[Inhibition of glutamatergic neurons in the dorsomedial periaqueductal gray alleviates excessive defensive behaviors of mice with post-traumatic stress disorder].

OBJECTIVE: To investigate the role of glutamatergic neurons in the dorsomedial periaqueductal grey (dmPAG) in regulating excessive defensive behaviors in mice with post-traumatic stress disorder (PTSD). METHODS: Eight-week-old male C57BL/6 mice were subjected to stereotactic injections of different recombinant adeno- associated viral vectors (rAAV2/9-CaMKII-mCherry, rAAV2/9-CaMKII-hM3Dq-mCherry and rAAV2/9-CaMKII-hM4Di-mCherry) into the bilateral dmPAG for chemogenetic activation or inhibition of the glutamatergic neurons, followed 2 weeks later by PTSD modeling by single prolonged stress. The looming test, response to whisker stimulation test and contextual fear conditioning (CFC) test were used to observe changes in defensive behaviors of the PTSD mice. The activity of glutamatergic neurons in the dmPAG were observed using immunofluorescence staining. RESULTS: Compared with the control mice, the mouse models of PTSD showed a shortened latency of flights with increased time spent in the nest, response scores of defensive behaviors and freezing time (all P<0.01). Immunofluorescence staining revealed significantly increased c-fos-positive glutamatergic neurons in the dmPAG of PTSD mice with defensive behaviors. Activation of the glutamatergic neurons in the dmPAG (in PTSD hM3Dq group) did not cause significant changes in the latency of flights or time in nest but obviously increased response scores of defensive behaviors and freezing time of the mice, whereas inhibiting the glutamatergic neurons in the dmPAG (in PTSD hM4Di group) caused the reverse changes and obviously alleviated defensive behaviors in the PTSD mice (P<0.05 or 0.01). CONCLUSION: Inhibiting the activity of glutamatergic neurons in the dmPAG can alleviate defensive behaviors in mice with PTSD.

Efficacy and safety of bicyclol for treating patients with antituberculosis drug-induced liver injury.

BACKGROUND: Bicyclol was used for treating idiosyncratic acute drug-induced liver injury (DILI) in a phase II trial. This study was aimed at evaluating the efficacy and safety of bicyclol 25 and 50 mg thrice a day (TID) for treating acute DILI caused by anti-TB drugs in the light of the trial results.METHODS: We analysed clinical data of patients with TB drug-induced DILI in the trial database. The primary endpoint was reduction in serum alanine aminotransferase (ALT) levels after 4 weeks of treatment compared to baseline.RESULTS: Overall, 148 patients were included, with respectively 48, 52 and 48 patients included in the control (456 mg polyene phosphatidylcholine TID), high-dose (50 mg bicyclol TID) and low-dose (25 mg bicyclol TID) groups. ALT levels decreased by respectively â-"149.0 (IQR â-"299.3 to â-"98.3 (), â-"225.5 (IQR â-"309.3 to â-"181.8 ) and â-"242.5 (IQR â-"364.8 to â-"153.8) U/L in the control, high-dose and low-dose groups (P < 0.001). The ALT normalisation rates at weeks 1, 2, 4, 6 and 8 were higher in the high- and low-dose groups, while adverse events and serious adverse events were similar across groups.CONCLUSIONS: Bicyclol (25 and 50 mg TID) is effective and safe in treating anti-TB DILI, and bicyclol 50 mg TID showed higher efficacy.

Graph neural networks for the identification of novel inhibitors of a small RNA.

MicroRNAs (miRNAs) play a crucial role in post-transcriptional gene regulation and have been implicated in various diseases, including cancers and lung disease. In recent years, Graph Neural Networks (GNNs) have emerged as powerful tools for analyzing graph-structured data, making them well-suited for the analysis of molecular structures. In this work, we explore the application of GNNs in ligand-based drug screening for small molecules targeting miR-21. By representing a known dataset of small molecules targeting miR-21 as graphs, GNNs can learn complex relationships between their structures and activities, enabling the prediction of potential miRNA-targeting small molecules by capturing the structural features and similarity between known miRNA-targeting compounds. The use of GNNs in miRNA-targeting drug screening holds promise for the discovery of novel therapeutic agents and provides a computational framework for efficient screening of large chemical libraries.

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.

Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.

