Efficient Sodium Storage in Cu1.96S@NC Anode Achieved by Robust S─C Bonds and Current Collector Self-Induced Forming Cu2S Quantum Dots.

Transition metal sulfides are investigation hotspots of anode material for sodium-ion batteries (SIBs) due to their structural diversity and high storage capacity. However, they are still plagued by inevitable volume expansion during sodiation/desodiation and an unclear energy storage mechanism. Herein, a one-step sulfidation-carbonization strategy is proposed for in situ confined growth of Cu1.96S nanoparticles in nitrogen-doped carbon (Cu1.96S@NC) using octahedral metal-organic framework (Cu-BTC) as a precursor and investigate the driving effect of Cu current collector on its sodium storage. The generation of S─C bonds in Cu1.96S@NC avoids the volume change and structural collapse of Cu1.96S nanoparticles during the cycling process and improves the adsorption and transport capacity of the material for Na+. More exciting, the Cu species in the Cu current collector are self-induced forming Cu2S quantum dots to enter the original anode material during the initial few charging and discharging cycles, which unique small-size effect and abundant edge-active sites enhance the energy storage capacity of Cu1.96S. Thus, the Cu1.96S@NC exhibits a superior first discharge capacity of 608.56 mAh g-1 at 0.2 A g-1 with an initial Coulomb efficiency (ICE) of 75.4%, as well as provides excellent rate performance and long cycle durability up to 2000 cycles.

Applications of MRI in Schizophrenia: Current Progress in Establishing Clinical Utility.

Schizophrenia is a severe mental illness that significantly impacts the lives of affected individuals and with increasing mortality rates. Early detection and intervention are crucial for improving outcomes but the lack of validated biomarkers poses great challenges in such efforts. The use of magnetic resonance imaging (MRI) in schizophrenia enables the investigation of the disorder's etiological and neuropathological substrates in vivo. After decades of research, promising findings of MRI have been shown to aid in screening high-risk individuals and predicting illness onset, and predicting symptoms and treatment outcomes of schizophrenia. The integration of machine learning and deep learning techniques makes it possible to develop intelligent diagnostic and prognostic tools with extracted or selected imaging features. In this review, we aimed to provide an overview of current progress and prospects in establishing clinical utility of MRI in schizophrenia. We first provided an overview of MRI findings of brain abnormalities that might underpin the symptoms or treatment response process in schizophrenia patients. Then, we summarized the ongoing efforts in the computer-aided utility of MRI in schizophrenia and discussed the gap between MRI research findings and real-world applications. Finally, promising pathways to promote clinical translation were provided. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Patumantanes A-D, seco-Polycyclic Polyprenylated Acylphloroglucinols with Diverse Carbon Skeletons from Hypericum patulum.

Patumantanes A-D (1-4), four new seco-polycyclic polyprenylated acylphloroglucinols (PPAPs) were isolated from Hypericum patulum. Patumantane A (1) was an unprecedented 1,2-seco-homoadamantane-type PPAP bearing a new 3,7-dioxatetracyclo[7.7.0.01,6.111,15]heptadecane architecture based on a 6/7/5/6 ring system. Patumantane B (2) was a unique 1,9-seco-adamantane-type PPAP with a tricyclo[4.4.4.0.02,12]tridecane core formed by a 6/6/6 carbon skeleton, and the further breakage between C-5 and C-9 decorated patumantane C (3) with the 9-nor-adamantane skeleton. More importantly, compounds 2 and 3 exhibited moderate immunosuppressive activity on Con A-induced T-lymphocyte proliferation in vitro, with IC50 values of 5.6 ± 1.2 and 11.2 ± 1.2 µM, respectively.

Discovery of adamantane-type polycyclic polyprenylated acylphloroglucinols that can prevent concanavalin A-induced autoimmune hepatitis in mice.

