Glycoursodeoxycholic Acid Alleviates Arterial Thrombosis via Suppressing Diacylglycerol Kinases Activity in Platelet.

BACKGROUND: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms. METHODS: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment. RESULTS: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05). CONCLUSIONS: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.

Prediction Model for Postoperative Pressure Injury in Patients with Acute Type A Aortic Dissection.

OBJECTIVE: To establish a risk assessment model to predict postoperative National Pressure Injury Advisory Panel stage 2 or higher pressure injury (PI) risk in patients undergoing acute type A aortic dissection surgery. METHODS: This retrospective assessment included consecutive patients undergoing acute type A aortic dissection surgery in the authors' hospital from September 2017 to June 2021. The authors used LASSO (logistic least absolute shrinkage and selection operator) regression analysis to identify the most relevant variables associated with PI by running cyclic coordinate descent with 10-times cross-validation. The variables selected by LASSO regression analysis were subjected to multivariate logistic analysis. A calibration plot, receiver operating characteristic curve, and decision curve analysis were used to validate the model. RESULTS: There were 469 patients in the study, including 94 (27.5%) with postoperative PI. Ten variables were selected from LASSO regression: body mass index, diabetes, Marfan syndrome, stroke, preoperative skin moisture, hemoglobin, albumin, serum creatinine, platelet, and d-dimer. Four risk factors emerged after multivariate logistic regression: Marfan syndrome, preoperative skin moisture, albumin, and serum creatinine. The area under the receiver operating characteristic curve of the model was 0.765. The calibration plot and the decision curve analysis both suggested that the model was suitable for predicting postoperative PI. CONCLUSIONS: This study built an efficient predictive model that could help identify high-risk patients.

Pectolinarigenin ameliorated airway inflammation and airway remodeling to exhibit antitussive effect.

Cough is a common symptom of several respiratory diseases. However, frequent coughing from acute to chronic often causes great pain to patients. It may turn into cough variant asthma, which seriously affects people's quality of life. For cough treatment, it is dominated by over-the-counter antitussive drugs, such as asmeton, but most currently available antitussive drugs have serious side effects. Thus, there is a great need for the development of new drugs with potent cough suppressant. BALB/c mice were used to construct mice model with cough to investigate the pharmacological effects of pectolinarigenin (PEC). Hematoxylin-eosin and Masson staining were used to assess lung injury and airway remodeling, and ELISA was used to assess the level of inflammatory factor release. In addition, inflammatory cell counts were measured to assess airway inflammation. Airway hyperresponsiveness assay was used to assess respiratory resistance in mice. Finally, we used Western blotting to explore the potential mechanisms of PEC. We found that PEC could alleviate lung tissue injury and reduce the release of inflammatory factors, inhibit of cough frequency and airway wall collagen deposition in mice model with cough. Meanwhile, PEC inhibited the Ras/ERK/c-Fos pathway to exhibit antitussive effect. Therefore, PEC may be a potential drug for cough suppression.

Coupled folding-upon-binding of human tumor suppressor MIG6 to lung cancer EGFR kinase domain and molecular trimming/stapling of MIG6-derived ß-hairpins to target the coupling event.

Human epidermal growth factor receptor (EGFR) is involved in strong association with malignant proliferation, which has been shown to play a central role in the development and progression of non-small cell lung cancer and other solid tumors. The tumor-suppressor protein MIG6 is a negative regulator of EGFR kinase activity by binding at the activation interface of asymmetric dimer of EGFR kinase domain to disrupt EGFR dimerization and then inactivate the kinase. The protein adopts two discrete fragments 1 and 2 to directly interact with EGFR. It is revealed that the MIG6 fragment 2 is intrinsically disordered in free unbound state, but would fold into a well-structured ß-hairpin when binding to EGFR, thus characterized by a so-called coupled folding-upon-binding process, which can be regarded as a compromise between favorable direct readout and unfavorable indirect readout. Here, a 23-mer F2P peptide was derived from MIG6 fragment 2, trimmed into a 17-mer tF2P peptide that contains the binding hotspot region of the fragment 2, and then constrained with an ordered hairpin conformation in free unbound state by disulfide stapling, finally resulting in a rationally stapled/trimmed stF2P peptide that largely minimizes the unfavorable indirect readout effect upon its binding to EGFR kinase domain, with affinity improved considerably upon the trimming and stapling/trimming. These rationally designed ß-hairpin peptides may be further exploited as potent anti-lung cancer agents to target the activation event of EGFR dimerization.

