Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells.

Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5-CD163+CD14+ cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies.

Integration of photothermal water evaporation with photocatalytic microplastics upcycling via nanofluidic thermal management.

Photothermal heating and photocatalytic treatment are two solar-driven water processing approaches by harnessing NIR and UV-vis light, respectively, which can fully utilize solar energy if integrated. However, it remains a challenge to achieve high performance in both approaches when integrated in a material due to uncontrollable heat diffusion. Here, we report a demonstration of heat confinement on photothermal sites and fluid cooling on photocatalysis sites at the nanoscale, within a well-designed heat and fluid confinement nanofiber reactor. Photothermal and photocatalytic nanostructures were alternatively aligned in electrospun nanofibers for on-demand nanofluidic thermal management as well as easy folding into 3D structures with enhanced light utilization and mass transfer. Such a design showed simultaneously high photothermal evaporation rate (2.59 kg m-2 h-1, exceeding the limit rate) and efficient photocatalytic upcycling of microplastics pollutant into valued products. Enabled by controlled photothermal heating, the valued main product (i.e., methyl acetate) can be evaporated out with 100% selectivity by in situ separation.

Astrocyte-specific inhibition of sigma-1 receptor leads to depressive-like behaviors in mice via activation of NF-κB-induced neuroinflammation.

Major depressive disorder (MDD) is a global health burden characterized by persistent low mood, deprivation of pleasure, recurrent thoughts of death, and physical and cognitive deficits. The current understanding of the pathophysiology of MDD is lacking, resulting in few rapid and effective antidepressant therapies. Recent studies have pointed to the sigma-1 (σ-1) receptor as a potential rapid antidepressant target; σ-1 agonists have shown promise in a variety of preclinical depression models. Hypidone hydrochloride (YL-0919), an independently developed antidepressant by our institute with faster onset of action and low rate of side effects, has recently emerged as a highly selective σ-1 receptor agonist; however, its underlying astrocyte-specific mechanism is unknown. In this study, we investigated the effect of YL-0919 treatment on gene expression in the prefrontal cortex of depressive-like mice by single-cell RNA sequencing. Furthermore, we knocked down σ-1 receptors on astrocytes in the medial prefrontal cortex of mice to explore the effects of YL-0919 on depressive-like behavior and neuroinflammation in mice. Our results demonstrated that astrocyte-specific knockdown of σ-1 receptor resulted in depressive-like behavior in mice, which was reversed by YL-0919 administration. In addition, astrocytic σ-1 receptor deficiency led to activation of the NF-κB inflammatory pathway, and crosstalk between reactive astrocytes and activated microglia amplified neuroinflammation, exacerbating stress-induced neuronal apoptosis. Furthermore, the depressive-like behavior induced by astrocyte-specific knockdown of the σ-1 receptor was improved by a selective NF-κB inhibitor, JSH-23, in mice. Our study not only reaffirms the σ-1 receptor as a key target of the faster antidepressant effect of YL-0919, but also contributes to the development of astrocytic σ-1 receptor-based novel drugs.

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus.

Postpartum depression (PPD) is a significant contributor to maternal morbidity and mortality. The Sigma-1 (σ-1) receptor has received increasing attention in recent years because of its ability to link different signaling systems and exert its function in the brain through chaperone actions, especially in neuropsychiatric disorders. YL-0919, a novel σ-1 receptor agonist developed by our institute, has shown antidepressive and anxiolytic effects in a variety of animal models, but effects on PPD have not been revealed. In the present study, excitatory/inhibitory signaling in the hippocampus was reflected by GABA and glutamate and their associated excitatory-inhibitory receptor proteins, the HPA axis hormones in the hippocampus were assessed by ELISA. Finally, immunofluorescence for markers of newborn neuron were undertaken in the dentate gyri, along with dendritic spine staining and dendritic arborization tracing. YL-0919 rapidly improves anxiety and depressive-like behavior in PPD-like mice within one week, along with normalizing the excitation/inhibition signaling as well as the HPA axis activity. YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future.

Enhancing CO2 electroreduction performance through transition metal atom doping and strain engineering in γ-GeSe: a first-principles study.