Hyperadamans A-G (1-7), seven new adamantane type polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from Hypericum wilsonii N. Robson. Structurally, 1-4 were the first adamantanes bearing an unusual 2,7-dioxabicyclo-[2.2.1]-heptane fragment, and compound 5 was the first adamantane with a rare 1,6-dioxaspiro[4.4]nonane section. Importantly, 1-7 exhibited significant immunosuppressive activity on Con A-induced T-lymphocyte proliferation in vitro, with IC50 values ranging from 3.97 ± 0.10 to 18.12 ± 1.07 µM. Pretreatment with 1 in Con A-challenged autoimmune hepatitis mice could dramatically ameliorate the levels of hepatic injury indexes (ALT and AST) and reduce the product of proinflammatory cytokines (COX-2, IL-6, IL-1ß, IL-18, IL-23A and TNF-α). Furthermore, the protective effect of 1 on the Con A-induced liver injury was corroborated by the histological analysis and the immunohistochemistry.

Radiomic features of gray matter in never-treated first-episode schizophrenia.

Alterations of radiomic features (RFs) in gray matter are observed in schizophrenia, of which the results may be limited by small study samples and confounding effects of drug therapies. We tested for RFs alterations of gray matter in never-treated first-episode schizophrenia (NT-FES) patients and examined their associations with known gene expression profiles. RFs were examined in the first sample with 197 NT-FES and 178 healthy controls (HCs) and validated in the second independent sample (90 NT-FES and 74 HCs). One-year follow-up data were available from 87 patients to determine whether RFs were associated with treatment outcomes. Associations between identified RFs in NT-FES and gene expression profiles were evaluated. NT-FES exhibited alterations of 30 RFs, with the greatest involvement of microstructural heterogeneity followed by measures of brain region shape. The identified RFs were mainly located in the central executive network, frontal-temporal network, and limbic system. Two baseline RFs with the involvement of microstructural heterogeneity predicted treatment response with moderate accuracy (78% for the first sample, 70% for the second sample). Exploratory analyses indicated that RF alterations were spatially related to the expression of schizophrenia risk genes. In summary, the present findings link brain abnormalities in schizophrenia with molecular features and treatment response.

First Report of Root Collar Canker Caused by Neoscytalidium dimidiatum on Jacaranda mimosifolia in China.

Jacaranda mimosifolia is widely cultivated as a garden ornamental tree. In July 2023, an unknown root collar canker of J. mimosifolia was discovered in green belts of Qingxiu District, Nanning, China, with a 8% incidence rate. Crowns of affected trees ranged from reddish brown leaves to deciduous or dead. Root collar tissue became necrotic matched by underbark dark brown lesions with irregular margins, and rotted at last. Six diseased plants distributed within 3000 m2 were choosed, and 24 root collar tissues were surface sterilized and placed on potato dextrose agar (PDA) plates to incubate at 28℃ for 3 to 5 days. Same colonies were consistently isolated from 18 tissues, and three isolates (M3-B1-1, M3-B1-2 and M3-B1-3) were purified for morphological and molecular determination. These isolates formed colonies with lush aerial mycelia rapidly, which covered a 90 mm plate in 72h. The colonies were initially white, then grayish-green to black. Arthrospores were colourless to light brown, short columnar, aseptate, truncate base, averaging 12.1±2.5 µm × 3.4±0.7 µm, sometimes formed arthric chains. Chlamydospores were dark brown, round or oval, aseptate, averaging 8.7±1.6 µm × 5.0±0.9 µm. Mature pycnidia and conidia produced for about 50 days on oatmeal agar medium (OMA), and conidia were colorless, oblong, aseptate, averaging 11.2±1.2 µm × 6.0±1.4 µm. These morphological characteristics were consistent with the description of Neoscytalidium dimidiatum (Penz.) Crous & Slippers (Crous et al. 2006). Genomic DNA was extracted from three isolates. The partial ITS region, TUB2 and TEF1-α genes were amplified (White et al., 1990; Glass and Donaldson 1995; Carbone and Kohn 1999). The sequences were deposited in GenBank (ITS: PP939650-PP939652; TUB2: PP942728-PP942730; TEF1-α: PP942731-PP942733). Blastn analysis revealed that ITS sequences of three isolates showed 99.8%, 100%, 100% identity (506 bp out of 507 bp, 507 bp out of 507 bp, 507 bp out of 507 bp) to N. dimidiatum C21 (KX447539), the TUB2 sequences showed 100% identity (436 bp out of 436 bp, 437 bp out of 437 bp, 437 bp out of 437 bp) to N.dimidiatum LNeo (ON099066), and the TEF1-α sequences showed 99.64% identity (276 bp out of 277 bp) to N.dimidiatum ARM230 (MK495384), respectively. Phylogenetic analysis based on concatenated ITS, TUB2 and TEF1-α sequences showed that three isolates were clustered into the same clade as N. dimidiatum. To fulfill Koch's postulates, pathogenicity of these isolates was tested on healthy two-year-old J. mimosifolia trees. Stem and root collar were wounded and placed mycelial plugs (8mm), and the inoculation sites were wrapped with parafilm or covered with nursery substrate to maintain the humidity. Four plants were inoculated with each isolate. As a control, four plants were inoculated with noncolonized PDA plugs. All treated plants were kept in a greenhouse at 28 ± 3°C and 70% relative humidity. Foliar blight and necrotic lesions around inoculation points were observed about 65 days after inoculation, and 50% of inoculated trees exhibited symptoms, whereas the control trees remained symptomless. Neoscytalidium dimidiatum was successfully reisolated from symptomatic tissue via morphological analysis. To our knowledge, this is the first report of root collar canker caused by N. dimidiatum on J. mimosifolia. Neoscytalidium dimidiatum has a wide range of hosts, including pitaya, pine, mulberry, pear, grape, locust tree (Luo et al. 2024). This finding will help in controlling of the disease epidemic.