Prediction model for postoperative severe acute lung injury in patients undergoing acute type A aortic dissection surgery.

OBJECTIVE: This study aimed to establish a risk assessment model to predict postoperative severe acute lung injury (ALI) risk in patients with acute type A aortic dissection (ATAAD). METHODS: Consecutive patients with ATAAD admitted to our hospital were included in this retrospective assessment and placed in the postoperative severe ALI and nonsevere ALI groups based on the presence or absence of ALI within 72 h postoperatively (oxygen index [OI] ≤ 100 mmHg). Patients were then randomly divided into training and validation groups in a ratio of 8:2. Univariate and multivariate stepwise forward logistic regression analyses were used to statistically assess data and establish the prediction model. The prediction model's effectiveness was evaluated via 10-fold cross-validation of the validation group to facilitate the construction of a nomogram. RESULTS: After the screening, 479 patients were included in the study: 132 (27.6%) in the postoperative severe ALI group and 347 (72.4%) in the postoperative nonsevere ALI group. Based on multivariate logistics regression analyses, the following variables were included in the model: coronary heart disease, cardiopulmonary bypass (CPB) ≥ 257.5 min, left atrium diameter ≥ 35.5 mm, hemoglobin ≤ 139.5 g/L, preCPB OI ≤ 100 mmHg, intensive care unit OI ≤ 100 mmHg, left ventricular posterior wall thickness ≥ 10.5 mm, and neutrophilic granulocyte percentage ≥ 0.824. The area under the receiver operating characteristic (ROC) curve of the modeling group was 0.805 and differences between observed and predicted values were not deemed statistically significant via the Hosmer-Lemeshow test (χ2 = 6.037, df = 8, p = .643). For the validation group, the area under the ROC curve was 0.778, and observed and predicted value differences were insignificant when assessed using the Hosmer-Lemeshow test (χ2 = 3.3782, df = 7; p = .848). The average 10-fold cross-validation score was 0.756. CONCLUSIONS: This study established a prediction model and developed a nomogram to determine the risk of postoperative severe ALI after ATAAD. Variables used in the model were easy to obtain clinically and the effectiveness of the model was good.

A comparison of single and double arterial cannulation for cardiopulmonary bypass for acute type A aortic surgery: A single center, retrospective observational study.

Background: Acute type A aortic dissection (ATAAD) is a cardiovascular emergency and has high mortality and morbidity. We retrospectively compared the effects on outcomes of single arterial cannulation via axillary artery (AAC) with double arterial cannulation via axillary and femoral artery (DAC) in patients who underwent cardiopulmonary bypass (CPB) for ATAAD.Methods: Between January 2017 and May 2021, four hundred 29 patients who underwent aortic arch repair with circulatory arrest for ATAAD were divided into AAC group (n = 283) and DAC group (n = 146). The propensity score-matched (PSM) analysis were performed to compare the characteristics and outcomes of the groups.Results: After PSM (n = 137 in each), the DAC group had a longer duration of CPB (229 vs 244, p = 0.011), aortic cross-clamp time (121 vs 149, p < 0.001), durations of Intensive Care Unit (ICU) stay (7 vs 8, p = 0.014) and hospital stay (19 vs 25, p < 0.001) compared with AAC group. The incidences of dialysis (21% vs. 31%, p = 0.073), postoperative stroke (9% vs 15%, p = 0.143), ECMO support (2% vs 7%, p = 0.077), in-hospital mortality (7% vs 14%, p = 0.071) and follow-up mortality (10% vs 19%, p = 0.059) showed no significant difference between two groups. Multivariate logistic regression analysis showed postoperative ECMO (OR: 16.69, 95% CI: 1.78-156.29; p = 0.014) or stroke (OR: 11.34, 95% CI: 2.64-48.72; p < 0.001) were associated with in-hospital mortality. Univariate Cox regression results showed stroke history (OR: 4.61, 95% CI: 1.90-11.16; p = 0.001), aortic valvuloplasty (OR: 0.21, 95% CI: 0.07-0.59; p = 0.003), postoperative ALT day1 (OR: 1.00, 95% CI: 1.00-1.00; p = 0.008), ECMO (OR: 16.30, 95% CI: 4.78-55.61; p < 0.001), tracheotomy (OR: 3.78, 95% CI: 1.08-13.20; p = 0.037), postoperative stroke (OR: 4.61, 95% CI: 1.90-11.16; p < 0.001) and re-exploration for bleeding (OR: 3.52, 95% CI: 1.01-12.27; p = 0.048) were associated to follow-up mortality.Conclusions: For surgical treatment of ATAAD with CPB when compared to double axillary and femoral artery, single axillary cannulation was associated with shorter durations of CPB and ACC as well as ICU and hospital stays but no with significant difference in mortality.

