tubes were synthesized and their physical, chemical and biological properties were evaluated, then DPSCs were employed as seed cells and G/CST as a scaffold to investigate their combined effect on promoting facial nerve injury repair. Results and Disscussion: The experimental results indicate that G/CST possesses favorable physical and chemical properties, along with good cyto-compatibility. making it suitable for repairing facial nerve transection injuries. Furthermore, the synergistic application of G/CST and DPSCs significantly enhanced the repair process for a 10 mm facial nerve defect in rabbits, highlighting the efficacy of graphene as a reinforcement material and DPSCs as a functional material in facial nerve injury repair. This approach offers an effective treatment strategy and introduces a novel concept for clinically managing facial nerve injuries.

Social support, psychological capital, multidimensional job burnout, and turnover intention of primary medical staff: a path analysis drawing on conservation of resources theory.

BACKGROUND: Job burnout is a prevalent and emerging challenge in the primary medical system, causing mass turnover, especially of primary medical staff. Little attention has been paid to the different dimensions of job burnout (emotional exhaustion, personality disintegration, and reduced sense of achievement), which may hinder efforts to tackle high turnover intention among primary medical staff. From the perspective of conservation of resources theory, social support and psychological capital are basic resources with potential to diminish job burnout and thus lower turnover intention. However, there is insufficient research evidence on the relationships between social support, psychological capital, and the three dimensions of job burnout within the primary medical system. OBJECTIVES: Focusing on primary medical staff, this study conducts a path analysis to examine the correlations between two types of resources (social support and psychological capital) and the three dimensions of job burnout, and to test the impact of the latter on turnover intention. Based on the results, effective management strategies to improve the work stability of primary medical staff are proposed. METHODS: Multi-stage cluster random sampling was used to select participants in Anhui Province, China. Data were collected using a self-administered questionnaire containing measures of the main variables and demographic questions. In total, 1132 valid questionnaires were returned by primary medical staff. Structural equation modeling was used for path analysis of the data. RESULTS: Social support was negatively associated with emotional exhaustion (ß = - 0.088, P = 0.020), personality disintegration (ß = - 0.235, P < 0.001), and reduced sense of achievement (ß = - 0.075, P = 0.040). Moreover, psychological capital was negatively associated with emotional exhaustion (ß = - 0.079, P = 0.030), personality disintegration (ß = - 0.156, P < 0.001), and reduced sense of achievement (ß = - 0.432, P < 0.001). All three dimensions of job burnout positively affected turnover intention (emotional exhaustion: ß = 0.246, P < 0.001; personality disintegration: ß = 0.076, P = 0.040; reduced sense of achievement: ß = 0.119, P = 0.001). CONCLUSIONS: The results highlight the importance of social support and psychological capital for diminishing the three dimensions of job burnout for primary medical staff and, in turn, lowering their turnover intention. Accordingly, to alleviate job burnout and improve staff retention, material and psychological supports from leaders, colleagues, family, relatives, and friends are essential, as are measures to improve the psychological energy of primary medical staff.

The Myopia Prevalence and Association With Physical Activity Among Primary School Students Aged 6-12 Years: A Cross-Sectional Study in Tianjin, China.

Purpose: This study aimed to investigate the prevalence of myopia and determine the association between physical activity and risk of myopia among primary school students in Tianjin, China. Methods: A cross-sectional study was conducted among subjects from nine primary schools. All of the subjects underwent visual acuity and spherical equivalent (SE) with noncycloplegic autorefraction measurement. Myopia was defined as an SE refraction ≤-0.50D and an uncorrected visual acuity <5.0 in either eye. Physical activity was measured via the Physical Activity Questionnaire for Children. Data were analyzed using the Pearson χ2 test and binary logistic regression. Stratification analysis by sex was also performed. Results: A total of 2976 participants (1408 boys and 1568 girls) aged six to 12 years (mean age 8.82 years) were included in this study. The overall prevalence of myopia was 52.92%. When stratified according to physical activity, myopia prevalence significantly decreased with increasing physical activity levels (χ2 trend test = 127.63, P < 0.001). In the binary logistic regression analysis, after adjusting for age, sex, and school region, the odds ratio for the association between physical activity and myopia was 0.762 (95% confidence interval, 0.675-0.862, P < 0.001). When stratified by sex, the significant statistical association between physical activity and myopia both can be found in two groups (P < 0.05). Conclusions: Higher levels of physical activity were independently associated with decreased risk of myopia. The significant reverse statistical association between physical activity and myopia can be found in male or female groups. Translational Relevance: Taking part in physical activities may be an effective way to reduce the prevalence of myopia.

