Associations between residential greenness and obesity phenotypes among adults in Southwest China.

BACKGROUND: Although exposure to greenness has generally benefited human metabolic health, the association between greenness exposure and metabolic obesity remains poorly studied. We aimed to investigate the associations between residential greenness and obesity phenotypes and the mediation effects of air pollutants and physical activity (PA) level on the associations. METHODS: We used the baseline of the China Multi-Ethnic Cohort (CMEC) study, which enrolled 87,613 adults. Obesity phenotypes were defined based on obesity and metabolic status, including metabolically unhealthy obesity (MUO), non-obesity (MUNO), metabolically healthy obesity (MHO), and non-obesity (MHNO). Greenness exposure was measured as the 3-year mean values of the normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI) within the 500-m buffer zones around the participants' residence. Multivariable logistic regression was used to estimate the associations between greenness and obesity phenotypes. Stratified analyses by age, sex, educational level, and urbanicity were performed to identify how the effect varies across different subgroups. Causal mediation analysis was used to examine the mediation effects of air pollutants and PA level. RESULTS: Compared with MHNO, each interquartile range (IQR) increase in greenness exposure was associated with reduced risks of MHO (ORNDVI [95% CI] = 0.87 [0.81, 0.93]; OREVI = 0.91 [0.86, 0.97]), MUO (ORNDVI = 0.83 [0.78, 0.88]; OREVI = 0.86 [0.81, 0.91]), and MUNO (ORNDVI = 0.88 [0.84, 0.91]; OREVI = 0.89 [0.86, 0.92]). For each IQR increase in both NDVI and EVI, the risks of MHO, MUO, and MUNO were reduced more in men, participants over 60 years, those with a higher level of education, and those living in urban areas, compared to their counterparts. Concentrations of particulate matter (PM) and PA level partially mediated the associations between greenness exposure and obesity phenotypes. CONCLUSIONS: Exposure to residential greenness was associated with decreased risks of MHO, MUO, and MUNO, which was mediated by concentrations of PM and PA level, and modified by sex, age, educational level, and urbanicity.

Engineering Streptomyces sp. CPCC 204095 for the targeted high-level production of isatropolone A by elucidating its pathway-specific regulatory mechanism.

BACKGROUND: Isatropolone A and C, produced by Streptomyces sp. CPCC 204095, belong to an unusual class of non-benzenoid aromatic compounds and contain a rare seven-membered ring structure. Isatropolone A exhibits potent activity against Leishmania donovani, comparable to the only oral drug miltefosine. However, its variably low productivity represents a limitation for this lead compound in the future development of new anti-leishmaniasis drugs to meet unmet clinical needs. RESULTS: Here we first elucidated the regulatory cascade of biosynthesis of isatropolones, which consists of two SARP family regulators, IsaF and IsaJ. Through a series of in vivo and in vitro experiments, IsaF was identified as a pathway-specific activator that orchestrates the transcription of the gene cluster essential for isatropolone biosynthesis. Interestingly, IsaJ was found to only upregulate the expression of the cytochrome P450 monooxygenase IsaS, which is crucial for the yield and proportion of isatropolone A and C. Through targeted gene deletions of isaJ or isaS, we effectively impeded the conversion of isatropolone A to C. Concurrently, the facilitation of isaF overexpression governed by selected promoters, prompted the comprehensive activation of the production of isatropolone A. Furthermore, meticulous optimization of the fermentation parameters was conducted. These strategies culminated in the attainment of an unprecedented maximum yield-980.8 mg/L of isatropolone A-achieved in small-scale solid-state fermentation utilizing the genetically modified strains, thereby establishing the highest reported titer to date. CONCLUSION: In Streptomyces sp. CPCC 204095, the production of isatropolone A and C is modulated by the SARP regulators IsaF and IsaJ. IsaF serves as a master pathway-specific regulator for the production of isatropolones. IsaJ, on the other hand, only dictates the transcription of IsaS, the enzyme responsible for the conversion of isatropolone A and C. By engineering the expression of these pivotal genes, we have devised a strategy for genetic modification aimed at the selective and high-yield biosynthesis of isatropolone A. This study not only unveils the unique regulatory mechanisms governing isatropolone biosynthesis for the first time, but also establishes an essential engineering framework for the targeted high-level production of isatropolone A.