Molecular design and systematic optimization of a halogen-bonding system between the asthma interleukin-5 receptor and its cyclic peptide ligand.

Human interleukin-5 (IL-5) functions as an important pro-inflammatory factor by binding to its specific receptor, IL-5Rα, which has been implicated in the pathogenesis of asthma. Previously, a disulfide-bonded cyclic peptide AF17121 obtained from random library screening and sequence variation was found to competitively disrupt the cognate IL-5Rα/IL-5 interaction with moderate potency. In this study, the crystal complex of IL-5Rα with AF17121 was investigated at structural and energetic levels. It is revealed that the side-chain indole moiety of the AF17121 Trp5 residue is a potential site for a stem putative halogen bond (X-bond) with IL-5Rα, which is just located within the key 3 EXXR6 motif region recognized specifically by IL-5Rα. We systematically examined four halogen substitution types at five positions of the indole moiety; QM/MM calculations theoretically unraveled that only halogenations at 5 and 6 positions can form effective X-bonds with the side-chain hydroxyl oxygen of the IL-5Rα Thr21 residue and the backbone carbonyl oxygen of Ala66 residue, respectively. Binding assays observed that I-substitution at the 5 position and Br-substitution at the 6 position can result in two potent halogenated peptides, [5I]AF17121 and [6Br]AF17121, which are improved by 1.6-fold and 3.5-fold relative to the native AF17121, respectively. 5I/6Br-double substitution, resulting in [5I/6Br]AF17121, can further enhance the peptide affinity by 7.5-fold. Structural analysis revealed that the X-bond stemming from 6Br-substitution is also involved in an orthogonal interaction system with a H-bond; they share a common backbone carbonyl oxygen acceptor of IL-5Rα Ala66 residue and exhibit a significant synergistic effect between them.

SHP-1 mediates cigarette smoke extract-induced epithelial-mesenchymal transformation and inflammation in 16HBE cells.

Src-homology region 2 domain-containing phosphatase 1 (SHP-1) is considered an anti-inflammatory factor, but its role in chronic obstructive pulmonary disease (COPD) remains unknown. Herein, overexpression of SHP-1 was utilized to explore the functions of SHP-1 in COPD models established by stimulating 16HBE cells with cigarette smoke extracts (CSE) in vitro. SHP-1 was downregulated in both COPD patients and CES-treated 16HBE cells. SHP-1 overexpression reinforced cell viability and significantly prevented CSE-induced cell apoptosis in 16HBE cells. Furthermore, SHP-1 overexpression greatly reversed the CSE-induced migration, epithelial-mesenchymal transition (EMT), and pro-inflammatory factor production in 16HBE cells. In addition, CSE activated the P65 and PI3K/AKT pathways in 16HBE cells, which was also reversed by SHP-1 overexpression. Our findings indicated that SHP-1 alleviated CSE-induced EMT and inflammation in 16HBE cells, suggesting that SHP-1 regulated the development of COPD, and these functions may be linked to the inhibition of the PI3K/AKT pathway.

Studying the Effect of Material and Geometry on Perceptual Outdoor Illumination.

