Agomelatine promotes differentiation of oligodendrocyte precursor cells and preserves white matter integrity after cerebral ischemic stroke.

White matter injury contributes to neurological disorders after acute ischemic stroke (AIS). The repair of white matter injury is dependent on the re-myelination by oligodendrocytes. Both melatonin and serotonin antagonist have been proved to protect against post-stroke white matter injury. Agomelatine (AGM) is a multi-functional treatment which is both a melatonin receptor agonist and selective serotonin receptor antagonist. Whether AGM protects against white matter injury after stroke and the underlying mechanisms remain elusive. Here, using the transient middle cerebral artery occlusion (tMCAO) model, we evaluated the therapeutic effects of AGM in stroke mice. Sensorimotor and cognitive functions, white matter integrity, oligodendroglial regeneration and re-myelination in stroke hemisphere after AGM treatment were analyzed. We found that AGM efficiently preserved white matter integrity, reduced brain tissue loss, attenuated long-term sensorimotor and cognitive deficits in tMCAO models. AGM treatment promoted OPC differentiation and enhanced re-myelination both in vitro, ex vivo and in vivo, although OPC proliferation was unaffected. Mechanistically, AGM activated low density lipoprotein receptor related protein 1 (LRP1), peroxisome proliferator-activated receptor γ (PPARγ) signaling thus promoted OPC differentiation and re-myelination after stroke. Inhibition of PPARγ or knock-down of LRP1 in OPCs reversed the beneficial effects of AGM. Altogether, our data indicate that AGM represents a novel therapy against white matter injury after cerebral ischemia.

Surface-engineered Mo2B: a promising electrode material for constructing Ohmic contacts with blue phosphorene for electronic device applications.

The Schottky barrier between a metal and a semiconductor plays an important role in determining the transport efficiency of carriers and improving the performance of devices. In this work, we systematically studied the structure and electronic properties of heterostructures of blue phosphorene (BP) in contact with Mo2B based on density functional theory. The semiconductor properties of BP are destroyed owing to strong interaction with bare Mo2B. The effect of modifying Mo2B with O and OH on the contact properties was investigated. A p-type Schottky contact can be obtained in BP/Mo2BO2. The height of the Schottky barrier can be modulated by interlayer distance to realize a transition from a p-type Schottky contact to a p-type Ohmic contact in BP/Mo2BO2. The BP/Mo2B(OH)2 forms robust Ohmic contacts, which are insensitive to interlayer distance and external electric fields due to the Fermi level pinning effect. Our work provides important clues for contact engineering and improvement of device performance based on BP.

Chemical composition analysis and transcriptomics reveal the R2R3-MYB genes and phenol oxidases regulating the melanin formation in black radish.

Melanins are dark-brown to black-colored biomacromolecules which have been thoroughly studied in animals and microorganisms. However, the biochemical and molecular basis of plant melanins are poorly understood. We first characterized melanin from the black radish (Raphanus sativus var. niger) 'HLB' through spectroscopic techniques. p-Coumaric acid was identified as the main precursor of radish melanin. Moreover, a joint analysis of transcriptome and coexpression network was performed for the two radish accessions with black and white cortexes, 'HLB' and '55'. A set of R2R3-type RsMYBs and enzyme-coding genes exhibited a coexpression pattern, and were strongly correlated with melanin formation in radish. Transient overexpression of two phenol oxidases RsLAC7 (laccase 7) or RsPOD22-1 (peroxidase 22-1) resulted in a deeper brown color around the infiltration sites and a significant increase in the total phenol content. Furthermore, co-injection of the transcriptional activator RsMYB48/RsMYB97 with RsLAC7 and/or RsPOD22-1, markedly increased the yield of black extracts. Spectroscopic analyses revealed that these extracts are similar to the melanin found in 'HLB'. Our findings advance the understanding of structural information and the transcriptional regulatory mechanism underlying melanin formation in radish.

Frustrated Lewis pair catalyst realizes efficient green diesel production.