Long-term exposure to particulate matter pollution and incidence of ischemic and hemorrhagic stroke: A prospective cohort study in Eastern China.

Although epidemiological studies have demonstrated significant associations of long-term exposure to particulate matter (PM) air pollution with stroke, evidence on the long-term effects of PM exposure on cause-specific stroke incidence is scarce and inconsistent. We incorporated 33,282 and 33,868 individuals aged 35 to 75 years without a history of ischemic or hemorrhagic stroke at the baseline in 2014, who were followed up till 2021. Residential exposures to particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) and particulate matter with an aerodynamic diameter less than 10 µm (PM10) for each participant were predicted using a satellite-based model with a spatial resolution of 1×1 km. We employed time-varying Cox proportional hazards models to assess the long-term effect of PM pollution on incident stroke. We identified 926 cases of ischemic stroke and 211 of hemorrhagic stroke. Long-term PM exposure was significantly associated with increased incidence of both ischemic and hemorrhagic stroke, with almost 2 times higher risk on hemorrhagic stroke. Specifically, a 10 µg/m³ increase in 3-year average concentrations of PM2.5 was linked to a hazard ratio (HR) of 1.35 (95% confidence interval (CI): 1.18-1.54) for incident ischemic stroke and 1.79 (95% CI: 1.36-2.34) for incident hemorrhagic stroke. The HR related to PM10, though smaller, remained statistically significant, with a HR of 1.25 for ischemic stroke and a HR of 1.51 for hemorrhagic stroke. The excess risks are larger among rural residents and individuals with lower educational attainment. The present cohort study contributed to the mounting evidence on the increased risk of incident stroke associated with long-term PM exposures. Our results further provide valuable evidence on the heightened sensitivity of hemorrhagic stroke to air pollution exposures compared with ischemic stroke.

Ssu72 phosphatase deficiency leads to spindle crossing during the second meiotic division process.

Ssu72 is a component of the yeast cleavage/polyadenylation factor (CPF) complex, which catalyzes the dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II at S5-P and S7-P. It has been shown that Ssu72 phosphatase is involved in regulating chromosome cohesion during mitosis. To further clarify whether Ssu72 phosphatase affects chromosome separation during meiotic division in Schizosaccharomyces pombe, we utilized green fluorescent protein (GFP) to label centromeres and red fluorescent protein to label microtubule protein Atb2. The entire meiotic chromosome separation process of ssu72∆ cells was observed in real-time under fluorescence microscope. It was found that two spindles of ssu72∆ cells crossed during the metaphase and anaphase of the second meiotic division, and this spindle crossing led to a new type of spore defect distribution pattern. The results of this study can provide important reference significance for studying the roles of phosphatase Ssu72 in higher organisms.

Pygo-F773W Mutation Reveals Novel Functions beyond Wnt Signaling in Drosophila.

Pygopus (Pygo) has been identified as a specific nuclear co-activator of the canonical Wingless (Wg)/Wnt signaling pathway in Drosophila melanogaster. Pygo proteins consist of two conserved domains: an N-terminal homologous domain (NHD) and a C-terminal plant homologous domain (PHD). The PHD's ability to bind to di- and trimethylated lysine 4 of histone H3 (H3K4me2/3) appears to be independent of Wnt signaling. There is ongoing debate regarding the significance of Pygo's histone-binding capacity. Drosophila Pygo orthologs have a tryptophan (W) > phenylalanine (F) substitution in their histone pocket-divider compared to vertebrates, leading to reduced histone affinity. In this research, we utilized CRISPR/Cas9 technology to introduce the Pygo-F773W point mutation in Drosophila, successfully establishing a viable homozygous Pygo mutant line for the first time. Adult mutant flies displayed noticeable abnormalities in reproduction, locomotion, heart function, and lifespan. RNA-seq and cluster analysis indicated that the mutation primarily affected pathways related to immunity, metabolism, and posttranslational modification in adult flies rather than the Wnt signaling pathway. Additionally, a reduction in H3K9 acetylation levels during the embryonic stage was observed in the mutant strains. These findings support the notion that Pygo plays a wider role in chromatin remodeling, with its involvement in Wnt signaling representing only a specific aspect of its chromatin-related functions.