The development of electrocatalysts that exhibit stability, high activity, and selectivity for CO2 reduction reactions (CO2RR) remains a significant challenge. Single-atom catalysts (SACs) hold promise in addressing this challenge due to their high atomic utilization efficiency. In this study, we explore the potential of monolayer γ-GeSe doped with transition metals, referred to as TM@γ-GeSe, for facilitating electrocatalytic CO2RR. Among the 26 TM@γ-GeSe SACs systematically designed, we have identified four stable transition metal catalysts (TM = Rh, Pd, Pt, and Au). Mechanistic investigations into the CO2RR pathways reveal exceptional electrocatalytic activity for Rh@γ-GeSe and Pd@γ-GeSe, with limiting potentials of -0.26 and -0.35 V, respectively. Particularly, Pd@γ-GeSe exhibits outstanding product selectivity toward formic acid. The introduction of strain engineering induces modifications in the catalytic activity and selectivity of Rh@γ-GeSe. Notably, a 1% tensile strain promotes formic acid as the preferred product, thereby improving the specific product selectivity of Rh@γ-GeSe. Conversely, compressive strain reduces CO2RR activity while enhancing the hydrogen evolution reaction, leading to a decrease in CO2RR selectivity. Furthermore, we use the work function as a descriptor to elucidate the underlying mechanism of strain tunability. We hope that our theoretical study will offer valuable insights for the design of catalysts based on γ-GeSe for electrocatalytic CO2RR.

PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release.

Acute kidney injury (AKI) is a worldwide public health problem characterized by the massive loss of tubular cells. However, the precise mechanism for initiating tubular cell death has not been fully elucidated. Here, we reported that phosphoglycerate mutase 5 (PGAM5) was upregulated in renal tubular epithelial cells during ischaemia/reperfusion or cisplatin-induced AKI in mice. PGAM5 knockout significantly alleviated the activation of the mitochondria-dependent apoptosis pathway and tubular apoptosis. Apoptosis inhibitors alleviated the activation of the mitochondria-dependent apoptosis pathway. Mechanistically, as a protein phosphatase, PGAM5 could dephosphorylate Bax and facilitate Bax translocation to the mitochondrial membrane. The translocation of Bax to mitochondria increased membrane permeability, decreased mitochondrial membrane potential and facilitated the release of mitochondrial cytochrome c (Cyt c) into the cytoplasm. Knockdown of Bax attenuated PGAM5 overexpression-induced Cyt c release and tubular cell apoptosis. Our results demonstrated that the increase in PGAM5-mediated Bax dephosphorylation and mitochondrial translocation was implicated in the development of AKI by initiating mitochondrial Cyt c release and activating the mitochondria-dependent apoptosis pathway. Targeting this axis might be beneficial for alleviating AKI.

COVID-19 mRNA vaccine immunogenicity decay and breakthrough illness in adolescents and young adults with childhood-onset rheumatic diseases.

OBJECTIVES: To evaluate the humoral immunogenicity for 6 months after the two-dose coronavirus disease 2019 (COVID-19) mRNA vaccination in adolescents and young adults (AYAs) with childhood-onset rheumatic diseases (cRDs). METHODS: This monocentric observational study was conducted between August 2020 and March 2022. Humoral immunogenicity was assessed at 2-3 weeks after first vaccine dose and 1, 3 and 6 months after the second dose by the cPass™ severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization antibody (nAb) assay. An inhibition signal of ≥30% defined the seroconversion threshold and the readings were calibrated against the World Health Organization International Standard for SARS-CoV-2 antibodies. RESULTS. ONE HUNDRED AND SIXTY-NINE: AYAs with cRDs were recruited [median age 16.8 years (interquartile range, IQR 14.7-19.5), 52% female, 72% Chinese]. JIA (58%) and SLE (18%) comprised the major diagnoses. After second vaccine dose, 99% seroconverted with a median nAb titre of 1779.8 IU/ml (IQR 882.8-2541.9), declining to 935.6 IU/ml (IQR 261.0-1514.9) and 683.2 IU/ml (IQR 163.5-1400.5) at the 3- and 6-month timepoints, respectively. The diagnosis of JIA [odds ratio (OR) 10.1, 95% CI 1.8-58.4, P = 0.010] and treatment with anti-TNF-α (aTNF) (OR 10.1, 95% CI 1.5-70.0, P = 0.019) were independently associated with a >50% drop of nAb titres at 6 months. Withholding MTX or MMF did not affect the vaccine response or decay rate. The COVID-19 breakthrough infection was estimated at 18.2 cases/1000 patient-months with no clinical risk factors identified. CONCLUSION: Over half of AYAs with cRDs had a significant drop in SARS-CoV-2 nAb at 6-month despite an initial robust humoral response. JIA and aTNF usage are predictors of a faster decay rate.