Understanding and modeling perceived properties of sky-dome illumination is an important but challenging problem due to the interplay of several factors such as the materials and geometries of the objects present in the scene being observed. Existing models of sky-dome illumination focus on the physical properties of the sky. However, these parametric models often do not align well with the properties perceived by a human observer. In this work, drawing inspiration from the Hosek-Wilkie sky-dome model, we investigate the perceptual properties of outdoor illumination. For this purpose, we perform a large-scale user study via crowdsourcing to collect a dataset of perceived illumination properties (scattering, glare, and brightness) for different combinations of geometries and materials under a variety of outdoor illuminations, totaling 5,000 distinct images. We perform a thorough statistical analysis of the collected data which reveals several interesting effects. For instance, our analysis shows that when there are objects in the scene made of rough materials, the perceived scattering of the sky increases. Furthermore, we utilize our extensive collection of images and their corresponding perceptual attributes to train a predictor. This predictor, when provided with a single image as input, generates an estimation of perceived illumination properties that align with human perceptual judgments. Accurately estimating perceived illumination properties can greatly enhance the overall quality of integrating virtual objects into real scene photographs. Consequently, we showcase various applications of our predictor. For instance, we demonstrate its utility as a luminance editing tool for showcasing virtual objects in outdoor scenes.

Nitrogen and Microelements Co-Drive the Decomposition of Typical Grass Litter in the Loess Plateau, China.

In grassland ecosystems, the decomposition of litter serves as a vital conduit for nutrient transfer between plants and soil. The aim of this study was to depict the dynamic process of grass litter decomposition and explore its major driver. Three typical grasses [Stipa bungeana Trin (St. B), Artemisia sacrorun Ledeb (Ar. S), and Thymus mongolicus Ronniger (Th. M)] were selected for long-term litter decomposition. Experiments were conducted using three single litters, namely, St. B, Ar. S, and Th. M, and four different compositions of mixed litter: ML1 (55% St. B and 45% Th. M), ML2 (55% St. B and 45% Ar. S), ML3 (75% St. B and 25% Th. M), and ML4 (75% St. B and 25% Ar. S). The dynamic patterns of mass and microelements (Ca, Mg, Fe, Mn, Cu, and Zn) within different litter groups were analyzed. Our findings indicated that, after 1035 days of decomposition, the proportion of residual mass for the single litters was as follows: Th. M (60.6%) > St. B (47.3%) > Ar. S (44.3%), and for the mixed groups it was ML1 (48.0%) > ML3 (41.6%) > ML2 (40.9) > ML4 (38.4%). Mixed cultivation of the different litter groups accelerated the decomposition process, indicating that the mixture of litters had a synergistic effect on litter decomposition. The microelements of the litter exhibited an initial short-term increase followed by long-term decay. After 1035 days of decomposition, the microelements released from the litter were, in descending order, Mg > Ca > Fe > Cu > Mn > Zn. Compared to the separately decomposed St. B litter, mixing led to an inhibition of the release of Ca (antagonistic effect), while it promoted the release of Mg, Cu, and Zn (synergistic effect). For the single litter, the stepwise regression analysis showed that Ca was the dominant factor determining early litter decomposition. Mg, Mn, and Cu were the dominant factors regulating later litter decomposition. For the mixed litter groups, Ca, Mn, and Mg were the dominant factors closely related to early decomposition, and TN emerged as a key factor regulating the mass loss of mixtures during later decomposition. In summary, nitrogen and microelements co-drive the decomposition of typical grass litter. Our study underscores that, in the succession process of grassland, the presence of multiple co-existing species led to a faster loss of plant-derived materials (litter mass and internal elements), which was primarily modulated by species identity and uniformity.