Proximal telomeric decompaction due to telomere shortening drives FOXC1-dependent myocardial senescence.

Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in aging and are targets of DNA damage response. Although we and others have demonstrated presence of short telomeres in genetic cardiomyopathic and heart failure cardiomyocytes, little is known about the role of telomere lengths in cardiomyocyte. Here, we demonstrate that in heart failure patient cardiomyocytes, telomeres are shortened compared to healthy controls. We generated isogenic human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) with short telomeres (sTL-CMs) and normal telomeres (nTL-CMs) as model. Compared to nTL-CMs, short telomeres result in cardiac dysfunction and expression of senescent markers. Using Hi-C and RNASeq, we observe that short telomeres induced TAD insulation decrease near telomeric ends and this correlated with a transcription upregulation in sTL-CMs. FOXC1, a key transcription factor involved in early cardiogenesis, was upregulated in sTL-CMs and its protein levels were negatively correlated with telomere lengths in heart failure patients. Overexpression of FOXC1 induced hiPSC-CM aging, mitochondrial and contractile dysfunction; knockdown of FOXC1 rescued these phenotypes. Overall, the work presented demonstrate that increased chromatin accessibility due to telomere shortening resulted in the induction of FOXC1-dependent expression network responsible for contractile dysfunction and myocardial senescence.

Addition of ruxolitinib to standard graft-versus-host disease prophylaxis for allogeneic stem cell transplantation in aplastic anemia patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers rapid hematopoietic and immune reconstitution for aplastic anemia (AA). As a non-malignant disorder, attenuation of GVHD remains a clinical priority in AA patients. Our study sought to investigate the safety and efficacy of the prophylactic use of ruxolitinib in allogeneic HSCT. A total of 35 AA patients were retrospectively consecutively treated with allo-HSCT whereby ruxolitinib was added to the standard GVHD prophylaxis regimen (rux group). The addition of peri-transplant ruxolitinib did not impact the engraftment and graft function, while better recovery of CD4+ Tregs in the rux group was observed. Interestingly, the rux group demonstrated significantly lower incidence of bacterial/fungal infections (17.14% vs 45.71%). Compared to the control group, the rux group exhibited significantly lower incidence of moderate to severe aGVHD (17.1% vs 48.6%) with a trend toward lower severe aGVHD (8.6% vs 20%) and cGVHD (26.2 vs 38.3). The rux group also demonstrated a trend toward higher GVHD and failure-free survival (GFFS: 85.7% vs 68.6%) and lower TRM (2.9% vs 14.3%). Addition of ruxolitinib to standard GVHD prophylaxis regimen, thus, represents a safe and highly efficient method for the attenuation of GVHD with better outcome of allo-HSCT.

Advances in tumor vascular growth inhibition.

Tumor growth and metastasis require neovascularization, which is dependent on a complex array of factors, such as the production of various pro-angiogenic factors by tumor cells, intercellular signaling, and stromal remodeling. The hypoxic, acidic tumor microenvironment is not only conducive to tumor cell proliferation, but also disrupts the equilibrium of angiogenic factors, leading to vascular heterogeneity, which further promotes tumor development and metastasis. Anti-angiogenic strategies to inhibit tumor angiogenesis has, therefore, become an important focus for anti-tumor therapy. The traditional approach involves the use of anti-angiogenic drugs to inhibit tumor neovascularization by targeting upstream and downstream angiogenesis-related pathways or pro-angiogenic factors, thereby inhibiting tumor growth and metastasis. This review explores the mechanisms involved in tumor angiogenesis and summarizes currently used anti-angiogenic drugs, including monoclonal antibody, and small-molecule inhibitors, as well as the progress and challenges associated with their use in anti-tumor therapy. It also outlines the opportunities and challenges of treating tumors using more advanced anti-angiogenic strategies, such as immunotherapy and nanomaterials.

Case report: A case of hyperthyroidism secondary to bone metastasis of differentiated thyroid cancer.