Big data from small animals: integrating multi-level environmental data into the Dog Aging Project.

Environmental exposures can have large impacts on health outcomes. While many resources have been dedicated to understanding how humans are influenced by the environment, few efforts have been made to study the role of built and natural environmental features on animal health. The Dog Aging Project (DAP) is a longitudinal community science study of aging in companion dogs. Using a combination of owner-reported surveys and secondary sources linked through geocoded coordinates, DAP has captured home, yard and neighbourhood variables for over 40,000 dogs. The DAP environmental data set spans four domains: the physical and built environment; chemical environment and exposures; diet and exercise; and social environment and interactions. By combining biometric data, measures of cognitive function and behaviour, and medical records, DAP is attempting to use a big-data approach to transform the understanding of how the surrounding world affects the health of companion dogs. In this paper, the authors describe the data infrastructure developed to integrate and analyse multi-level environmental data that can be used to improve the understanding of canine co-morbidity and aging.

L'impact des expositions environnementales sur la santé est parfois considérable. Si diverses ressources ont été consacrées à décrire l'influence de l'environnement sur les humains, les efforts visant à étudier l'effet des paramètres environnementaux, tant naturels qu'anthropiques, sur la santé animale sont plus rares. Le Dog Aging Project (DAP) est une étude scientifique longitudinale à base communautaire portant sur le vieillissement du chien de compagnie. À partir d'observations notifiées par les propriétaires de chiens et de sources secondaires reliées par des coordonnées de géocodage, le DAP a réuni des variables sur le foyer d'habitation, l'environnement extérieur immédiat et le voisinage de plus de 40 000 chiens. Les séries de données environnementales du DAP couvrent quatre domaines : l'environnement physique et bâti ; l'environnement chimique et les expositions ; le régime alimentaire et la dépense physique ; et les interactions et l'environnement social. En combinant les données biométriques, les mesures du fonctionnement cognitif et comportemental et les dossiers médicaux, le DAP cherche à utiliser l'approche des mégadonnées pour transformer notre perception de la manière dont le monde qui nous entoure affecte la santé des chiens de compagnie. Les auteurs décrivent l'infrastructure des données mise au point pour intégrer et analyser des données environnementales multi-niveaux, afin de mieux comprendre les phénomènes de comorbidité et de vieillissement chez le chien.

La exposición a factores ambientales puede tener muchas e importantes repercusiones en los resultados sanitarios. Si bien se han dedicado cuantiosos recursos a aprehender la influencia del entorno en las personas, poco se ha hecho para estudiar el modo en que las características del medio, tanto natural como artificial, repercuten en la salud de los animales. El proyecto sobre Envejecimiento canino [Dog Aging Project: DAP] es un estudio longitudinal de ciencia ciudadana centrado en el envejecimiento de los perros de compañía. Combinando la información de encuestas realizadas a propietarios y de fuentes secundarias y vinculando los datos a coordenadas geográficas codificadas, el DAP ha permitido reunir información de variables ligadas al hogar, el jardín y el barrio de más de 40 000 perros. El conjunto de datos ambientales del DAP cubre cuatro grandes ámbitos: medio físico y urbanizado; condiciones químicas del entorno y exposición a sustancias químicas; régimen alimentario y ejercicio; y medio e interacciones sociales. Pasando por el uso combinado de datos biométricos, historias clínicas y mediciones de la función cognitiva y el comportamiento, el DAP apunta ahora a emplear técnicas de trabajo con macrodatos para hacer evolucionar nuestras ideas sobre la influencia del mundo que nos rodea en la salud de los perros de compañía. Los autores describen la infraestructura de datos establecida para integrar y analizar datos ambientales multiestratificados que nos ayuden a conocer mejor los procesos de comorbilidad y envejecimiento en el perro.