Malignant transformation rate of oral leukoplakia in the past 20 years: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to assess the rate of malignant transformation (MT) of oral leukoplakia (OL) and to study potential risk factors for the MT of OL into oral squamous cell carcinoma (OSCC). METHOD: We performed a bibliographic search on nine electronic databases, including PubMed, MEDLINE, and Wanfang Data, for data on the MT rate of OL. Possible risk factors were calculated using Comprehensive Meta-Analysis and Open Meta [Analyst] software. RESULTS: The pooled proportion of OL MT for the total population described in the 26 selected studies was 7.20% (95% confidence interval: 5.40-9.10%). Nonhomogeneous type lesions, higher grades of dysplasia, the location of the lesion (tongue and multifocal), and female sex had significant effects on the MT of OL. CONCLUSION: OL tended to develop into OSCC (7.2%), and those with significant MT risk factors should be subjected to regular follow-up and observation. However, we require large-scale prospective studies to validate these results, together with unified clinicopathological diagnostic criteria, standardized risk factor recording/assessment methods, and long-term follow-up guidelines.

CO2 electroreduction performance of PtS2 supported single transition metal atoms: a theoretical study.

Electrocatalytic CO2 reduction is a sustainable strategy to convert CO2 into valuable carbon products. Atomically dispersed single-atom catalysts (SACs) have great potential as effective electrocatalysts for the CO2 reduction reaction (CO2RR). Transition metal dichalcogenides (TMDs) are considered to be a kind of promising SAC supports. In this work, ten different 3d TM single atoms (TM = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu and Zn) embedded in PtS2 with single S-vacancy (TM-PtS2) were designed by density functional theory (DFT) as candidate electrocatalysts for the CO2RR. Possible reaction pathways of CO2 reduction to different C1 products were systematically investigated. The results show that for all these TM-PtS2 SACs, higher selectivity was achieved for CO2 reduction to C1 products than for the competing hydrogen evolution. HCOOH is the most favorable reduction product on PtS2-Sv supported Sc, Ti, V, Cr, Mn, Fe and Cu SACs, while multiple C1 products are generated on Co-, Ni- and Zn-PtS2. In particular, it is found that Sc-, V-, Fe-, Co- and Cu-PtS2 exhibit higher electrocatalytic performance for the CO2RR than Cu(211). Therefore, these five SACs are promising CO2RR electrocatalysts.

Deubiquitinating enzyme USP11 promotes renal tubular cell senescence and fibrosis via inhibiting the ubiquitin degradation of TGF-ß receptor II.