It is usually believed that differentiated thyroid cancer is less likely to have distant metastases and rarely occurs secondary to hyperthyroidism. In our case report, we describe a patient diagnosed with thyroid fetal adenoma in 2002 who subsequently presented with a painful lump in her right rib. Through puncture biopsy, the mass was considered as metastatic follicular thyroid carcinoma, and then she appeared to have hyperthyroidism. The results of SPECT examination and other tests suggested that the hyperthyroidism was secondary to the thyroid cancer. The patient further underwent total thyroidectomy, and the pathology did not find any follicular thyroid foci. In this article, we analyze and discuss this case and review the relevant literature.

Cross-cultural perception of strength, attractiveness, aggressiveness and helpfulness of Maasai male faces calibrated to handgrip strength.

Previous research has demonstrated that Maasai and Europeans tend to align in their ratings of the physical strength and aggressiveness of Maasai male faces, calibrated to hand grip strength (HGS). However, perceptions of attractiveness of these faces differed among populations. In this study, three morphs of young Maasai men created by means of geometric morphometrics, and depicting the average sample and two extrema (± 4 SD of HGS), were assessed by men and women from Tanzania, Czech Republic, Russia, Pakistan, China, and Mexico (total sample = 1540). The aim of this study was to test cross-cultural differences in the perception of young Maasai men's composites calibrated to HGS, focusing on four traits: physical strength, attractiveness, aggressiveness, and helpfulness. Individuals from all six cultures were able to distinguish between low, medium, and high HGS portraits. Across all study populations, portrait of Maasai men with lower HGS was perceived as less attractive, more aggressive, and less helpful. This suggests that people from diverse populations share similar perceptions of physical strength based on facial shape, as well as attribute similar social qualities like aggressiveness and helpfulness to these facial images. Participants from all samples rated the composite image of weak Maasai men as the least attractive.

Preliminary study on early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice using multimodal magnetic resonance imaging.

Alzheimer's disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer's treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and 1H-magnetic resonance spectroscopy (1H-MRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, 1H-MRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD.

Nitrous oxide induced subacute combined degeneration of the spine cord: A case report.

RATIONALE: In recent years, recreational use of inhaled nitrous oxide (N2O) is on the increase among young people, accompanied by a corresponding rise in reports about its toxicity. Subacute combined degeneration of the spine cord (SCD) is the typical clinical picture of the nervous system disorder caused by N2O intoxication, as a result of metabolic disturbance of vitamin B12. PATIENT CONCERNS, DIAGNOSES, INTERVENTIONS AND OUTCOMES: We report a 28-year-old female of SCD due to prolonged use of N2O, presented with paresthesia and unsteady in walking progressing within 1 month. Symptoms gradually improved with the treatment of intramuscular injections of hydroxocobalamin combined with N2O abstinence, and the patient recovered completely with normal neurological examination after 4 months of follow-up. LESSONS: Clinicians should be aware of the clinical features and pathogenesis of SCD caused by N2O intoxication in order to lead effective treatment as soon as possible. Recreational N2O use should always be considered as an etiology when dealing with patients presented with myelopathy and/or neuropathy suspected of vitamin B12 deficiency.

Chemical Vapor Deposition of a Single-Crystalline MoS2 Monolayer through Anisotropic 2D Crystal Growth on Stepped Sapphire Surface.

Recently, a step-flow growth mode has been proposed to break the inherent molybdenum disulfide (MoS2) crystal domain bimodality and yield a single-crystalline MoS2 monolayer on commonly employed sapphire substrates. This work reveals an alternative growth mechanism during the metal-organic chemical vapor deposition (MOCVD) of a single-crystalline MoS2 monolayer through anisotropic 2D crystal growth. During early growth stages, the epitaxial symmetry and commensurability of sapphire terraces rather than the sapphire step inclination ultimately govern the MoS2 crystal orientation. Strikingly, as the MoS2 crystals continue to grow laterally, the sapphire steps transform the MoS2 crystal geometry into diamond-shaped domains presumably by anisotropic diffusion of ad-species and facet development. Even though these MoS2 domains nucleate on sapphire with predominantly bimodal 0 and 60° azimuthal rotation, the individual domains reach lateral dimensions of up to 200 nm before merging seamlessly into a single-crystalline MoS2 monolayer upon coalescence. Plan-view transmission electron microscopy reveals the single-crystalline nature across 50 µm by 50 µm inspection areas. As a result, the median carrier mobility of MoS2 monolayers peaks at 25 cm2 V-1 s-1 with the highest value reaching 28 cm2 V-1 s-1. This work details synthesis-structure correlations and the possibilities to tune the structure and material properties through substrate topography toward various applications in nanoelectronics, catalysis, and nanotechnology. Moreover, shape modulation through anisotropic growth phenomena on stepped surfaces can provide opportunities for nanopatterning for a wide range of materials.