Riociguat inhibits ultra-large VWF string formation on pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by elevated pulmonary arterial pressure and organized thrombi within pulmonary arteries. Riociguat is a soluble guanylate cyclase stimulator and is approved for patients with inoperable CTEPH or residual pulmonary hypertension after pulmonary endarterectomy (PEA). Previous work suggested that riociguat treatment is associated with an increased risk of bleeding, although the mechanism is unclear. The aim of this study is to assess how riociguat affects primary hemostasis by studying its effect on the interaction between platelets and endothelial cells derived from CTEPH patients. Pulmonary artery endothelial cells (PAECs) were isolated from thrombus-free regions of PEA material. Purified PAECs were cultured in flow chambers and were stimulated with 0.1 and 1 µM riociguat for 24 h before flow experiments. After stimulation with histamine, PAECs were exposed to platelets under shear stress. Platelet adhesion and expression of von Willebrand Factor (VWF) were evaluated to assess the role of riociguat in hemostasis. Under dynamic conditions, 0.1 and 1.0 µM of riociguat suppressed platelet adhesion on the surface of PAECs. Although riociguat did not affect intracellular expression and secretion of VWF, PAECs stimulated with riociguat produced fewer VWF strings than unstimulated PAECs. Flow cytometry suggested that decreased VWF string formation upon riociguat treatment may be associated with suppressed cell surface expression of P-selectin, a protein that stabilizes VWF anchoring on the endothelial surface. In conclusion, Riociguat inhibits VWF string elongation and platelet adhesion on the surface of CTEPH-PAECs, possibly by reduced P-selectin cell surface expression.

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19

Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fc{gamma} receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation while simultaneously minimizing inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.

C/EBPδ Suppresses Motility-Associated Gene Signatures and Reduces PDAC Cell Migration.

Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive human cancers and occurs globally at an increasing incidence. Metastases are the primary cause of cancer-related death and, in the majority of cases, PDAC is accompanied by metastatic disease at the time of diagnosis, making it a particularly lethal cancer. Regrettably, to date, no curative treatment has been developed for patients with metastatic disease, resulting in a 5-year survival rate of only 11%. We previously found that the protein expression of the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) negatively correlates with lymph node involvement in PDAC patients. To better comprehend the etiology of metastatic PDAC, we explored the role of C/EBPδ at different steps of the metastatic cascade, using established in vitro models. We found that C/EBPδ has a major impact on cell motility, an important prerequisite for tumor cells to leave the primary tumor and to reach distant sites. Our data suggest that C/EBPδ induces downstream pathways that modulate actin cytoskeleton dynamics to reduce cell migration and to induce a more epithelial-like cellular phenotype. Understanding the mechanisms dictating epithelial and mesenchymal features holds great promise for improving the treatment of PDAC.

[HIV/AIDS surveillance in men who have sex with men aged 15-24 based on internet in Fuzhou,2016-2021].

Objective: To analyze HIV/AIDS surveillance data in men who have sex with men (MSM) aged from 15 to 24 years in Fuzhou and understand the HIV infection status in MSM and related factors. Methods: From 2016 to 2021, MSM aged 15-24 years who had oral or anal sex with men in the past 6 months were recruited through internet, and their demographic and behavioral characteristics, HIV antibody positive rate and risk factors were analyzed. Results: From 2016 to 2021, a total of 4 234 MSM aged 15-24 years were surveyed. The proportion of MSM from other provinces increased from 13.00% (85/654) to 23.42% (163/696) (trend χ2=60.23, P<0.001); and the proportion of MSM seeking male partners through internet increased from 93.27% (610/654) to 99.71% (694/696) (trend χ2=65.20, P<0.001); In the last anal sex in the past 6 months, the proportion of MSM using condom decreased from 88.16% (484/549) to 74.11% (415/560) (trend χ2=32.32, P<0.001); and in the past 6 months, the proportion of MSM using condom at each anal sex decreased from 65.76% (361/549) to 55.54% (311/560) (trend χ2 =6.82, P<0.001); The proportion of MSM with HIV antibody testing increased from 5.66% (37/654) to 25.29% (176/696) (trend χ2=98.51, P<0.001). The cumulative HIV antibody positive rate in the MSM was 3.64% (154/4 234), and there was no significant difference in annual HIV antibody positive rate in the MSM (trend χ2=0.50, P=0.453). The HIV antibody positive rate in the MSM with education level of junior high school or below and the MSM living in Fuzhou for 1-2 years showed an upward trend (P<0.05). The results of multivariate logistic regression analysis showed that the risk for HIV infection in the MSM with education level of high school or technical secondary school was 0.54 times higher than that in those with education level of junior high school or below (95%CI: 0.30-0.99), and the risk for HIV infection in the MSM with education level of junior college or below was 0.29 times higher than that in those with education level of junior high school or below (95%CI: 0.17-0.51). The risk for HIV infection in the MSM who lived in Fuzhou for 1-2 years was 0.35 times higher than that in those who lived in Fuzhou for less than 1 year (95%CI: 0.16-0.74), the risk for HIV infection in the MSM who lived in Fuzhou for more than two years was 0.58 times higher than that in those who lived in Fuzhou for less than 1 year (95%CI: 0.37-0.91). The number of MSM using condoms at each anal sex was 0.18 times higher than that in the those never using condoms (95%CI: 0.08-0.42), and the number of the MSM who didn't suffered from sexually transmitted diseases was 0.25 times higher than that in those who suffered from sexually transmitted diseases (95%CI: 0.13-0.50). Conclusions: The MSM aged 15-24 years in Fuzhou have higher risk for HIV infection, and internet based intervention should be strengthened in adolescent MSM without permanent residence and with low education level.