Hydrotreating renewable oils over sulfided metal catalysts is commercially applied to produce green diesel, but it requires a continuous sulfur replenishment to maintain catalyst activity, which inevitably results in sulfur contamination and increases production costs. We report a robust P-doped NiAl-oxide catalyst with frustrated Lewis pairs (i.e., P atom bonded with the O atom acts as an electron donor, while the spatially separated Ni atom acts as an electron acceptor) that allows efficient green diesel production without sulfur replenishment. The catalyst runs more than 500 h at a weight hourly space velocity (WHSV) of 28.3 h-1 without deactivation (methyl laurate as a model compound), and is able to completely convert a real feedstock of soybean oil to diesel-range hydrocarbons with selectivity >90% during 500 h of operation. This work is expected to open up a new avenue for designing non-sulfur catalysts that can make the green diesel production greener.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Tamoxifen Alleviates Endometrial Fibrosis Induced by Anhydrous Ethanol in Rats.

BACKGROUND: As an estrogen receptor modulator, tamoxifen has been utilized in the treatment of fibrotic diseases. However, there is a limited body of research focusing on its potential application in addressing endometrial fibrosis conditions. Our research aims to investigate the effects of tamoxifen at different dosage levels in alleviating endometrial fibrosis and to elucidate its mechanisms of action during the initial stages of endometrial damage. METHODS: A total of thirty sexually mature, unmated female Sprague-Dawley (SD) rats were divided into six distinct groups. To establish the rat uterine adhesion model, the uterine cavity was subjected to perfusion with anhydrous ethanol. The control group received a saline solution, while the treatment group was administered oral estrogen in combination with tamoxifen at doses of 4 mg/kg/d, 20 mg/kg/d, and 40 mg/kg/d. Various techniques, including Hematoxylin and Eosin (HE) staining, Masson's Trichrome staining, Western Blotting analysis, and immunohistochemistry, were employed to assess changes in endometrial thickness, fibrosis, as well as alterations in indicators related to epithelial-mesenchymal transition (EMT), fibrosis, estrogen receptors within the endometrium, and vascular endothelial growth factor (VEGF). RESULTS: In the model group, the levels of endometrial thickness, E-cadherin, Vimentin, estrogen receptor α (ERα), G protein-coupled receptor 30 (GPR30), and VEGF proteins were significantly lower compared to the control group. Conversely, the levels of collagen accumulation, Smooth Muscle Actin (SMA), Transforming Growth Factor ß1 (TGFß1), Drosophila mothers against decapentaplegic protein 2 (Smad2) , and Smad3 were markedly higher than those observed in the control group (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). In contrast, the low-dose tamoxifen group demonstrated significant increases in endometrial thickness, E-cadherin, Vimentin, ERα, GPR30, and VEGF when compared to the model group (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, the levels of collagen accumulation, TGFß1, SMA, Smad2, and Smad3, which are indicative of fibrosis and the TGFß1/Drosophila mothers against decapentaplegic (smad) pathway, were notably reduced compared to the model group (p < 0.05, p < 0.0001). CONCLUSIONS: The results of this study suggest that the administration of a low dose (4 mg/kg/d) of tamoxifen in the early stages of endometrial injury may mitigate epithelial-mesenchymal transition (EMT) indicators and reduce fibrosis within the endometrium induced by anhydrous ethanol.

Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse.

Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.

Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation.

BACKGROUNDS: Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties. METHODS: Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells. RESULTS: Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role. CONCLUSION: IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

BDNF-enriched small extracellular vesicles protect against noise-induced hearing loss in mice.