CT hyperdense lesions after endovascular therapy in acute ischemic stroke: imaging findings and clinical significance.

Background The hyperdense lesion on non-contrast CT (NCCT) is a common postoperative phenomenon in acute ischemic stroke (AIS) patients who are treated with endovascular therapy (EVT). Both contrast extravasation and hemorrhagic transformation presented hyperdense lesions on NCCT, which are sometimes difficult to distinguish them. Summary of Review Radiographic findings are important for identifying contrast extravasation and hemorrhagic transformation. We recommended a standardized follow-up protocol involving imaging and clinical evaluation as it will allow neurologists and neuroradiologists to reveal the relationships between these hyperdensities and various clinical outcomes. Key Messages Dual-energy CT and susceptibility weighted imaging are capable of distinguishing contrast extravasation and hemorrhagic transformation at an early stage after EVT. However, in institutions without access to such technology, a follow-up protocol based on NCCT is crucial.

Discovery of ergosterol derivative from Aspergillus sp. TJ507 that protects against hepatic ischemia/reperfusion injury.

Hepatic ischemia/reperfusion injury is a major cause of hypohepatia after surgical procedures such as hypovolemic shock, transplantation, and so on. In our continuous study of bioactive natural products from fungus, eight ergosterol-type sterides (1-8), including two undescribed compounds, sterolaspers A (1) and B (2), were isolated from Aspergillus sp. TJ507. Structure elucidation was accomplished by extensive spectroscopic analysis and comparison with the reported NMR data as well as X-Ray single crystal diffraction tests. Activity screen of these isolates showed 5α-stigmast-3,6-dione (3) possessing anti-hypoxia injury effects against CoCl2-induced hypoxia damage in hepatocytes. More importantly, compound 3 could improve liver function, alleviate liver damage, and restrain the hepatocellular apoptosis in hepatic ischemia/reperfusion injury murine model. As such, this ergosterol-type steride, 5α-stigmast-3,6-dione (3), might serve as lead structure for the development of novel hepatoprotective agents in the clinical treatment of hepatic ischemia/reperfusion injury.

UGCG modulates heart hypertrophy through B4GalT5-mediated mitochondrial oxidative stress and the ERK signaling pathway.

