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Abstract Depression is a prevalent mental disorder characterized by unknown pathogenesis and challenging treatment. Recent meta-analyses reveal an association between cardiovascular risk factors and an elevated risk of depression. Despite this, the precise role of vascular injury in depression development remains unclear. In this investigation, we assess vascular system function in three established animal models of depression— chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS) and maternal separation (MS)—utilizing ultrasonography and laser Doppler measurement. All three model animals exhibit anhedonia and despair-like behavior. However, significant microvascular dysfunction (not macrovascular) is observed in animals subjected to CUMS and CSDS models, while such dysfunction is absent in the MS model. Statistical analysis further indicates that microcirculation dysfunction is not only associated with depression-like behavior but is also intricately involved in the development of depression in the CUMS and CSDS models. Furthermore, our study has proved for the first time that endothelial nitric oxide synthase-deficient (eNOS +/− ) mice, which is a classic model of vascular endothelial injury, showed depression-like behavior which occurred two months later than microvascular dysfunction. Notably, the mitigation of microvascular dysfunction successfully reverses depression-like behavior in eNOS +/− mice by enhancing nitric oxide production. In conclusion, this study unveils the pivotal role of microvascular dysfunction in the onset of depression induced by chronic stress in adulthood and proposes that modulating microvascular function may serve as a potential intervention in the treatment of depression.

Abstract Background Microorganisms play pivotal roles in seagrass ecosystems by facilitating material and elemental cycling as well as energy flux. However, our understanding of how seasonal factors and seagrass presence influence the assembly of bacterial communities in seagrass bed sediments is limited. Employing high-throughput sequencing techniques, this study investigates and characterizes bacterial communities in the rhizosphere of eelgrass (Zostera marina) and the bulk sediments across different seasons. The research elucidates information on the significance of seasonal variations and seagrass presence in impacting the microbial communities associated with Zostera marina. Results The results indicate that seasonal variations have a more significant impact on the bacterial community in seagrass bed sediments than the presence of seagrass. We observed that the assembly of bacterial communities in bulk sediments primarily occurs through stochastic processes. However, the presence of seagrass leading to a transition from stochastic to deterministic processes in bacterial community assembly. This shift further impacts the complexity and stability of the bacterial co-occurrence network. Through LEfSe analysis, different candidate biomarkers were identified in the bacterial communities of rhizosphere sediments in different seasons, indicating that seagrass may possess adaptive capabilities to the environment during different stages of growth and development. Conclusions Seasonal variations play a significant role in shaping these communities, while seagrass presence influences the assembly processes and stability of the bacterial community. These insights will provide valuable information for the ecological conservation of seagrass beds.

Abstract Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Abstract Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic joint inflammation and cartilage damage. Current therapeutic strategies often result in side effects, necessitating the development of targeted and safer treatment options. This study introduces a novel nanotherapeutic system, 2-APB@DGP-MM, which utilizes macrophage membrane (MM)-encapsulated nanoparticles (NPs) for the targeted delivery of 2-Aminoethyl diphenylborinate (2-APB) to inflamed joints more effectively. The NPs are designed with a matrix metalloproteinase (MMP)-cleavable peptide, allowing for MMP-responsive drug release within RA microenvironment. Comprehensive in vitro and in vivo assays confirmed the successful synthesis and loading of 2-APB into the DSPE-GPLGVRGC-PEG (DGP) NPs, as well as their ability to repolarize macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. The NPs demonstrated high biocompatibility, low cytotoxicity, and enhanced cellular uptake. In a collagen-induced arthritis (CIA) mouse model, intra-articular injection of 2-APB@DGP-MM significantly reduced synovial inflammation and cartilage destruction. Histological analysis corroborated these findings, demonstrating marked improvements in joint structure and delayed disease progression. Above all, the 2-APB@DGP-MM nanotherapeutic system offers a promising and safe approach for RA treatment by modulating macrophage polarization and delivering effective agents to inflamed joints. Graphical Abstract