Regulation of VWF (Von Willebrand Factor) in Inflammatory Thrombosis.

Increasing evidence indicates that inflammation promotes thrombosis via a VWF (von Willebrand factor)-mediated mechanism. VWF plays an essential role in maintaining the balance between blood coagulation and bleeding, and inflammation can lead to aberrant regulation. VWF is regulated on a transcriptional and (post-)translational level, and its secretion into the circulation captures platelets upon endothelial activation. The significant progress that has been made in understanding transcriptional and translational regulation of VWF is described in this review. First, we describe how VWF is regulated at the transcriptional and post-translational level with a specific focus on the influence of inflammatory and immune responses. Next, we describe how changes in regulation are linked with various cardiovascular diseases. Recent insights from clinical diseases provide evidence for direct molecular links between inflammation and thrombosis, including atherosclerosis, chronic thromboembolic pulmonary hypertension, and COVID-19. Finally, we will briefly describe clinical implications for antithrombotic treatment.

[Relationship between preoperative inflammatory indexes and prognosis of patients with rectal cancer and establishment of prognostic nomogram prediction model].

Objective: To compare the prognostic evaluation value of preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) in rectal cancer patients. Nomogram survival prediction model based on inflammatory markers was constructed. Methods: The clinical and survival data of 585 patients with rectal cancer who underwent radical resection in the First Affiliated Hospital of Xi'an Jiao tong University from January 2013 to December 2016 were retrospectively analyzed. The optimal cut-off values of NLR, PLR, LMR, and SII were determined by the receiver operating characteristic (ROC) curve. The relationship between different NLR, PLR, LMR and SII levels and the clinic pathological characteristics of the rectal cancer patients were compared. Cox proportional risk model was used for univariate and multivariate regression analysis. Nomogram prediction models of overall survival (OS) and disease-free survival (DFS) of patients with rectal cancer were established by the R Language software. The internal validation and accuracy of the nomograms were determined by the calculation of concordance index (C-index). Calibration curve was used to evaluate nomograms' efficiency. Results: The optimal cut-off values of preoperative NLR, PLR, LMR and SII of OS for rectal cancer patients were 2.44, 134.88, 4.70 and 354.18, respectively. There was statistically significant difference in tumor differentiation degree between the low NLR group and the high NLR group (P<0.05), and there were statistically significant differences in T stage, N stage, TNM stage, tumor differentiation degree and preoperative carcinoembryonic antigen (CEA) level between the low PLR group and the high PLR group (P<0.05). There was statistically significant difference in tumor differentiation degree between the low LMR group and the high LMR group (P<0.05), and there were statistically significant differences in T stage, N stage, TNM stage, tumor differentiation degree and preoperative CEA level between the low SII group and the high SII group (P<0.05). The multivariate Cox regression analysis showed that the age (HR=2.221, 95%CI: 1.526-3.231), TNM stage (Ⅲ grade: HR=4.425, 95%CI: 1.848-10.596), grade of differentiation (HR=1.630, 95%CI: 1.074-2.474), SII level (HR=2.949, 95%CI: 1.799-4.835), and postoperative chemoradiotherapy (HR=2.123, 95%CI: 1.506-2.992) were independent risk factors for the OS of patients with rectal cancer. The age (HR=2.107, 95%CI: 1.535-2.893), TNM stage (Ⅲ grade, HR=2.850, 95%CI: 1.430-5.680), grade of differentiation (HR=1.681, 95%CI: 1.150-2.457), SII level (HR=2.309, 95%CI: 1.546-3.447), and postoperative chemoradiotherapy (HR=1.837, 95%CI: 1.369-2.464) were independent risk factors of the DFS of patients with rectal cancer. According to the OS and DFS nomograms predict models of rectal cancer patients established by multivariate COX regression analysis, the C-index were 0.786 and 0.746, respectively. The calibration curve of the nomograms showed high consistence of predict and actual curves. Conclusions: Preoperative NLR, PLR, LMR and SII levels are all correlated with the prognosis of rectal cancer patients, and the SII level is an independent prognostic risk factor for patients with rectal cancer. Preoperative SII level can complement with the age, TNM stage, differentiation degree and postoperative adjuvant chemoradiotherapy to accurately predict the prognosis of rectal cancer patients, which can provide reference and help for clinical decision.