Time-restricted feeding ameliorates non-alcoholic fatty liver disease through modulating hepatic nicotinamide metabolism via gut microbiota remodeling.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a global health concern, lacking specific therapeutic strategies. Time-restricted feeding (TRF) regimen demonstrated beneficial effects in NAFLD; however, the underlying mechanisms remain unclear. In this study, we established a NAFLD mouse model through a high-fat diet (HFD) and implemented the 16:8 TRF regimen for a duration of 6 weeks. We demonstrated that TRF remarkably alleviated hepatic steatosis in HFD mice. Of note, aldehyde oxidase 1 (AOX1), a key enzyme in hepatic nicotinamide (NAM) catabolism, exhibited apparent upregulation in response to HFD, leading to abnormal accumulation of N-Methyl-6-pyridone-3-carboxamide (N-Me-6-PY, also known as 2PY) and N-Methyl-4-pyridone-5-carboxamide (N-Me-4-PY, also known as 4PY), whereas it was almost restored by TRF. Both N-Me-6-PY and N-Me-4-PY promoted de novo lipogenesis and fatty acid uptake capacities in hepatocyte, and aggravated hepatic steatosis in mice either fed chow diet or HFD. In contrast, pharmacological inhibition of AOX1 was sufficient to ameliorate the hepatic steatosis and lipid metabolic dysregulation induced by HFD. Moreover, transplantation of fecal microbiota efficiently mimicked the modulatory effect of TRF on NAM metabolism, thus mitigating hepatic steatosis and lipid metabolic disturbance, suggesting a gut microbiota-dependent manner. In conclusion, our study reveals the intricate relationship between host NAM metabolic modification and gut microbiota remodeling during the amelioration of NAFLD by TRF, providing promising insights into the prevention and treatment of NAFLD.

Generation of an induced pluripotent stem cell line from an aortic dissection patient carrying MCTP2/c.2635T > G mutation.

Aortic dissection (AD) is a lethal cardiovascular disease that is related to a genetic mutation. This study showed the generation of induced pluripotent stem cell (iPSC) line (iPSC-ZPR-4-P10) from AD patients' peripheral blood mononuclear cells that carried a c.2635T > G mutation in MCTP2. The iPSC line demonstrated normal karyotype and expression of pluripotency markers, which could be an efficient tool to better investigate the mechanism of aortic dissection.

Prognostic significance of neutrophil count on in-hospital mortality in patients with acute type A aortic dissection.

Backgrounds: The goal of this study was to assess the impact of neutrophil count, in patients with acute type A aortic dissection (ATAAD). Methods: This study retrospectively collected data from patients between September 2017 and June 2021. Youden's index was used to determine the optimal cut-off value for the neutrophil count and patients were divided into two subgroups. A restricted cubic spline (RCS) was used to model the relationship between variables and in-hospital mortality. The least absolute shrinkage and selection operator (LASSO) method and multivariate logistic regression analyses were used to investigate the independent prognostic factors for in-hospital mortality in patients with ATAAD. Results: A total of 467 patients were enrolled in this study. In-hospital mortality was 7.28%. The group with elevated neutrophil counts had significantly higher mortality than the group with decreased neutrophil counts (10.8% vs. 3.2%, P = 0.02). This data shows that elevated neutrophil count was significantly associated with in-hospital mortality (OR 3.07, 95% CI 1.22-7.62, P = 0.02). Conclusions: Neutrophil count is an independent risk factor for in-hospital mortality in patients with ATAAD. It is an effective inflammatory index, which can be individualized for patients.

Inclusion of interleukin-6 improved the performance of postoperative acute lung injury prediction for patients undergoing surgery for thoracic aortic disease.

Background: We studied acute lung injury (ALI) in thoracic aortic disease (TAD) patients and investigated the predictive effect of interleukin-6 (IL-6) in acute lung injury after thoracic aortic disease. Methods: Data on 188 TAD patients, who underwent surgery between January 2016 to December 2021 at our hospital, were enrolled in. We analyzed acute lung injury using two patient groups. Patients with No-ALI were 65 and those with ALI were 123. Univariate logistic, LASSO binary logistic regression model and multivariable logistic regression analysis were performed for acute lung injury. Results: Preoperative IL-6 level was lower (15.80[3.10,43.30] vs. 47.70[21.40,91.60] pg/ml, p < 0.001) in No-ALI group than in ALI group. The cut-off points, determined by the ROC curve, were preoperative IL-6 > 18 pg/ml (area under the curve: AUC = 0.727). Univariate logistic regression analysis showed 19 features for TAD appeared to be early postoperative risk factors of acute lung injury. Using LASSO binary logistic regression, 19 features were reduced to 9 potential predictors (i.e., Scrpost + PLTpost + CPB > 182 min + D-dimerpost + D-dimerpre + Hypertension + Age > 58 years + IL6 > 18 pg/ml + IL6). Multivariable logistic regression analysis showed that Postoperative creatinine, CPB > 182 min and IL-6 > 18 pg/ml were early postoperative risk factors for ALI after TAD, and the odds ratios (ORs) of postoperative creatinine, CPB > 182 min and IL-6 > 18 pg/ml were 1.006 (1.002-1.01), 4.717 (1.306-19.294) and 2.96 (1.184-7.497), respectively. When postoperative creatinine, CPB > 182 min and IL-6 > 18 pg/ml (AUC = 0.819), the 95% confidence interval [CI] was 0.741 to 0.898. Correction curves were nearly diagonal, suggesting that the nomogram fit well. The DCA curve was then drawn to demonstrate clinical applicability. The DCA curve showed that the threshold probability of a patient is in the range of 30% to 90%. Conclusions: The inclusion of interleukin-6 demonstrated good performance in predicting ALI after TAD surgery.