Abstract Prophylactic dissection of paratracheal lymph nodes in clinically lymph node-negative (cN0) papillary thyroid carcinoma (PTC) remains controversial. This study aims to integrate preoperative and intraoperative variables to compare traditional nomograms and machine learning (ML) models, developing and validating an interpretable predictive model for paratracheal lymph node metastasis (PLNM) in cN0 PTC patients. We retrospectively selected 3213 PTC patients treated at the First Affiliated Hospital of Chongqing Medical University from 2016 to 2020. They were randomly divided into the training and test datasets with a 7:3 ratio. The 533 PTC patients treated at the Guangyuan Central Hospital from 2019 to 2022 were used as an external test sets. We developed and validated nine ML models using 10-fold cross-validation and grid search for hyperparameter tuning. The predictive performance was evaluated using ROC curves, decision curve analysis (DCA), calibration curves, and precision-recall curves. The best model was compared to a traditional logistic regression-based nomogram. The XGBoost model achieved AUC values of 0.935, 0.857, and 0.775 in the training, validation, and test sets, respectively, significantly outperforming the traditional nomogram model with AUCs of 0.85, 0.844, and 0.769, respectively. SHapley Additive exPlanations (SHAP)-based visualization identified the top 10 predictive features of the XGBoost model, and a web-based calculator was created based on these features. ML is a reliable tool for predicting PLNM in cN0 PTC patients. The SHAP method provides valuable insights into the XGBoost model, and the resultant web-based calculator is a clinically useful tool to assist in the surgical planning for paratracheal lymph node dissection.

The laboratory plays a crucial role in science education. However, teacher education for pre-service teachers' design performance in the laboratory is still challenging. This study paved the way for redesigning traditional laboratory teaching into a student-centered approach: inquiry-based design thinking (IBDT). To investigate the impact of the IBDT approach on students' design performance of science experiments, 25 pre-service science teachers participated in a series of laboratory activities guided by the IBDT approach in a teacher education program in this study. Mixed research methods were employed to collect and analyze students' responses to pre- and post-surveys, their designed artifacts, and self-reflection reports. The overall positive results were obtained except for students' performance in art design, organization of the materials, and the gap between students' understanding of theories and their practices/practical skills. The findings will inform the laboratory instruction in teacher education in science or science-oriented Science-Technology-Engineering-Mathematics (STEM) education.

Epithelial and stromal/mesenchymal limbal stem cells contribute to corneal homeostasis and cell renewal. Extracellular vesicles (EVs), including exosomes (Exos), can be paracrine mediators of intercellular communication. Previously, we described cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos in non-diabetic (N) and diabetic (DM) limbal epithelial cells (LECs). Presently, we quantify the miRNA and proteome profiles of human LEC-derived Exos and their regulatory roles in N- and DM-LSC. We revealed some miRNA and protein differences in DM vs. N-LEC-derived Exos cargos, including proteins involved in Exo biogenesis and packaging that may affect Exo production and ultimately cellular crosstalk and corneal function. Treatment by N-Exos, but not by DM-Exos, enhanced wound healing in cultured N-LSCs and increased proliferation rates in N and DM LSCs vs. corresponding untreated (control) cells. N-Exos-treated LSCs reduced the keratocyte markers ALDH3A1 and lumican and increased the MSC markers CD73, CD90, and CD105 vs. control LSCs. These being opposite to the changes quantified in wounded LSCs. Overall, N-LEC Exos have a more pronounced effect on LSC wound healing, proliferation, and stem cell marker expression than DM-LEC Exos. This suggests that regulatory miRNA and protein cargo differences in DM- vs. N-LEC-derived Exos could contribute to the disease state.

AIMS/HYPOTHESIS: Diabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression. METHODS: Human LEC were isolated, or organ-cultured corneas were obtained, from autopsy eyes from non-diabetic (59.87±20.89 years) and diabetic (71.93±9.29 years) donors. The groups were not statistically different in age. DNA was extracted from LEC for methylation analysis using Illumina Infinium 850K MethylationEPIC BeadChip and protein was extracted for Wnt phospho array analysis. Wound healing was studied using a scratch assay in LEC or 1-heptanol wounds in organ-cultured corneas. Organ-cultured corneas and LEC were transfected with WNT5A siRNA, miR-203a mimic or miR-203a inhibitor or were treated with recombinant Wnt-5a (200 ng/ml), DNA methylation inhibitor zebularine (1-20 µmol/l) or biodegradable nanobioconjugates (NBCs) based on polymalic acid scaffold containing antisense oligonucleotide (AON) to miR-203a or a control scrambled AON (15-20 µmol/l). RESULTS: There was significant differential DNA methylation between diabetic and non-diabetic LEC. WNT5A promoter was hypermethylated in diabetic LEC accompanied with markedly decreased Wnt-5a protein. Treatment of diabetic LEC and organ-cultured corneas with exogenous Wnt-5a accelerated wound healing by 1.4-fold (p