Bone tissue engineering using 3D silk scaffolds and human dental pulp stromal cells epigenetic reprogrammed with the selective histone deacetylase inhibitor MI192.

Epigenetics plays a critical role in regulating mesenchymal stem cells' (MSCs) fate for tissue repair and regeneration. There is increasing evidence that the inhibition of histone deacetylase (HDAC) isoform 3 can enhance MSC osteogenesis. This study investigated the potential of using a selective HDAC2 and 3 inhibitor, MI192, to promote human dental pulp stromal cells (hDPSCs) bone-like tissue formation in vitro and in vivo within porous Bombyx Mori silk scaffolds. Both 2 and 5 wt% silk scaffolds were fabricated and characterised. The 5 wt% scaffolds possess thicker internal lamellae, reduced scaffold swelling and degradation rates, whilst increased compressive modulus in comparison to the 2 wt% silk scaffold. MI192 pre-treatment of hDPSCs on 5 wt% silk scaffold significantly enhanced hDPSCs alkaline phosphatase activity (ALP). The expression of osteoblast-related genes (RUNX2, ALP, Col1a, OCN) was significantly upregulated in the MI192 pre-treated cells. Histological analysis confirmed that the MI192 pre-treated hDPSCs-silk scaffold constructs promoted bone extracellular matrix (ALP, Col1a, OCN) deposition and mineralisation compared to the untreated group. Following 6 weeks of subcutaneous implantation in nude mice, the MI192 pre-treated hDPSCs-silk scaffold constructs enhanced the vascularisation and extracellular matrix mineralisation compared to untreated control. In conclusion, these findings demonstrate the potential of using epigenetic reprogramming and silk scaffolds to promote hDPSCs bone formation efficacy, which provides evidence for clinical translation of this technology for bone augmentation.

Epigenetic Modification of the von Willebrand Factor Promoter Drives Platelet Aggregation on the Pulmonary Endothelium in Chronic Thromboembolic Pulmonary Hypertension.

Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role of this protein in CTEPH has remained enigmatic. Objectives: To identify the role of vWF in CTEPH. Methods: CTEPH-specific patient plasma and pulmonary endarterectomy material from patients with CTEPH were used to study the relationship between inflammation, vWF expression, and pulmonary thrombosis. Cell culture findings were validated in human tissue, and proteomics and chromatin immunoprecipitation were used to investigate the underlying mechanism of CTEPH. Measurements and Main Results: vWF is increased in plasma and the pulmonary endothelium of CTEPH patients. In vitro, the increase in vWF gene expression and the higher release of vWF protein upon endothelial activation resulted in elevated platelet adhesion to CTEPH endothelium. Proteomic analysis revealed that nuclear factor (NF)-κB2 was significantly increased in CTEPH. We demonstrate reduced histone tri-methylation and increased histone acetylation of the vWF promoter in CTEPH endothelium, facilitating binding of NF-κB2 to the vWF promoter and driving vWF transcription. Genetic interference of NFκB2 normalized the high vWF RNA expression levels and reversed the prothrombotic phenotype observed in CTEPH-pulmonary artery endothelial cells. Conclusions: Epigenetic regulation of the vWF promoter contributes to the creation of a local environment that favors in situ thrombosis in the pulmonary arteries. It reveals a direct molecular link between inflammatory pathways and platelet adhesion in the pulmonary vascular wall, emphasizing a possible role of in situ thrombosis in the development or progression of CTEPH.