Vav2 promotes ductus arteriosus anatomic closure via the remodeling of smooth muscle cells by Rac1 activation.

The ductus arteriosus (DA), bridging the aorta and pulmonary artery, immediately starts closing after birth. Remodeling of DA leads to anatomic obstruction to prevent repatency. Several histological changes, especially extracellular matrices (ECMs) deposition and smooth muscle cells (SMCs) migration bring to anatomic closure. The genetic etiology and mechanism of DA closure remain elusive. We have previously reported a novel copy number variant containing Vav2 in patent ductus arteriosus (PDA) patients, but its specific role in DA closure remains unknown. The present study revealed that the expression of Vav2 was reduced in human patent DA, and it was less enrichment in the adjacent aorta. Matrigel experiments demonstrated that Vav2 could promote SMC migration from PDA patient explants. Smooth muscle cells with Vav2 overexpression also presented an increased capacity in migration and downregulated contractile-related proteins. Meanwhile, SMCs with Vav2 overexpression exhibited higher expression of collagen III and lessened protein abundance of lysyl oxidase, and both changes are beneficial to DA remodeling. Overexpression of Vav2 resulted in increased activity of Rac1, Cdc42, and RhoA in SMCs. Further investigation noteworthily found that the above alterations caused by Vav2 overexpression were particularly reversed by Rac1 inhibitor. A heterozygous, rare Vav2 variant was identified in PDA patients. Compared with the wild type, this variant attenuated Vav2 protein expression and weakened the activation of downstream Rac1, further impairing its functions in SMCs. In conclusion, Vav2 functions as an activator for Rac1 in SMCs to promote SMCs migration, dedifferentiation, and ECMs production. Deleterious variant potentially induces Vav2 loss of function, further providing possible molecular mechanisms about Vav2 in PDA pathogenesis. These findings enriched the current genetic etiology of PDA, which may provide a novel target for prenatal diagnosis and treatment. KEY MESSAGES: Although we have proposed the potential association between Vav2 and PDA incidence through whole exome sequencing, the molecular mechanisms underlying Vav2 in PDA have never been reported. This work, for the first time, demonstrated that Vav2 was exclusively expressed in closed DAs. Moreover, we found that Vav2 participated in the process of anatomic closure by mediating SMCs migration, dedifferentiation, and ECMs deposition through Rac1 activation. Our findings first identified a deleterious Vav2 c.701C>T variant that affected its function in SMCs by impairing Rac1 activation, which may lead to PDA defect. Vav2 may become an early diagnosis and an effective intervention target for PDA clinical therapy.

Mechanisms of Banxia Xiexin Decoction Underlying Chronic Atrophic Gastritis via Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulations.

Chronic atrophic gastritis (CAG) is a common chronically digestive disease which is notoriously characterized by atrophy of the epithelium and glands of the gastric mucosa, reduced number, thinning of the gastric mucosa, thickening of the mucosal base, or pyloric glandular hyperplasia and intestinal glandular hyperplasia, or with atypical hyperplasia. Banxia Xiexin decoction (BXD) has been applied for two thousand years and is considered an effective therapy for functional dyspepsia, gastroesophageal reflux disease and colon cancer. In this current study, to probe into the underlying mechanism of BXD on CAG, network pharmacology was conducted to collect druggable ingredients and predicted targets of BXD and the CAG-associated targets were harvested to take intersection with druggable ingredients from BXD predicted targets to obtain potential critical action targets. Subsequently, GO enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were conducted to elucidate the underlying mechanisms and roles from the perspective of overall pathways and cellular functions. Eventually, molecular docking integrated with molecular dynamics simulations was conducted to further investigate the mechanism of action of BXD active ingredients on CAG from drug molecule-target interactions and to provide a theoretical basis for BXD drug development.