Transforming growth factor-ß1 (TGF-ß1) is regarded as a key factor in promoting renal fibrosis during chronic kidney disease (CKD). Signaling transduction of TGF-ß1 starts with binding to TGF-ß type II receptor (Tgfbr2), a constitutively activated kinase that phosphorylates TGF-ß type I receptor (Tgfbr1), and then activates downstream Smad2/3 or noncanonical pathways. Previous studies show that cellular senescence is associated with the progression of CKD, and accelerated tubular cell senescence is implicated in promoting renal fibrosis. In the present study we investigated the renal parenchymal cell senescence in fibrosis from the sight of posttranslational regulation and focused on Tgfbr2, the important gatekeeper for TGF-ß1 downstream signaling. In mice with unilateral ureteral obstruction (UUO) and folic acid (FA)-induced fibrotic kidneys, we found that Tgfbr2 was markedly elevated without obvious change in its mRNA levels. As an important member of deubiquitinating enzymes, ubiquitin-specific protease 11 (Usp11) was also significantly increased in fibrotic kidneys, and co-distributed with Tgfbr2 in tubular epithelial cells. Pretreatment with Usp11 inhibitor mitoxantrone (MTX, 30 mg · kg-1 · d-1, i.p.) twice a week, for 2 weeks significantly attenuated the elevation of Tgfbr2, activation in downstream senescence-related signaling pathway, as well as renal senescence and fibrosis. In cultured mouse tubular epithelial cells (MTECs), treatment with angiotensin II (Ang-II, 10-7, 10-6 M) dose-dependently elevated both Tgfbr2 and Usp11 levels. Inhibition or knockdown on Usp11 attenuated Ang-II-induced elevation in Tgfbr2 level, and attenuated the activation of downstream senescent-related signaling pathway and as well as cell senescence. We conducted Co-IP experiments, which revealed that Usp11 was able to interact with Tgfbr2, and inhibition of Usp11 increased the ubiquitination of Tgfbr2. Taken together, these results demonstrate that the elevation of Usp11 under pathological condition is implicated in promoting renal fibrosis. Usp11 promotes the development of renal fibrosis by deubiquitinating Tgfbr2, reducing Tgfbr2 ubiquitination degradation, and then facilitating the activation of downstream senescent signaling pathway.

[Research Progress and New Immunotherapy Strategies of Tumor Microenvironment Metabolism].

The tumor microenvironment (TME), the environment of tumorigenesis and tumor progression, incorporates multiple types of cells and non-cellular components. TME plays an important role in tumorigenesis and tumor progression. Due to the abnormal proliferation of tumors, the TME has a unique chemophysiology environment and complex metabolic patterns, which subsequently affects the role of immune cells. Understanding the metabolic patterns of TME can help us develop immunotherapy regimens that target TME. Microbial metabolism and lipid metabolism, the key metabolic processes of TME, have emerged as important foci of research. The metabolites released by the microbiome and the reprogramming of cellular lipid metabolism affect the subsistence of tumor and immune cells. In this review, we summarized the composition and metabolic characteristics of TME and discussed the latest research progress in microbial metabolism and lipid metabolism in TME. We also provided an update on relevant metabolic regulatory targets and immunotherapy strategies, stressing that identifying highly effective therapeutic targets, in spite of the apparent difficulty, is what future research should be focused on.

A Significant Two-Dimensional Structural Transformation in a Coordination Polymer that Changes Its Electronic and Protonic Behavior.

A 2D-to-2D (2D: two-dimensional) structural transformation accompanying significant bond rearrangement and coordination environment change is demonstrated in a coordination polymer (CP) comprised of copper(II) ions and terephthalate (BDC2- ) ligands for the first time. When immersed in water, a free-standing membrane of 2D Cu(BDC)(DMF) (Cu-1; DMF: N,N-dimethylformamide) transforms into 2D Cu(BDC)(H2 O)2 (Cu-2) while maintaining its highly oriented layered structure. In the 2D sheet, paddlewheel-type CuII dimers coordinated with four bidentate BDC ligands in a square-planar array in Cu-1 were released to form uniform aqua-bridged CuII chains, which are cross-linked with each other by unidentate BDC ligands, in Cu-2. The present facile approach to implement the 2D-to-2D transformation accompanied by bond rearrangement, which is characteristic of CPs, leads to a marked increase in in-plane magnetic susceptibility and proton conductivity. In situ experiments in support of theoretical calculations unveiled the energy diagram that governs the unique structural transformation.

Accurate and Efficient SIMS Oxygen Isotope Analysis of Composition-Variable Minerals: Online Matrix Effect Calibration for Dolomite.