The protective effect of mangiferin on osteoarthritis: An in vitro and in vivo study.

Mangiferin is a kind of polyphenol chemical compound separated from these herbal medicines of Mangifera indica L., Anemarrhena asphodeloides Bge. and Belamcanda chinensis L., which has anti-inflammatory, anti-virus, and other physiological activities without toxic effects. Osteoarthritis (OA) is a chronic disease that is also a kind of arthritis disease in which articular cartilage or bones under the joint is damaged. In addition, artificial replacements are required in severe cases. At present, there are not too much researches on the potential biological activities of mangiferin that plays a protective role in the treatment of OA. In this study, we evaluated the protective effect of mangiferin on osteoarthritis (OA) in vitro and in vivo. First, the effect of different concentrations of mangiferin on rat chondrocytes was determined by MTT assay. Second, the effects of mangiferin on the expression levels of matrix metalloproteinase (MMP)-13, TNF alpha, Collagen II, Caspase-3, and cystatin-C in interleukin-1beta (IL-1beta)-induced rat chondrocytes were examined by the real-time polymerase chain reaction in vitro, meanwhile the effects of mangiferin on the nuclear factor kappa-B (NF-kappaB) signaling pathway were also investigated by Western Blot. Finally, the anti-osteoarthritic protective effect of mangiferin was evaluated in the rat model by anterior cruciate ligament transection (ACLT) combined with bilateral ovariectomy-induced OA in vivo. The results showed that the mangiferin was found to inhibit the expression of MMP-13, TNF-alpha, and Caspase-3 which also increased the expression of Collagen II and cystatin-C in IL 1beta induced rat chondrocytes. In addition, IL-1beta-induced activation of nuclear factor kappa-B (NF-kappaB) and the degradation of inhibitor of kappaB (IkappaB)-alpha were suppressed by mangiferin. For the in vivo study in a rat model of OA, 100 microl of mangiferin was administered by intra-articular injections for rats, the results showed that the cartilage degradation was suppressed by mangiferin through Micro CT and Histological Examination. According to both in vitro and in vivo results, mangiferin has a protective effect in the treatment of OA which may be a promising therapeutic agent for OA.

Development of a 3-Dimensional Model to Study Right Heart Dysfunction in Pulmonary Arterial Hypertension: First Observations.

Pulmonary arterial hypertension (PAH) patients eventually die of right heart failure (RHF). Currently, there is no suitable pre-clinical model to study PAH. Therefore, we aim to develop a right heart dysfunction (RHD) model using the 3-dimensional engineered heart tissue (EHT) approach and cardiomyocytes derived from patient-induced pluripotent stem cells (iPSCs) to unravel the mechanisms that determine the fate of a pressure-overloaded right ventricle. iPSCs from PAH and healthy control subjects were differentiated into cardiomyocytes (iPSC-CMs), incorporated into the EHT, and maintained for 28 days. In comparison with control iPSC-CMs, PAH-derived iPSC-CMs exhibited decreased beating frequency and increased contraction and relaxation times. iPSC-CM alignment within the EHT was observed. PAH-derived EHTs exhibited higher force, and contraction and relaxation times compared with control EHTs. Increased afterload was induced using 2× stiffer posts from day 0. Due to high variability, there were no functional differences between normal and stiffer EHTs, and no differences in the hypertrophic gene expression. In conclusion, under baseline spontaneous conditions, PAH-derived iPSC-CMs and EHTs show prolonged contraction compared with controls, as observed clinically in PAH patients. Further optimization of the hypertrophic model and profound characterization may provide a platform for disease modelling and drug screening.

High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.

Interferometric control of magnon-induced nearly perfect absorption in cavity magnonics.

The perfect absorption of electromagnetic waves has promoted many applications, including photovoltaics, radar cloaking, and molecular detection. Unlike conventional methods of critical coupling that require asymmetric boundaries or coherent perfect absorption that require multiple coherent incident beams, here we demonstrate single-beam perfect absorption in an on-chip cavity magnonic device without breaking its boundary symmetry. By exploiting magnon-mediated interference between two internal channels, both reflection and transmission of our device can be suppressed to zero, resulting in magnon-induced nearly perfect absorption (MIPA). Such interference can be tuned by the strength and direction of an external magnetic field, thus showing versatile controllability. Furthermore, the same multi-channel interference responsible for MIPA also produces level attraction (LA)-like hybridization between a cavity magnon polariton mode and a cavity photon mode, demonstrating that LA-like hybridization can be surprisingly realized in a coherently coupled system.