Noise-induced hearing loss (NIHL) is one of the most prevalent acquired sensorineural hearing loss etiologies and is characterized by the loss of cochlear hair cells, synapses, and nerve terminals. Currently, there are no agents available for the treatment of NIHL because drug delivery to the inner ear is greatly limited by the blood-labyrinth barrier. In this study, we used mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) as nanoscale vehicles to deliver brain-derived neurotrophic factor (BDNF) and evaluated their protective effects in a mouse model of NIHL. Following intravenous administration, BDNF-loaded sEVs (BDNF-sEVs) efficiently increased the expression of BDNF protein in the cochlea. Systemic application of sEVs and BDNF-sEVs significantly attenuated noise-induced cochlear hair cell loss and NIHL in CBA/J mice. BDNF-sEVs also alleviated noise-induced loss of inner hair cell ribbon synapses and cochlear nerve terminals. In cochlear explants, sEVs and BDNF-sEVs effectively protected hair cells against H2O2-induced cell loss. Additionally, BDNF-sEVs remarkably ameliorated H2O2-induced oxidative stress, cell apoptosis, and cochlear nerve terminal degeneration. Transcriptomic analysis revealed that many mRNAs and miRNAs were involved in the protective actions of BDNF-sEVs against oxidative stress. Collectively, our findings reveal a novel therapeutic strategy of MSC-sEVs-mediated BDNF delivery for the treatment of NIHL.

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people.

Tibeto-Burman (TB) people have endeavored to adapt to the hypoxic, cold, and high-UV high-altitude environments in the Tibetan Plateau and complex disease exposures in lowland rainforests since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB-speaking people, as well as their interaction mechanism, remain unknown. Here, we generate a whole-genome meta-database of 500 individuals from 39 TB-speaking populations and present a comprehensive landscape of genetic diversity, admixture history, and differentiated adaptative features of geographically different TB-speaking people. We identify genetic differentiation related to geography and language among TB-speaking people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between the Tibetan-Yi corridor and the ancient Yellow River people supports their Northern China origin hypothesis. We finally report substructure-related differentiated biological adaptative signatures between highland Tibetans and Loloish speakers. Adaptative signatures associated with the physical pigmentation (EDAR and SLC24A5) and metabolism (ALDH9A1) are identified in Loloish people, which differed from the high-altitude adaptative genetic architecture in Tibetan. TB-related genomic resources provide new insights into the genetic basis of biological adaptation and better reference for the anthropologically informed sampling design in biomedical and genomic cohort research.

Genome-Wide Identification of the CDPK Gene Family and Their Involvement in Taproot Cracking in Radish.

Taproot cracking, a severe and common physiological disorder, markedly reduces radish yield and commercial value. Calcium-dependent protein kinase (CDPK) plays a pivotal role in various plant developmental processes; however, its function in radish taproot cracking remains largely unknown. Here, 37 RsCDPK gene members were identified from the long-read radish genome "QZ-16". Phylogenetic analysis revealed that the CDPK members in radish, tomato, and Arabidopsis were clustered into four groups. Additionally, synteny analysis identified 13 segmental duplication events in the RsCDPK genes. Analysis of paraffin-embedded sections showed that the density and arrangement of fleshy taproot cortex cells are important factors that affect radish cracking. Transcriptome sequencing of the fleshy taproot cortex revealed 5755 differentially expressed genes (DEGs) (3252 upregulated and 2503 downregulated) between non-cracking radish "HongYun" and cracking radish "505". These DEGs were significantly enriched in plant hormone signal transduction, phenylpropanoid biosynthesis, and plant-pathogen interaction KEGG pathways. Furthermore, when comparing the 37 RsCDPK gene family members and RNA-seq DEGs, we identified six RsCDPK genes related to taproot cracking in radish. Soybean hairy root transformation experiments showed that RsCDPK21 significantly and positively regulates root length development. These findings provide valuable insights into the relationship between radish taproot cracking and RsCDPK gene function.

Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy.

Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC-sEV is an obstacle for clinical applications. The potential application of MSC-sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC-sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC-sEV, and the methods for obtaining high-quality human MSC-sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC-sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation.

Salvianolic acid C promotes osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporotic rats through activation of AMPK/SIRT1 pathway.