Mechanical pressure overload and other stimuli often contribute to heart hypertrophy, a significant factor in the induction of heart failure. The UDP-glucose ceramide glycosyltransferase (UGCG) enzyme plays a crucial role in the metabolism of sphingolipids through the production of glucosylceramide. However, its role in heart hypertrophy remains unknown. In this study, UGCG was induced in response to pressure overload in vivo and phenylephrine stimulation in vitro. Additionally, UGCG downregulation ameliorated cardiomyocyte hypertrophy, improved cardiomyocyte mitochondrial oxidative stress, and reduced the ERK signaling pathway. Conversely, UGCG overexpression in cardiomyocytes promoted heart hypertrophy development, aggravated mitochondrial oxidative stress, and stimulated ERK signaling. Furthermore, the interaction between beta-1,4-galactosyltransferase 5 (B4GalT5), which catalyses the synthesis of lactosylceramide, and UGCG was identified, which also functions as a synergistic molecule of UGCG. Notably, limiting the expression of B4GalT5 impaired the capacity of UGCG to promote myocardial hypertrophy, suggesting that B4GalT5 acts as an intermediary for UGCG. Overall, this study highlights the potential of UGCG as a modulator of heart hypertrophy, rendering it a potential target for combating heart hypertrophy.

Influencing Factors of Recurrence of Lumbar Disc Herniation After Percutaneous Transforaminal Endoscopic Discectomy: A Meta-Analysis.

Background: Lumbar disc herniation (LDH) remains one of the extremely common diseases in the elderly population, and despite the fact that percutaneous transforaminal endoscopic discectomy (PTED) can be an effective treatment for LDH, prognostic recurrence of the patients is still a clinical problem that needs to be addressed. Objective: To perform a meta-analysis of the influencing factors of disease recurrence after PTED for LDH to provide evidence for clinical practice. Methods: By screening the PubMed, EMbase, and Cochrane Library databases for relevant studies on disease recurrence after PTED for LDH, we extracted the authors, publication time, outcome measures, and other indicators were extracted for meta-analyses using RevMan 5.3 software. Results: The online retrieval and rigorous screening returned 8 valid articles for analysis, all with high reference value, as their Newcastle Ottawa Scale (NOS) scores were above 6. According to meta-analyses, there were no differences in gender and LDH type and location among patients with LDH recurrence after PTED treatment (P > .05); however, statistical significance was present in Pfirrmann grading, incomplete nucleus pulposus removal during surgery, and Modic changes (P < .05), indicating that these indexes were the influencing factors of LDH recurrence. Conclusions: Pfirrmann grading, incomplete nucleus pulposus removal during surgery, and Modic changes are related factors affecting LDH recurrence after PTED.

Residue dynamics of florpyrauxifen-benzyl and its effects on bacterial community structure in paddy soil of Northeast China.

Florpyrauxifen-benzyl is an herbicide that has been developed in recent years. Its degradation mode in paddy soil environments is not clear. In this study, the degradation dynamics in paddy soil and water were studied by ultrahigh-performance liquid chromatography. Microbial degradation was the main degradation pathway. Using third-generation high-throughput sequencing technology, the changes in the soil bacterial community structure were studied. After 30 days of application, compared with the control group (F0), the abundance of Sphingomonas, Lysobacter, and Flavisolibacter in the recommended and repeated application groups (F1, F5 and F10) increased significantly, and uncultured bacterium and Terrimonas decreased significantly. Compared with the F0 and F1 groups, the species diversity of the F0 and F1 groups showed a significant increase over time. The species diversity of the F5 and F10 groups decreased significantly on Days 5 and 15. On Day 30, the recovery even exceeded that of the control group. Luteimonas and five other genera were positively correlated with herbicide residues, and Pseudolabrys and two other genera were negatively correlated. Repeated application showed a significant effect on the structure of the soil bacterial community, mainly showing a trend of a significant decrease in the initial stage and gradual recovery in the later stage. The results will guide the safe and rational use of florpyrauxifen-benzyl and provide a scientific basis for florpyrauxifen-benzyl dynamic supervision of environmental pollution and protection of black soil in Northeast China.