Abstract Streets and roads have been constantly identified as key spaces to improve walkability and—by extension—the entire urban environment. Such improvements lie on planning and design theories that are often supported by qualitative evidence and as such, tend to remain highly speculative on how street design influences walkability in more deterministic ways. Drawbacks in further exploring this street-walkability correlation are partly defined by an explicit rejection to ‘spatial determinism’ in urban morphology and social sciences, but also because combining differing epistemological approaches for understanding social processes linked to the physical aspects of the space is complex. In this paper, it is proposed that qualitative (social-based) theories of the space and quantitative (positivist) understandings of people’s behaviour can complement each other to elaborate upon ‘spatial determinism’ with focus on streetscapes and pedestrian behaviour. By using Agent-Based Modelling (ABMs), morphological components of streets linked to population characteristics are analysed to understand walkability from the perspective of spatial determinism. The findings suggest that the street settings directly affect pedestrian behaviour, and that changes in the built environment result in changes on walkability patterns. Ultimately, the modelling exercise shed light on street design and walkability, but also on wider debates on how urban design and social processes correlate in more deterministic and, therefore, predictable ways.

Abstract Background Renal cell carcinoma (RCC) is a type of cancer that can develop at any point in adulthood, spanning the range of age-related changes that occur in the body. However, the specific molecular mechanisms underlying the connections between age and genetic mutations in RCC have not been extensively investigated. Methods Clinical and genetic data from patients diagnosed with RCC were collected from two prominent medical centers in China as well as the TCGA dataset. The patients were categorized into two groups based on their prognosticated age: young adults (YAs) and older adults (OAs). Univariate and multivariate analysis were employed to evaluate the relationships between age and genetic mutations. Furthermore, a mediation analysis was conducted to assess the association between age and overall survival, with genetic disparities serving as a mediator. Results Our analysis revealed significant differences in clinical presentation between YAs and OAs with RCC, including histopathological types, histopathological tumor stage, and sarcomatoid differentiation. YAs were found to have lower mutation burden and significantly mutated genes (SMGs) of RCC. However, we did not observe any significant differences between the two groups in terms of 10 canonical oncogenic signaling pathways-related genes mutation, telomerase-related genes (TRGs) mutation, copy number changes, and genetic mutations associated with clinically actionable targeted drugs. Importantly, we demonstrate superior survival outcomes in YAs, and we confirmed the mediating effect of genetic disparities on these survival outcome differences between YAs and OAs. Conclusion Our findings reveal previously unrecognized associations between age and the molecular underpinnings of RCC. These associations may serve as valuable insights to guide precision diagnostics and treatments for RCC.

Abstract Molecular weight (MW) of organics was one of the important factors influencing membrane fouling propensity. This study identified critical foulants of reverse osmosis (RO) membranes in reclaimed water by MW fractionation. MW > 10 kDa component was identified as the critical fouling contributor (CFC) in secondary effluent (SE), which accounted for only 13 ± 5% of dissolved organic carbon (DOC) but contributed to 86 ± 11% of flux decline. Throughout 12-month monitoring, SE and MW > 10 kDa component showed a similar fouling variation tendency: apparently higher fouling potential in winter and lower in summer, while MW 10 kDa component and glean valuable insights into RO fouling mechanisms of reclaimed water in practical application.

Although hypervalent iodine(III) reagents have become staples in organic chemistry, the exploration of their isoelectronic counterparts, namely hypervalent bromine(III) and chlorine(III) reagents, has been relatively limited, partly due to challenges in synthesizing and stabilizing these compounds. In this study, we conduct a thorough examination of both homolytic and heterolytic bond dissociation energies (BDEs) critical for assessing the chemical stability and functional group transfer capability of cyclic hypervalent halogen compounds using density functional theory (DFT) analysis. A moderate linear correlation was observed between the homolytic BDEs across different halogen centers, while a strong linear correlation was noted among the heterolytic BDEs across these centers. Furthermore, we developed a predictive model for both homolytic and heterolytic BDEs of cyclic hypervalent halogen compounds using machine learning algorithms. The results of this study could aid in estimating the chemical stability and functional group transfer capabilities of hypervalent bromine(III) and chlorine(III) reagents, thereby facilitating their development.