Femoral Anteversion Is Associated With a Thinner Anterior Capsule in Patients With Femoroacetabular Impingement Syndrome.

PURPOSE: To measure femoral torsion on computed tomography images in patients with femoroacetabular impingement syndrome and explore whether femoral torsion was significantly correlated with anterior capsular thickness. METHODS: Prospectively collected data of surgical patients were retrospectively reviewed. Only patients aged 16 to 55 years who underwent primary hip surgery were included in this study. Patients with a history of revision hip surgery, previous knee surgery, hip dysplasia, hip synovitis, and/or incomplete radiographs and medical records were excluded from the study. Femoral torsion was measured via computed tomography imaging using transcondylar slices of the knee. Anterior capsular thickness was measured using oblique-sagittal sequences on a 3.0-T magnetic resonance imaging system. The association between anterior capsular thickness and related variables, including femoral torsion, was assessed via multiple linear regression. The patients were then divided into 2 groups to further confirm the effect of femoral torsion on capsular thickness: Patients in the study group had hips with moderate (20°-25°) or severe (>25°) antetorsion, whereas patients in the control group had hips with normal torsion (5°-20°) or retrotorsion (<5°). Anterior capsular thickness was also compared between the 2 groups. RESULTS: A total of 156 patients (89 female patients [57.1%] and 67 male patients [42.9%]) were finally included in the study. The mean age and body mass index of the included patients were 35.8 ± 11.2 years and 22.7 ± 3.5, respectively. The mean femoral torsion for the entire study population was 15.9° ± 8.9°. Multivariable regression analysis showed that femoral torsion (P < .001) and sex (P = .002) were significantly correlated with anterior capsular thickness. Propensity-score matching yielded 50 hips in the study group and 50 hips in the control group on femoral torsion subanalysis. The results showed that anterior capsular thickness was significantly smaller in the study group than in the control group (3.8 ± 0.5 mm vs 4.7 ± 0.7 mm, P < .001). CONCLUSIONS: Femoral torsion is significantly inversely correlated with anterior capsular thickness. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Guben Qingfei decoction attenuates LPS-induced acute lung injury by modulating the TLR4/NF-κB and Keap1/Nrf2 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is a life-threatening and widespread disease, with exceptionally high morbidity and mortality rates. Unfortunately, effective drugs for ALI treatment are currently lacking. Guben Qingfei decoction (GBQF) is a Chinese herbal compound known for its efficacy in treating viral pneumonia, yet the precise underlying mechanisms remain unknown. AIM OF THE STUDY: This study aimed to validate the mitigating effect of GBQF on ALI and to further investigate its mechanism. MATERIALS AND METHODS: An ALI mice model was established by infusing LPS into the endotracheal tube. The effects of GBQF on ALI were investigated by measuring lung W/D; MPO; BALF total protein concentration; total number of cells; TNF-α, IL-1ß, and IL-6 levels; pathological changes in lung tissue, and oxidation products. Immunohistochemistry and Western Blotting were performed to verify the underlying mechanisms. MH-S and BEAS-2B cells were induced by LPS, and the effects of GBQF were confirmed by RT-PCR and immunofluorescence. RESULTS: GBQF significantly reduced LPS-induced ALI in mice, improved lung inflammation, reduced the production of oxidative products, increased the activity of antioxidant enzymes, and reduced the degree of lung tissue damage. GBQF prevents MH-S cells from releasing inflammatory factors and reduces oxidative damage to BEAS-2B cells. In vivo studies have delved deeper into the mechanism of action of GBQF, revealing its correlation with the TLR4/NF-κB and Keap1/Nrf2 pathways. CONCLUSIONS: Our study demonstrates that GBQF is an effective treatment for ALI, providing a new perspective on medication development for ALI treatment.