[Alcohol extract of root and root bark of Toddalia asiatica alleviates CIA in rats through anti-inflammatory and proapoptotic effects].

This study aims to investigate the therapeutic effect of alcohol extract of root and root bark of Toddalia asiatica(TAAE) on collagen-induced arthritis(CIA) in rats through phosphatidylinoinosidine-3 kinase/protein kinase B(PI3K/Akt) signaling pathway. To be specific, CIA was induced in rats, and then the rats were treated(oral, daily) with TAAE and Tripterygium Glycoside Tablets(TGT), respectively. The swelling degree of the hind leg joints was scored weekly. After 35 days of administration, the histopathological changes were observed based on hematoxylin and eosin(HE) staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the levels of cytokines [tumor necrosis factor-α(TNF-α), interleukin(IL)-6)]. Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) staining was performed to detect the apoptosis of synoviocytes in rats. Western blot was used to detect the expression levels of apoptosis-related proteins B-cell lymphoma 2(Bcl-2)-associated X(Bax), Bcl-2, and caspase-3 and pathway-related proteins phosphoinositide 3-kinase(PI3K), phosphorylated(p)-PI3K, protein kinase B(Akt), and p-Akt. RT-qPCR was conducted to examine the mRNA levels of Bax, Bcl-2, caspase-3, TNF-α, IL-6, and IL-1ß and pathway-related proteins PI3K, p-PI3K, Akt, and p-Akt. TAAE can alleviate the joint swelling in CIA rats, reduce serum levels of inflammatory cytokines, improve synovial histopathological changes, promote apoptosis of synoviocytes, and inhibit synovial inflammation. In addition, RT-qPCR and Western blot results showed that TAAE up-regulated the level of Bax, down-regulated the level of Bcl-2, and activated caspase-3 to promote apoptosis in synoviocytes. TAAE effectively down-regulated the protein levels of p-PI3K and p-Akt. In this study, TAAE shows therapeutic effect on CIA in rats and reduces the inflammation. The mechanism is that it suppresses PI3K/Akt signaling pathway and promotes synoviocyte apoptosis. Overall, this study provides a new clue for the research on the anti-inflammatory mechanism of TAAE and lays a theoretical basis for the better clinical application of TAAE in the treatment of inflammatory and autoimmune diseases.

Characterization of white-light non-diffracting beams generated using a deformable mirror.

White-light non-diffraction beams such as Airy beam and Bessel beam have potential applications in multispectral imaging and micromanipulation. Generation of white-light Airy beam and Bessel beam with high quality and high efficiency still remains challenging for conventional diffractive or refractive optics which suffers from significant chromatic dispersion. In this paper, both high-quality white-light Airy beam and Bessel beam are generated using a deformable mirror by modulating the incident LED beam with tunable cubic and conical wavefronts. The main lobe of the generated white-light non-diffraction beams does not suffer from chromatic dispersion along the propagation. The results also show that the generation of the white-light Bessel beam has higher requirements for spatial coherence than white-light Airy beams. Our work expands the understanding of the white-light non-diffraction beams and paves the way for the applications.

The Tumor-Suppressive Human Circular RNA CircITCH Sponges miR-330-5p to Ameliorate Doxorubicin-Induced Cardiotoxicity Through Upregulating SIRT6, Survivin, and SERCA2a.