Abstract The synthesis of constrained 12-membered rings is notably difficult. The main challenges result from constraints during the linear peptide cyclization. Attempts to overcome constraints through excessive activation frequently cause peptidyl epimerization, while insufficient activation of the C-terminus hampers cyclization and promotes intermolecular oligomer formation. We present a β-thiolactone framework that enables the synthesis of cyclo-tetrapeptides via direct aminolysis. This tactic utilizes a mechanism that restricts C-terminal carbonyl rotation while maintaining high reactivity, thereby enabling efficient head-to-tail amidation, reducing oligomerization, and preventing epimerization. A broad range of challenging cyclo-tetrapeptides ( > 20 examples) are synthesized in buffer and exhibits excellent tolerance toward nearly all proteinogenic amino acids. Previously unattainable macrocycles, such as cyclo-L-(Pro-Tyr-Pro-Val), have been produced and identified as μ-opioid receptor (MOR) agonists, with an EC50 value of 2.5 nM. Non-epimerizable direct aminolysis offers a practical solution for constrained peptide cyclization, and the discovery of MOR agonist activity highlights the importance of overcoming synthetic challenges for therapeutic development.

Abstract Objectives Endocardial trabeculae undergo varicose changes and hyperplasia in response to hemodynamic influences and are a variable phenotype reflecting changes in disease. Fractal analysis has been used to analyze the complexity of endocardial trabeculae in a variety of cardiomyopathies. The aim of this paper was to quantify the myocardial trabecular complexity through fractal analysis and to investigate its predictive value for the diagnosis of heart failure with preserved ejection fraction (HFpEF) in patients with multivessel coronary artery disease (CAD). Methods The retrospective study population consisted of 97 patients with multivessel CAD, 39 of them were diagnosed with HFpEF, while 46 healthy volunteers were recruited as controls. Fractal dimension (FD) was obtained through fractal analysis of endocardial trabeculae on LV short-axis cine images. Logistic regression analyses were used to confirm the predictors and compare different prediction models. Results Mean basal FD was significantly higher in patients with HFpEF than in patients without HFpEF or in the healthy group (median: 1.289; IQR: 0.078; p

In spite of the close relationship between gestures and expressive language, little research has examined the roles of the parents' and children's gestures in the development of expressive language abilities in autistic children. Previous findings are also inconclusive. In the present study, we coded the gestures produced by the parents and their autistic children in parent-child interactions and compared the influence of their gestures on the children's expressive language abilities (N = 35; M = 4;10). Autistic children's deictic gestures positively predicted their Mean Length Utterance (MLU), word types, and word tokens whereas parents' deictic gesture inputs negatively predicted MLU and word types. The findings shed light on the importance of the gestures made by autistic children, which may trigger parents' gesture-to-word translation.

ObjectivePhysical activity (PA) plays an important role in human health. However, the relationship between the PA and dysthyreosis was not clear. This study aimed to explore this question.MethodsWe performed a population-based study on the basis of the participant’s information that was collected from the National Health and Nutrition Examination Survey (NHANES) database. The association of the thyroid hormone and total PA metabolic equivalent task (MET) were assessed via linear regression analysis with adjusting for different covariates. Moreover, we also used path analysis to explore the causality between PA, thyroid hormone index, and dysthyreosis. The restricted cubic spline analysis was used to explore the non-linear relationship between the thyroid hormone index and the PA total MET.ResultsA total of 2118 participants aged≥20, including 969 females and 1149 males, were collected from NHANES. The linear regression with multivariate adjustment suggested a linear relationship between the PA total MET and Thyroid-Stimulating Hormone Index (TSHI), and Thyroid Feedback Quantile-Based Index (TFQI), respectively. And TFQI and dysthyresis occurrence were significantly correlated (P

This is the first report of NUP98::LEDGF positive malignant hematological tumor expressing T cell and myeloid lineage antigens. Patients carrying this fusion gene have a high relapse rate and a poor prognosis, allo-HSCT may be an option to cure this disease. This patient underwent allo-HSCT, a relapse occurred three months post-transplantation. Subsequent screening at our hospital confirmed the presence of the NUP98::LEDGF fusion gene, salvage therapy was administered, followed by a successful second allo-HSCT. Furthermore, we included eight previously reported cases from the literature for analysis and discuss.