High-quality oxygen isotope analysis of composition-variable minerals (e.g., ubiquitous carbonates) using secondary ion mass spectrometry (SIMS) is extremely challenging. The classical off-line procedure, which requires additional electron probe microanalyzer (EPMA) chemical compositions for calibrating instrumental mass fractionation (IMF), is inherently inaccurate and analytically inefficient. In this study, the first accurate and paired SIMS analysis of δ18O and Fe# [molar Fe/(Mg + Fe)] in dolomite is reported. Based on five newly developed dolomite O-isotopic standards with an Fe# range of 0.01-0.35 obtained by SIMS, a novel accurate and rapid online matrix effect calibration method for dolomite O-isotope analysis was developed using concurrent SIMS 18O-16O-56Fe16O-24Mg16O measurements without additional chemical electron probe microanalysis. A logistic equation was proposed as the best-fit curve to represent the δ18O matrix effect based on the 56Fe16O/24Mg16O ratios. For CTD-4 carbonatitic dolomite with variable Fe# but homogeneous oxygen isotopes, the off-line method exhibited highly variable apparent δ18O values in the range of 5.74-10.11‰. The online method yielded a homogeneous δ18O value of 7.94 ± 0.34‰ (2SD, n = 40), which is comparable with that of bulk analysis (7.94 ± 0.20‰; 2SD). Comprehensive analyses validated the online method as the best strategy for performing accurate δ18O analysis of samples with highly heterogeneous compositions. Based on its accuracy, simplicity, and economic feasibility, this method has potential applications in the analysis of composition-complex dolomites, detrital dolomites, and other precious terrestrial and extraterrestrial materials.

Robust neutralizing antibody response to SARS-CoV-2 mRNA vaccination in adolescents and young adults with childhood-onset rheumatic diseases.

OBJECTIVES: Immunogenicity to the SARS-CoV-2 mRNA vaccines in adolescents and young adults (AYA) with childhood-onset rheumatic diseases (cRD) is unknown. We aimed to evaluate the humoral immunogenicity and safety of the vaccines in our AYA with cRD. METHODS: A monocentric observational study with 159 AYA (50.3% female and 70.4% Chinese). Humoral immunogenicity was assessed at 2-3 and 4-6 weeks following first and second vaccination by cPass™ SARS-CoV-2 Neutralization Antibody Assay. Inhibition signal of ≥30% defined the cut-off for positive detection of the SARS-CoV-2 neutralizing antibodies. Vaccine safety and disease activity were assessed within 6 weeks after second vaccination. RESULTS: A total of 64.9% and 99.1% of 159 patients (median age: 16.9, IQR: 14.7-19.5) mounted positive SARS-CoV-2 neutralizing responses after first and second vaccination, respectively. Most patients (89.8%) had ≥90% inhibition signal after second vaccination. Methotrexate and mycophenolate mofetil increased the risk associated with negative cPass neutralization responses following the first vaccination. Holding both medications after each vaccination did not affect immunogenicity. There was no symptomatic COVID-19 infection. Local reaction remained the most common (23.3-25.2%) adverse event, without serious complication. Two and seven patients flared following the first and second vaccination, respectively. Subgroup analyses of the 12-18-year-old cohort did not show any differences in vaccine efficacy, predictors of poor response and general safety, but higher proportion of disease flares. CONCLUSIONS: SARS-CoV-2 mRNA vaccines were efficacious after the two-dose regimen in almost all AYA with cRD without serious adverse event. The rate of disease flare observed is 4.4% after the second mRNA vaccine dose.

Ultra-wideband RCS reduction based on coupling effects between beam diffuse and absorptive structures.

A hybrid design method for broadband radar cross section (RCS) reduction is proposed and successfully demonstrated based on the coupling effects between diffuse and absorptive structures. The reflection energy is distributed into more directions away from the source direction by the one-bit diffuse coding metasurface (CM). The two-layer resistive frequency selective surface (RFSS) is employed in the one-bit CM structure, reducing the amplitude of the co- and cross-polarized reflected waves under circularly polarized wave incidence by converting it into ohmic loss. In addition, the bandwidth of RCS reduction is further broadened through the coupling effects between the metallic patterns and the two-layer RFSS. The coupling effect shows that the absorption rate of the composite structure is significantly improved compared to the only RFSS structure. A lightweight CM loaded with RFSS (the area density is 597 g/m2) was fabricated, analyzed, simulated, and measured. The results show that the proposed mechanism can effectively break the bandwidth constraints of traditional diffusion and absorption methods. Furthermore, the proposed mechanism significantly expands the bandwidth of RCS reduction. The proposed metasurface can achieve a 10 dB RCS reduction in an ultra-wideband from 7.3 to 44.2 GHz with about 143.3% fractional bandwidth. Moreover, the metasurface also has good performances under wide-angle oblique incidences. Under the condition of maintaining lightweight, the design provides an idea for broadening the frequency band.

ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFκB/NLRP3 pathway.

BACKGROUND: Microglia-mediated neuroinflammatory response following traumatic brain injury (TBI) is considered as a vital secondary injury factor, which drives trauma-induced neurodegeneration and is lack of efficient treatment. ACT001, a sesquiterpene lactone derivative, is reportedly involved in alleviation of inflammatory response. However, little is known regarding its function in regulating innate immune response of central nervous system (CNS) after TBI. This study aimed to investigate the role and underlying mechanism of ACT001 in TBI. METHODS: Controlled cortical impact (CCI) models were used to establish model of TBI. Cresyl violet staining, evans blue extravasation, neurobehavioral function assessments, immunofluorescence and transmission electron microscopy were used to evaluate therapeutic effects of ACT001 in vivo. Microglial depletion was induced by administering mice with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Cell-cell interaction models were established as co-culture system to simulate TBI conditions in vitro. Cytotoxic effect of ACT001 on cell viability was assessed by cell counting kit-8 and activation of microglia cells were induced by Lipopolysaccharides (LPS). Pro-inflammatory cytokines expression was determined by Real-time PCR and nitric oxide production. Apoptotic cells were detected by TUNEL and flow cytometry assays. Tube formation was performed to evaluate cellular angiogenic ability. ELISA and western blot experiments were used to determine proteins expression. Pull-down assay was used to analyze proteins that bound ACT001. RESULTS: ACT001 relieved the extent of blood-brain barrier integrity damage and alleviated motor function deficits after TBI via reducing trauma-induced activation of microglia cells. Delayed depletion of microglia with PLX5622 hindered therapeutic effect of ACT001. Furthermore, ACT001 alleviated LPS-induced activation in mouse and rat primary microglia cells. Besides, ACT001 was effective in suppressing LPS-induced pro-inflammatory cytokines production in BV2 cells, resulting in reduction of neuronal apoptosis in HT22 cells and improvement of tube formation in bEnd.3 cells. Mechanism by which ACT001 functioned was related to AKT/NFκB/NLRP3 pathway. ACT001 restrained NFκB nuclear translocation in microglia cells through inhibiting AKT phosphorylation, resulting in decrease of NLRP3 inflammasome activation, and finally down-regulated microglial neuroinflammatory response. CONCLUSIONS: Our study indicated that ACT001 played critical role in microglia-mediated neuroinflammatory response and might be a novel potential chemotherapeutic drug for TBI. Video Abstract.

Hydrogen Sulfide Diminishes Activation of Adventitial Fibroblasts Through the Inhibition of Mitochondrial Fission.

ABSTRACT: Activation of adventitial fibroblasts (AFs) on vascular injury contributes to vascular remodeling. Hydrogen sulfide (H2S), a gaseous signal molecule, modulates various cardiovascular functions. The aim of this study was to explore whether exogenous H2S ameliorates transforming growth factor-ß1 (TGF-ß1)-induced activation of AFs and, if so, to determine the underlying molecular mechanisms. Immunofluorescent staining and western blot were used to determine the expression of collagen I and α-smooth muscle actin. The proliferation and migration of AFs were performed by using cell counting Kit-8 and transwell assay, respectively. The mitochondrial morphology was assessed by using MitoTracker Red staining. The activation of signaling pathway was evaluated by western blot. The mitochondrial reactive oxygen species and mitochondrial membrane potential were determined by MitoSOX and JC-1 (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolyl carbocyanine iodide) staining. Our study demonstrated exogenous H2S treatment dramatically suppressed TGF-ß1-induced AF proliferation, migration, and phenotypic transition by blockage of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and regulated mitochondrial reactive oxygen species generation. Moreover, exogenous H2S reversed TGF-ß1-induced mitochondrial fission and AF activation by modulating Rho-associated protein kinase 1-dependent phosphorylation of Drp1. In conclusion, our results suggested that exogenous H2S attenuates TGF-ß1-induced AF activation through suppression of Drp1-mediated mitochondrial fission in a Rho-associated protein kinase 1-dependent fashion.

Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexin1 in acute kidney disease.

Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) in clinic. The activation of NLRP3 inflammasome is associated with inflammation and renal injury in I/R-induced AKI. In the current study we explored the molecular and cellular mechanisms for NLRP3 inflammasome activation following renal I/R. Mice were subjected to I/R renal injury by clamping bilateral renal pedicles. We showed that I/R injury markedly increased caspase-11 expression and the cleavage of pannexin 1 (panx1) in the kidneys accompanied by NLRP3 inflammasome activation evidenced by the activation of caspase-1 and interlukin-1ß (IL-1ß) maturation. In Casp-11-/- mice, I/R-induced panx1 cleavage, NLRP3 inflammasome activation as well as renal functional deterioration and tubular morphological changes were significantly attenuated. In cultured primary tubular cells (PTCs) and NRK-52E cells, hypoxia/reoxygenation (H/R) markedly increased caspase-11 expression, NLRP3 inflammasome activation, IL-1ß maturation and panx1 cleavage. Knockdown of caspase-11 attenuated all those changes; similar effects were observed in PTCs isolated from Casp-11-/- mice. In NRK-52E cells, overexpression of caspase-11 promoted panx1 cleavage; pretreatment with panx1 inhibitor carbenoxolone or knockdown of panx1 significantly attenuated H/R-induced intracellular ATP reduction, extracellular ATP elevation and NLRP3 inflammasome activation without apparent influence on H/R-induced caspase-11 increase; pretreatment with P2X7 receptor inhibitor AZD9056 also attenuated NLRP3 inflammasome activation. The above results demonstrate that the cleavage of panx1 by upregulated caspase-11 is involved in facilitating ATP release and then NLRP3 inflammasome activation in I/R-induced AKI. This study provides new insight into the molecular mechanism of NLRP3 inflammasome activation in AKI.

[Identification of key enzyme genes involved in biosynthesis pathways of lignan and lignin in Eucommia ulmoides based on transcriptome assembly].

Lignan is the main medicinal component of Eucommia ulmoides, and lignin is involved in the defense of plants against diseases and insect pests.They are synthesized from coniferyl alcohol with the help of dirigent(DIR) and peroxidase(POD), respectively.In this study, transcriptome assembly of stems and leaves of E.ulmoides was performed, yielding 112 578 unigenes.Among them, 70 459 were annotated in seven databases.A total of 59 unigenes encodes 11 key enzymes in the biosynthesis pathways of lignin and lignin, of which 11 encode POD and 8 encode DIR.A total of 13 unigenes encoding transcription factors are involved in phenylpropanoid metabolism. Compared with leaves of E.ulmoides, 7 575 unigenes were more highly expressed in stems, of which 462 were involved in phenylpropanoid biosynthesis.Our results extend the public transcriptome dataset of E.ulmoides, which provide valuable information for the analysis of biosynthesis pathways of lignan and lignin in E.ulmoides and lay a foundation for further study on the functions and regulation mechanism of key enzymes in lignan and lignin biosynthesis pathways.

Reversible One- to Two- to Three-Dimensional Transformation in CuII Coordination Polymer.

A reversible transformation between 1D, 2D, and 3D is demonstrated for the first time in coordination polymers comprising CuII ions and bidentate terephthalate (BDC2- ). 1D uniform chains were reversibly transformed into 2D layers with the construction of Cu-paddlewheels by eliminating water molecules. 2D/3D reversible transformation was achieved by removing/rebinding N,N-dimethylformamide coordinated to the paddlewheels. These dimensional transformations significantly changed chemical and physical properties such as gas sorption and magnetism. Although the uptake in open-framework 1D and 2D Cu-BDC was insignificant, pronounced absorption was observed for 3D Cu-BDC. Drastic difference in magnetic behavior is consistent with their coordination structures; uniform 1D chain of CuII in 1D Cu-BDC and 2D sheet based on CuII -paddlewheel dimers in 2D Cu-BDC. Ferromagnetic behavior observed in air-exposed 3D Cu-BDC is attributed to the 3D structure formed by the connection of 2D sheets.