RATIONALE: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is restricted because it poses a risk of severe cardiotoxicity. Previous work has established that CircITCH (circular RNA ITCH [E3 ubiquitin-protein ligase]) is a broad-spectrum tumor-suppressive circular RNA and that its host gene, ITCH (E3 ubiquitin protein ligase), is involved in doxorubicin-induced cardiotoxicity (DOXIC). Whether CircITCH plays a role in DOXIC remains unknown. OBJECTIVE: We aimed to dissect the role of CircITCH in DOXIC and further decipher its potential mechanisms. METHODS AND RESULTS: Circular RNA sequencing was performed to screen the potentially involved circRNAs in DOXI pathogenesis. Quantitative polymerase chain reaction and RNA in situ hybridization revealed that CircITCH was downregulated in doxorubicin-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in the autopsy specimens from cancer patients who suffered from doxorubicin-induced cardiomyopathy. Cell death/viability assays, detection of cardiomyocyte necrosis markers, microelectrode array, and cardiomyocyte functional assays revealed that CircITCH ameliorated doxorubicin-induced cardiomyocyte injury and dysfunction. Detection of cellular/mitochondrial oxidative stress and DNA damage markers verified that CircITCH alleviated cellular/mitochondrial oxidative stress and DNA damage induced by doxorubicin. RNA pull-down assays, Ago2 immunoprecipitation and double fluorescent in situ hybridization identified miR-330-5p as a direct target of CircITCH. Moreover, CircITCH was found to function by acting as an endogenous sponge that sequestered miR-330-5p. Bioinformatic analysis, luciferase reporter assays, and quantitative polymerase chain reaction showed that SIRT6 (sirtuin 6), BIRC5 (baculoviral IAP repeat containing 5, Survivin), and ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2, SERCA2a [SR Ca2+-ATPase 2]) were direct targets of miR-330-5p and that they were regulated by the CircITCH/miR-330-5p axis in DOXIC. Further experiments demonstrated that CircITCH-mediated alleviation of DOXIC was dependent on the interactions between miR-330-5p and the 3'-UTRs of SIRT6, BIRC5, and ATP2A2 mRNA. Finally, AAV9 (adeno-associated virus serotype 9) vector-based overexpression of the well-conserved CircITCH partly prevented DOXIC in mice. CONCLUSIONS: CircITCH represents a novel therapeutic target for DOXIC because it acts as a natural sponge of miR-330-5p, thereby upregulating SIRT6, Survivin and SERCA2a to alleviate doxorubicin-induced cardiomyocyte injury and dysfunction.

Discovery of 13,15-nor-polycyclic polyprenylated acylphloroglucinols from Hypericum longistylum with anti-inflammatory activity.

Spihyperglucinols A (1) and B (2), the first 13,15-nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) featuring a 7/6/5 tricyclic ring system based on an unexpected bicyclo[3.2.2]nonane core, along with three new congeners, spihyperglucinols C-E (3-5), were isolated from Hypericum longistylum. Importantly, 1 and 2 displayed potential inhibitory effects on the production of nitric oxide in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, with IC50 values of (8.70 ± 1.18) and (9.23 ± 1.26) µM, respectively, comparable to the positive control, dexamethasone, with an IC50 value of (9.76 ± 1.13) µM.

Isolation of a degrading strain of Fusarium verticillioides and bioremediation of glyphosate residue.

Glyphosate is a broad-spectrum and nonselective organophosphorus herbicide that inhibits 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), an enzyme in the shikimate pathway in plants. A glyphosate-resistant fungus identified as Fusarium verticillioides was screened from soil subjected to long-term glyphosate application, and this fungus could grow in inorganic salt medium containing 90 mmol/L glyphosate. The optimum culture conditions identified via the response surface curve method were 28 °C and pH 7.0. The target gene epsps was cloned in this study, and the open reading frame contained 1170 nucleotides and putatively encoded 389 amino acid residues. Phylogenetic analysis showed that this gene belonged to class I, genes naturally sensitive to glyphosate. q-PCR confirmed that the relative expression level of the epsps gene was low, and no significant difference in expression was observed among different glyphosate concentrations at 12 h or 48 h. On day 28, the degradation by Fusarium verticillioides C-2 of sterilized soil and unsterilized soil supplemented with 60 mg/kg glyphosate reached 72.17% and 89.07%, respectively, and a significant difference was observed between the treatments with and without the glyphosate-degrading strain. The recovery of soil dehydrogenase activity after the addition of Fusarium verticillioides was significantly higher than that in the absence of the degrading fungus on the 28th day. The results showed that C-2 is a highly effective glyphosate-degrading strain with bioremediation potential for glyphosate-contaminated soil.

BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells.

Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9-mediated internalization of ALK-1, BMP-9-dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9-induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9-mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.

miR-145 attenuates cardiac fibrosis through the AKT/GSK-3ß/ß-catenin signaling pathway by directly targeting SOX9 in fibroblasts.

Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA-145 (miR-145) and transcription factor sex-determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI-induced fibrosis. Flow cytometry, cell counting kit-8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR-145 expression was measured by quantitative real-time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham-operated group, the expression of miR-145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR-145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR-145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR-145. Overexpression of miR-145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR-145 or suppression of SOX9 inhibited AKT and ß-catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR-145, and our findings indicate that miR-145 exerts anti-fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK-3ß/ß-catenin pathways.

Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/ß-catenin pathway.

OBJECTIVE: The glucocorticoid receptor (GR) is a member of the nuclear receptor family that controls key biological processes in the cardiovascular system and has recently been shown to modulate Wnt signaling in endothelial cells. Wnt/ß-catenin signaling has been demonstrated to be crucial in the process of angiogenesis. In the current study, we studied whether GR could regulate angiogenesis via the Wnt/ß-catenin pathway. APPROACH AND RESULTSA: Key components of the Wnt/ß-catenin pathway were evaluated using quantitative PCR and Western blot in the presence or absence of GR. Enhanced angiogenesis was found in GR deficiency in vitro and confirmed with cell viability assays, proliferation assays and tube formation assays. Consistent with these in vitro findings, endothelial cell-specific GR loss GR in vivo promoted angiogenesis in both a hind limb ischemia model and sponge implantation assay. Results were further verified in a novel mouse model lacking endothelial LRP5/6, a key receptor in canonical Wnt signaling, and showed substantially suppressed angiogenesis using these same in vitro and in vivo assays. To further investigate the mechanism of GR regulation of Wnt signaling, autophagy flux was investigated in endothelial cells by visualizing auto phagolysosomes as well as by assessing P62 degradation and LC3B conversion. Results indicated that potentiated autophagy flux participated in GR-Wnt regulation. CONCLUSIONS: Lack of endothelial GR triggers autophagy flux, leads to activation of Wnt/ß-catenin signaling and promotes angiogenesis. There may also be a synergistic interaction between autophagy and Wnt/ß-catenin signaling.

Characteristics of the corpus callosum in chronic schizophrenia treated with clozapine or risperidone and those never-treated.

BACKGROUND: The corpus callosum (CC) deficits have been well documented in chronic schizophrenia. However, the long-term impacts of antipsychotic monotherapies on callosal anatomy remain unclear. This cross-sectional study sought to explore micro- and macro-structural characteristics of the CC in never-treated patients and those with long-term mono-antipsychotic treatment. METHODS: The study included 23 clozapine-treated schizophrenia patients (CT-SCZ), 19 risperidone-treated schizophrenia patients (RT-SCZ), 23 never-treated schizophrenia patients (NT-SCZ), and 35 healthy controls (HCs). High resolution structural images and diffusion tensor imaging (DTI) data for each participant were obtained via a 3.0 T MR scanner. FreeSurfer was used to examine the volumes and fractional anisotropy (FA) values of the CC for each participant. RESULTS: There were significant deficits in the total and sub-regional CC volume and white matter integrity in NT-SCZ in comparison with healthy subjects. Compared with NT-SCZ, both CT-SCZ and RT-SCZ showed significantly increased FA values in the anterior CC region, while only RT-SCZ showed significantly increased volume in the mid-anterior CC region. Moreover, the volume of the mid-anterior CC region was significantly smaller in CT-SCZ compared to HCs. No correlations of clinical symptoms with callosal metrics were observed in schizophrenia patients. CONCLUSIONS: Our findings provide insight into micro- and macro-structural characteristics of the CC in chronic schizophrenia patients with or without antipsychotics. These results suggest that the pathology itself is responsible for cerebral abnormalities in schizophrenia and that chronic exposure to antipsychotics may have an impact on white matter structure of schizophrenia patients, especially in those with risperidone treatment.