Integrating Network Pharmacology and Experimental Validation to Elucidate the Mechanism of Jiegeng Decoction in Improving Allergic Asthma.

Allergic asthma is a prevalent form of asthma that is characterized primarily by airway inflammation. Jiegeng decoction (JGT) is a traditional Chinese herbal formula known for its anti-inflammatory properties and has been used to treat respiratory diseases for centuries. This study aimed to investigate the biological effects and mechanisms of action of JGT in improving allergic asthma. An experimental allergic asthma mouse model was established using ovalbumin. The results showed that JGT significantly improved inflammation cell infiltration in the lung tissue of allergic asthmatic mice and the inflammatory environment of Th2 cells in the bronchoalveolar lavage fluid while also reducing serum IgE levels. Subsequently, 38 components of JGT were identified through liquid chromatography-mass spectrometry. Network pharmacology revealed that regulating inflammation and immune responses is the primary biological process by which JGT improves allergic asthma, with Th2 cell differentiation and the JAK-STAT signaling pathway being the key mechanisms of action. Finally, qPCR, flow cytometry, and Western blotting were used to validate that JGT inhibited Th2 cell differentiation by blocking the JAK1-STAT6 signaling pathway in CD4+ T cells, ultimately improving allergic asthma. This study provides a novel perspective on the therapeutic potential of JGT in the treatment of allergic asthma.

Expanding structural diversity of 5'-aminouridine moiety of sansanmycin via mutational biosynthesis.

Sansanmycins represent a family of uridyl peptide antibiotics with antimicrobial activity specifically against Mycobacterium tuberculosis (including drug-resistant M. tuberculosis) and Pseudomonas aeruginosa. They target translocase I (MraY) to inhibit bacterial cell wall assembly. Given the unique mechanism of action, sansanmycin has emerged as a potential lead compound for developing new anti-tuberculosis drugs, while the 5'-aminouridine moiety plays a crucial role in the pharmacophore of sansanmycin. For expanding the structural diversity of the 5'-aminouridine moiety of sansanmycin through biosynthetic methods, we firstly demonstrated that SsaM and SsaK are responsible for the biosynthesis of the 5'-aminouridine moiety of sansanmycin in vivo. Using the ssaK deletion mutant (SS/KKO), we efficiently obtained a series of new analogues with modified 5'-aminouridine moieties through mutational biosynthesis. Based on molecular networking analysis of MS/MS, twenty-two new analogues (SS-KK-1 to -13 and SS-KK-A to -I) were identified. Among them, four new analogues (SS-KK-1 to -3 and SS-KK-C) were purified and bioassayed. SS-KK-2 showed better antibacterial activity against E. coli ΔtolC than the parent compound sansanmycin A. SS-KK-3 showed the same anti-TB activity as sansanmycin A against M. tuberculosis H37Rv as well as clinically isolated, drug-sensitive and multidrug-resistant M. tuberculosis strains. Furthermore, SS-KK-3 exhibited significantly improved structural stability compared to sansanmycin A. The results suggested that mutasynthesis is an effective and practical strategy for expanding the structural diversity of 5'-aminouridine moiety in sansanmycin.

Pepper mildew resistance locus O 1 (MLO1) context-specifically induces high-temperature-specific immunity and thermotolerance.