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.

Mechanical Strain Induces and Increases Vesicular Release Monitored by Microfabricated Stretchable Electrodes.

Exocytosis involving the fusion of intracellular vesicles with cell membrane, is thought to be modulated by the mechanical cues in the microenvironment. Single-cell electrochemistry can offer unique information about the quantification and kinetics of exocytotic events; however, the effects of mechanical force on vesicular release have been poorly explored. Herein, we developed a stretchable microelectrode with excellent electrochemical stability under mechanical deformation by microfabrication of functionalized poly(3,4-ethylenedioxythiophene) conductive ink, which achieved real-time quantitation of strain-induced vesicular exocytosis from a single cell for the first time. We found that mechanical strain could cause calcium influx via the activation of Piezo1 channels in chromaffin cell, initiating the vesicular exocytosis process. Interestingly, mechanical strain increases the amount of catecholamines released by accelerating the opening and prolonging the closing of fusion pore during exocytosis. This work is expected to provide revealing insights into the regulatory effects of mechanical stimuli on vesicular exocytosis.

Prevotella copri promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway.

Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.

Microplastics alter cadmium accumulation in different soil-plant systems: Revealing the crucial roles of soil bacteria and metabolism.

Cadmium (Cd) and microplastics (MPs) gradually increased to be prevalent contaminants in soil, it is important to understand their combined effects on different soil-plant systems. We studied how different doses of polylactic acid (PLA) and polyethylene (PE) affected Cd accumulation, pakchoi growth, soil chemical and microbial properties, and metabolomics in two soil types. We found that high-dose MPs decreased Cd accumulation in plants in red soil, while all MPs decreased Cd bioaccumulation in fluvo-aquic soil. This difference was primarily attributed to the increase in dissolved organic carbon (DOC) and pH in red soil by high-dose MPs, which inhibited Cd uptake by plant roots. In contrast, MPs reduced soil nitrate nitrogen and available phosphorus, and weakened Cd mobilization in fluvo-aquic soil. In addition, high-dose PLA proved detrimental to plant health, manifesting in shortened shoot and root lengths. Co-exposure of Cd and MPs induced the shifts in bacterial populations and metabolites, with specific taxa and metabolites closely linked to Cd accumulation. Overall, co-exposure of Cd and MPs regulated plant growth and Cd accumulation by driving changes in soil bacterial community and metabolic pathways caused by soil chemical properties. Our findings could provide insights into the Cd migration in different soil-plant systems under MPs exposure. ENVIRONMENTAL IMPLICATION: Microplastics (MPs) and cadmium (Cd) are common pollutants in farmland soil. Co-exposure of MPs and Cd can alter Cd accumulation in plants, and pose a potential threat to human health through the food chain. Here, we investigated the effects of different types and doses of MPs on Cd accumulation, plant growth, soil microorganisms, and metabolic pathways in different soil-plant systems. Our results can contribute to our understanding of the migration and transport of Cd by MPs in different soil-plant systems and provide a reference for the control of combined pollution in the future research.

Large skin defect in Type V aplasia cutis congenita treated with conservative treatment: a case report.

Aplasia cutis congenita (ACC) is a congenital disorder that can be classified into nine types, with Type I ACC being the most common. Type V ACC associated with fetus papyraceus is a rare subtype of ACC. We report the case of a Type V ACC in a male newborn with extensive abdominal skin defects. The patient received conservative treatment using hydrogel foam and silicone foam dressings. Approximately five weeks later, the patient was discharged when more than 60% of the skin had completed epithelialization. After discharge from West China Second University Hospital, Chengdu , the patient continued to be followed up regularly at the Burns and Plastic Surgery Clinic at local hospital in Gansu. We followed up the child by telephone. After 4 months of follow-up, scar tissue formation was observed in the trunk area. The infant is 2 years and 5 months old now, physical examination did not reveal any organ problems.