PURPOSE: This study aimed to explore the molecular mechanism underlying the therapeutic effect of salvianolic acid C (SAC) on osteoporosis. METHODS: Osteoporotic (OVX) rats were used as the model, and the impacts of SAC treatment on their serum and urine biochemical indicators were assessed. The biomechanical parameters of these rats were also evaluated. The effects of SAC treatment on the bone of OVX rats was quantified using hematoxylin & eosin staining and alizarin red staining, which reflect calcium deposition. The potential signaling pathway involved in SAC treatment was identified and confirmed through Western blotting, AMP-activated protein kinase (AMPK) inhibitors, and sirtuin-1 (small interfering RNA-SIRT1). RESULTS: The results showed that SAC could ameliorate the serum and urine biochemical metabolism, and the pathological alterations of bone tissue in OVX rats. SAC promoted the osteogenic differentiation of bone marrow mesenchymal cells in OVX rats, one of the key mechanisms for modulation of Runx2, Osx, and OCN, involved in the AMPK/SIRT1 signaling pathway. CONCLUSION: The findings from this study suggest that SAC promotes the osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporotic rats by activating the AMPK/SIRT1 pathway.

Evolution of channel flow and Darcy's law beyond the critical Reynolds number.

For incompressible channel flow, there is a critical state, characterized by a critical Reynolds number Rec and a critical wavevector mc along the channel direction, beyond which the channel flow becomes unstable in the linear regime. In this work, we investigate the channel flow beyond the critical state and find the existence of a new fluctuating, quasi-stationary flow that comprises the laminar Poiseuille flow superposed with a counter-flow component, accompanied by vortices and anti-vortices. The net flow rate is reduced by ~ 15% from the linear, laminar regime. Our study is facilitated by the analytical solution of the linearized, incompressible, three-dimensional (3D) Navier-Stokes (NS) equation in the channel geometry, with the Navier boundary condition, alternatively denoted as the hydrodynamic modes (HMs). By using the HMs as the complete mathematical basis for expanding the velocity in the NS equation, the Rec is evaluated to 5-digit accuracy when compared to the well-known Orszag result, without invoking the standard Orr-Sommerfeld equation. Beyond Rec, the analytical solution is indispensable in offering physical insight to those features of the counter-flow component that differs from any of the pressure-driven channel flows. In particular, the counter flow is found to comprise multiple HMs, some with opposite flow direction, that can lead to a net boundary reaction force along the counter-flow direction. The latter is analyzed to be necessary for satisfying Newton's law. Experimental verification of the predictions is discussed.

Bone Marrow Mesenchymal Stem Cell-Derived Dermcidin-Containing Migrasomes enhance LC3-Associated Phagocytosis of Pulmonary Macrophages and Protect against Post-Stroke Pneumonia.

Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.

Effect of Random Lateral Ballast Resistance on Force-Deformation Characteristics of CWR with a Small-Radius Curve.

To address the randomness of lateral ballast resistance in the field and its effect on the force-deformation behavior of Continuous Welded Rail (CWR) with small-radius curves, field tests were first conducted to investigate longitudinal and lateral ballast resistance on a 250 m-radius curve. It was found that the lateral ballast resistance follows a normal distribution based on the Shapiro-Wilk test. A finite element model of a small-radius curve CWR track was then established based on actual field conditions, and the force-deformation characteristics were analyzed under thermal loading. The results showed that it is of great significance to incorporate the randomness of the lateral ballast resistance as the deformation mode is closer to the actual field situation. In particular, attention should be given to areas where the lateral ballast resistance is weak. The research presented here has significant implications for railway maintenance practice.

Development and validation of a risk prediction model for frailty in patients with diabetes.