LINC00641 induces the malignant progression of colorectal carcinoma through the miRNA-424-5p/PLSCR4 feedback loop.

OBJECTIVE: To illustrate the role of LINC00641 in inducing the malignant progression of colorectal cancer (CRC) through the miRNA-424-5p/PLSCR4 feedback loop. PATIENTS AND METHODS: LINC00641 levels in paired CRC and non-tumoral tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Its prognostic potential in CRC was assessed by Kaplan-Meier method. Changes in proliferative and migratory abilities of HCT116 and SW620 cells transfected with si-LINC00641 were evaluated by 5-Ethynyl-2'- deoxyuridine (EdU), cell counting kit-8 (CCK-8) and transwell assay. The feedback loop LINC00641/miRNA-424-5p/PLSCR4 was identified through Dual-Luciferase reporter assay and its involvement in CRC progression was finally explored by rescue experiments. RESULTS: LINC00641 was upregulated in CRC tissues, which was an unfavorable factor to the overall survival of CRC. Proliferative and migratory abilities of HCT116 and SW620 cells were inhibited by knockdown of LINC00641. LINC00641 could competitively bind miRNA-424-5p, thereby abolishing its inhibitory effect on PLSCR4 expression. Knockdown of PLSCR4 could inhibit proliferative and migratory abilities of HCT116 and SW620 cells. CONCLUSIONS: LINC00641 stimulates proliferative and migratory abilities of CRC through the miRNA-424-5p/PLSCR4 feedback loop.

Correlation between microRNA-766 expression in patients with advanced gastric cancer and the efficacy of platinum-containing chemotherapy.

OBJECTIVE: We aimed at observing the correlation between microRNA-766 expression and the efficacy of platinum-containing chemotherapy in patients with stage IV gastric cancer (GCa). PATIENTS AND METHODS: Tissue specimens were obtained from 100 patients with stage IV GCa who received platinum-based chemotherapy, and microRNA-766 expression in these samples was examined by quantitative real-time polymerase chain reaction (qPCR) analysis. Survival analysis was carried out through Kaplan-Meier test. The influencing factors of survival were assessed through COX univariate and multivariate regression. RESULTS: GCa tissues contained significant lower expression of microRNA-766 than adjacent tissues. The degree of tumor differentiation and peritoneal metastasis were confirmed to have great relevance to microRNA-766 level. Patients with high microRNA-766 expression have better chemotherapy efficacy and longer progression-free survival. CONCLUSIONS: Our study shows for the first time that the highly expressed microRNA-766 in tumor tissues of patients with stage Ⅳ GCa predicts better platinum-containing chemotherapy efficacy and prognosis.

CircRNA_009934 induces osteoclast bone resorption via silencing miR-5107.

OBJECTIVE: We aimed to explore the expression of circRNA_009934 in osteoclast, as well as its potential roles in regulating osteoclastogenesis and bone resorption via regulating miR-5107. MATERIALS AND METHODS: We performed qRT-PCR analysis to examine the expression of circRNA_009934 in osteoclast in distinctive stages. We used CCK-8 assay to detect the cell proliferation ability. Correlation analysis between the expression levels of circRNA_009934 and miR-5107 was performed using statistical analysis. Bioinformatics prediction was performed to predict the binding site of circRNA_009934 and miR-5107, subsequently followed by Luciferase assay for validation. The mice TRAF6 3'-UTR were cloned into the Luciferase reporter vector and miR-5107 binding mutants were constructed to validate the inhibited regulation of miR-5107 to the expression of TRAF6. RESULTS: Our results showed that expression of circRNA_009934 was increased during osteoclast differentiation. CircRNA_009934 expression was closely correlated with osteoclastogenesis and bone resorption activity. Bioinformatics prediction and Luciferase assay demonstrated that circRNA_009934 served as a ceRNA of miR-5107 and regulated its downstream TRAF6 expression. CONCLUSIONS: We first demonstrated that circRNA_009934 expression was increased in osteoclasts, which promoted osteoclastogenesis by serving as a ceRNA of miR-5107 and regulated the expression of TRAF6.