Plant diseases tend to be more serious under high-temperature/high-humidity (HTHH) conditions than at room temperature; thus, disease resistance under HTHH is a bottleneck for plant survival. However, how plants cope with diseases under HTHH remains poorly understood. Herein, using the pathosystem consisting of pepper and R. solanacearum as an example and expression profiling, loss- and gain-of-function assays involving virus-induced gene silencing and overexpression in pepper plants, and protein-protein interaction assays, the functions of CaMLO1 and CaPUB21 in pepper immunity against R. solanacearum at 28°C or 37°C (with 80% humidity) were comparatively characterized. The results showed that CaMLO1 acted negatively in pepper immunity against R. solanacearum at 28°C but positively at 37°C. In contrast, CaPUB21 acted positively upon R. solanacearum at 28°C but negatively at 37°C. Importantly, CaPUB21 interacted with CaMLO1 under all of the tested conditions, but only the CaPUB21-CaMLO1 interaction in response to R. solanacearum at 37°C or exposure to 37°C led to CaMLO1 degradation, thereby turning off inappropriate defence responses against R. solanacearum at 37°C and high-temperature stress. The results highlight that CaMLO1 and CaPUB21 function distinctly in pepper immunity against R. solanacearum in an environment-dependent manner and interact with each other, leading to the degradation of CaMLO1 specifically in response to R. solanacearum at 37°C or exposure to high temperature stress to turn off the inappropriate defence response mediated by CaMLO1.

Loop Closure Detection Method Based on Similarity Differences between Image Blocks.

Variations with respect to perspective, lighting, weather, and interference from dynamic objects may all have an impact on the accuracy of the entire system during autonomous positioning and during the navigation of mobile visual simultaneous localization and mapping (SLAM) robots. As it is an essential element of visual SLAM systems, loop closure detection plays a vital role in eradicating front-end-induced accumulated errors and guaranteeing the map's general consistency. Presently, deep-learning-based loop closure detection techniques place more emphasis on enhancing the robustness of image descriptors while neglecting similarity calculations or the connections within the internal regions of the image. In response to this issue, this article proposes a loop closure detection method based on similarity differences between image blocks. Firstly, image descriptors are extracted using a lightweight convolutional neural network (CNN) model with effective loop closure detection. Subsequently, the image pairs with the greatest degree of similarity are evenly divided into blocks, and the level of similarity among the blocks is used to recalculate the degree of the overall similarity of the image pairs. The block similarity calculation module can effectively reduce the similarity of incorrect loop closure image pairs, which makes it easier to identify the correct loopback. Finally, the approach proposed in this article is compared with loop closure detection methods based on four distinct CNN models with a recall rate of 100% accuracy; said approach performs significantly superiorly. The application of the block similarity calculation module proposed in this article to the aforementioned four CNN models can increase the recall rate's accuracy to 100%; this proves that the proposed method can successfully improve the loop closure detection effect, and the similarity calculation module in the algorithm has a certain degree of universality.

Umbilical cord mesenchymal stem cell-derived apoptotic extracellular vesicles ameliorate cutaneous wound healing in type 2 diabetic mice via macrophage pyroptosis inhibition.

BACKGROUND: Delayed healing of diabetic cutaneous wounds is one of the most common complications of type 2 diabetes mellitus (T2DM), which can bring great distress to patients. In diabetic patients, macrophages accumulate around skin wounds and produce NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasomes, which in turn undergo pyroptosis and produce inflammatory factors such as interleukin-1ß that affect wound healing. Although our previous study revealed that apoptotic extracellular vesicles (ApoEVs) produced from mesenchymal stem cells (MSCs) improve cutaneous wound healing in normal C57BL/6 mice, whether ApoEVs can also improve diabetic wound healing remains unclear. METHODS: Umbilical cord mesenchymal stem cells (UCMSCs) were cultured in vitro and apoptosis was induced. ApoEVs were extracted and identified and used in a T2DM mouse cutaneous wound model to evaluate the efficacy. The inhibitory effect of ApoEVs on macrophage pyroptosis was verified in vivo and in vitro, and the level of oxidative stress in macrophages was assessed to explore the mechanism by which ApoEVs play a role. RESULTS: UCMSC-derived ApoEVs improved skin defect healing in T2DM mice. Moreover, UCMSC-derived ApoEVs inhibited macrophage pyroptosis in T2DM mice in vivo as well as in vitro under high-glucose culture conditions. In addition, we demonstrated that ApoEVs reduce oxidative stress levels, which is a possible mechanism by which they inhibit macrophage pyroptosis. CONCLUSIONS: Our study confirmed that local application of UCMSC-derived ApoEVs improved cutaneous wound healing in T2DM mice. ApoEVs, as products of MSC apoptosis, can inhibit macrophage pyroptosis and regulate the death process by decreasing the level of oxidative stress.