BACKGROUND: Frailty is the third most common complication of diabetes after macrovascular and microvascular complications. The aim of this study was to develop a validated risk prediction model for frailty in patients with diabetes. METHODS: The research used data from the China Health and Retirement Longitudinal Study (CHARLS), a dataset representative of the Chinese population. Twenty-five indicators, including socio-demographic variables, behavioral factors, health status, and mental health parameters, were analyzed in this study. The study cohort was randomly divided into a training set and a validation set at a ratio of 70 to 30%. LASSO regression analysis was used to screen the variables for the best predictors of the model based on a 10-fold cross-validation. The logistic regression model was applied to explore the associated factors of frailty in patients with diabetes. A nomogram was constructed to develop the prediction model. Calibration curves were applied to evaluate the accuracy of the nomogram model. The area under the receiver operating characteristic curve and decision curve analysis were conducted to assess predictive performance. RESULTS: One thousand four hundred thirty-six patients with diabetes from the CHARLS database collected in 2013 (n = 793) and 2015 (n = 643) were included in the final analysis. A total of 145 (10.9%) had frailty symptoms. Multivariate logistic regression analysis showed that marital status, activities of daily living, waist circumference, cognitive function, grip strength, social activity, and depression as predictors of frailty in people with diabetes. These factors were used to construct the nomogram model, which showed good concordance and accuracy. The AUC values of the predictive model and the internal validation set were 0.912 (95%CI 0.887-0.937) and 0.881 (95% CI 0.829-0.934). Hosmer-Lemeshow test values were P = 0.824 and P = 0.608 (both > 0.05). Calibration curves showed significant agreement between the nomogram model and actual observations. ROC and DCA indicated that the nomogram had a good predictive performance. CONCLUSIONS: Comprehensive nomogram constructed in this study was a promising and convenient tool to evaluate the risk of frailty in patients with diabetes, and contributed clinicians to screening the high-risk population.

Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy.

Mesenchymal stem cells (MSCs) have shown promise for the therapy of cerebral ischemia in animal studies and clinical trials, yet their clinical application still faces many challenges. Utilizing small extracellular vesicles (sEVs) may overcome these challenges. In the study, we overexpressed brain-derived neurotrophic factor (BDNF) in cultured MSCs and purified sEVs using anion exchange chromatography. In an ischemic stroke mouse model, sEVs selectively targeted the peri-infarct region after intranasal administration, and BDNF loading enhanced the efficacy of sEVs in improved functional behavior, neural repair indicated by infarct volume reduction, increased neurogenesis, angiogenesis, synaptic plasticity, and fiber preservation, as well as decreased inflammatory-cytokine expression and glial response. Intranasal administration of sEVs and BDNF-sEVs resulted in upregulation of neuroprotection-related genes and downregulation of inflammation-related genes, and BDNF-sEVs treatment activated the BDNF/TrkB signaling in the ischemic brain. Transcriptomic and proteomic analysis of sEVs and BDNF-sEVs disclosed abundant proteins and miRNAs involved in neuroprotection and anti-inflammation, and BDNF-sEVs showed different characteristics from sEVs. In conclusion, intranasal delivery of sEVs-loaded BDNF is a promising alternative strategy for the therapy of cerebral ischemia.

A General and Scalable Approach to Sulfur-Doped Mono-/Bi-/Trimetallic Nanoparticles Confined in Mesoporous Carbon.

Metal nanoparticles confined in porous carbon materials have been widely used in various heterogeneous catalytic processes due to their enhanced activity and stability. However, fabrication of such catalysts in a facile and scalable way remains challenging. Herein, we report a general and scalable thiol-assisted strategy to synthesize sulfur-doped mono-/bi-/trimetallic nanoparticles confined in mesoporous carbon (S-M@MC, M = Pt, Pd, Rh, Co, Zn, etc.), involving only two synthetic steps, i.e., a hydrothermal process and pyrolysis. The strategy is based on coordination chemistry and hydro-phobic interaction that the metal precursors coordinated with the hydrophobic thiol ligands are located at the hydrophobic core of micelles, in situ confined in the hydrothermally prepared mesostructured polymer, and then converted into sulfur-doped metal nanoparticles confined in MC after pyrolysis. It is demonstrated that the S-PtCo@MC exhibits enhanced catalytic activity and improved durability toward acidic hydrogen evolution reaction due to the confinement effect and S-doping.