Chemical-induced phase transition and global conformational reorganization of chromatin.

Chemicals or drugs can accumulate within biomolecular condensates formed through phase separation in cells. Here, we use super-resolution imaging to search for chemicals that induce phase transition within chromatin at the microscale. This microscopic screening approach reveals that adriamycin (doxorubicin) - a widely used anticancer drug that is known to interact with chromatin - specifically induces visible local condensation and global conformational change of chromatin in cancer and primary cells. Hi-C and ATAC-seq experiments systematically and quantitatively demonstrate that adriamycin-induced chromatin condensation is accompanied by weakened chromatin interaction within topologically associated domains, compartment A/B switching, lower chromatin accessibility, and corresponding transcriptomic changes. Mechanistically, adriamycin complexes with histone H1 and induces phase transition of H1, forming fibrous aggregates in vitro. These results reveal a phase separation-driven mechanism for a chemotherapeutic drug.

Effects of Pregnancy on Plasma Sphingolipids Using a Metabolomic and Quantitative Analysis Approach.

Changes in the maternal metabolome, and specifically the maternal lipidome, that occur during pregnancy are relatively unknown. The objective of this investigation was to evaluate the effects of pregnancy on sphingolipid levels using metabolomics analysis followed by confirmational, targeted quantitative analysis. We focused on three subclasses of sphingolipids: ceramides, sphingomyelins, and sphingosines. Forty-seven pregnant women aged 18 to 50 years old participated in this study. Blood samples were collected on two study days for metabolomics analysis. The pregnancy samples were collected between 25 and 28 weeks of gestation and the postpartum study day samples were collected ≥3 months postpartum. Each participant served as their own control. These samples were analyzed using a Ultra-performance liquid chromatography/mass spectroscopy/mass spectroscopy (UPLC/MS/MS) assay that yielded semi-quantitative peak area values that were used to compare sphingolipid levels between pregnancy and postpartum. Following this lipidomic analysis, quantitative LC/MS/MS targeted/confirmatory analysis was performed on the same study samples. In the metabolomic analysis, 43 sphingolipid metabolites were identified and their levels were assessed using relative peak area values. These profiled sphingolipids fell into three categories: ceramides, sphingomyelins, and sphingosines. Of the 43 analytes measured, 35 were significantly different during pregnancy (p < 0.05) (including seven ceramides, 26 sphingomyelins, and two sphingosines) and 32 were significantly higher during pregnancy compared to postpartum. Following metabolomics, a separate quantitative analysis was performed and yielded quantified concentration values for 23 different sphingolipids, four of which were also detected in the metabolomics study. Quantitative analysis supported the metabolomics results with 17 of the 23 analytes measured found to be significantly different during pregnancy including 11 ceramides, four sphingomyelins, and two sphingosines. Fourteen of these were significantly higher during pregnancy. Our data suggest an overall increase in plasma sphingolipid concentrations with possible implications in endothelial function, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy, and fetal development. This study provides evidence for alterations in maternal sphingolipid metabolism during pregnancy.

Design, Synthesis, and Biological Evaluation of Proteolysis-Targeting Chimeras as Highly Selective and Efficient Degraders of Extracellular Signal-Regulated Kinase 5.

Extracellular signal-regulated kinase 5 (ERK5) is recognized as a key member of the mitogen-activated protein kinase family and is involved in tumor growth, migration, and angiogenesis. However, the results of ERK5 inhibition in multiple studies are controversial, and a highly specific ERK5-targeting agent is required to confirm physiological functions. Using proteolysis-targeting chimera technology, we designed the selective ERK5 degrader PPM-3 and examined its biological effect on cancer cells. Interestingly, the selective degradation of ERK5 with PPM-3 did not influence tumor cell growth directly. Based on proteomics analysis, the ERK5 deletion may be associated with tumor immunity. PPM-3 influences tumor development by affecting the differentiation of macrophages. Therefore, PPM-3 is an effective small-molecule tool for studying ERK5 and a promising immunotherapy drug candidate.