Severe phenotypes of B3GAT3-related disorder caused by two heterozygous variants: a case report and literature review.

BACKGROUND: Linkeropathies refers to a series of extremely rare hereditary connective tissue diseases affected by various glycosyltransferases in the biosynthesis of proteoglycans. We report for the first time two heterozygous variants of B3GAT3 in a Chinese infant, in whom Marfan syndrome was suspected at birth. CASE PRESENTATION: A 2-month-old boy from a non-consanguineous Chinese family without a family history presented severe phenotypes of joint dislocation, obvious flexion contractures of the elbow, arachnodactyly with slightly adducted thumbs, cranial dysplasia, foot abnormalities and aortic root dilation; Marfan syndrome was suspected at birth. Our patient was the youngest, at the age of 2 months, to experience aortic root dilation. Two B3GAT3 variants, NM_012200.2, c.752T>C, p.V251A and c.47C>A, p.S16*, with heterozygosity were identified in the patient by whole-exome sequencing; the variants were inherited from his parents. During close follow-up, significant changes in the cranial profile and obvious external hydrocephalus were present at the age of 7 months, which differs from previously reported cases. CONCLUSION: We diagnosed a patient with congenital heart defects at an early age with a B3GAT3-related disorder instead of Marfan syndrome and expanded the spectrum of B3GAT3-related disorders. We also provide a literature review of reported B3GAT3 cases; for at least one of the variants, this is the first report of genotype-phenotype correlations in individuals with cardiovascular defects being related to the acceptor substrate-binding subdomain of B3GAT3.

Significant Prediction of In-hospital Major Adverse Events by D-Dimer Level in Patients With Acute Type A Aortic Dissection.

Background: Acute type A aortic dissection (ATAAD) is a rare, life-threatening condition affecting the aorta. This study explores the relationship between the level of admission D-dimer, which was assessed during the first 2 h from admission, and in-hospital major adverse events (MAE) with ATAAD. Methods: A total of 470 patients with enhanced computed tomography (CT) confirmed diagnosis of ATAAD who underwent operation treatment in Guangdong Provincial People's hospital between September 2017 and June 2021 were enrolled in the present study. The X-tile program was used to determine the optimal D-dimer thresholds for risk. Restricted cubic spline (RSC) was performed to assess the association between D-dimer and endpoint. The perioperative data were compared between the two groups, univariate and multivariate analyses were used to investigate the risk factors of major adverse events (in-hospital mortality, gastrointestinal bleeding, paraplegia, acute kidney failure, reopen the chest, low cardiac output syndrome, cerebrovascular accident, respiratory insufficiency, MODS, gastrointestinal bleeding, and severe infection). Results: Among 470 patients, 151 (32.1%) had MAE. In-hospital mortality was 7.44%. The patients with D-dimer >14,500 ng/ml were more likely to present with acute kidney failure, low cardiac output, cerebrovascular accident, multiple organ dysfunction syndromes (MODS), gastrointestinal bleeding, and severe infection. D-dimer level was an independent risk factor for acute kidney failure (OR 2.09, 95% CI: 1.25-3.51, p = 0.005), MODS (OR 6.40, 95% CI: 1.23-33.39, p = 0.028), gastrointestinal bleeding (OR 17.76, 95% CI: 1.99-158.78, p = 0.010) and mortality (OR 3.17, 95% CI: 1.32-7.63, p = 0.010). Multivariate regression analysis of adverse events also suggested that D-dimer >14,500 ng/ml (OR 1.68, 95% CI: 1.09-2.61, p = 0.020) was the independent risk factor of major adverse events. Conclusions: Increasing D-dimer levels were independently associated with the in-hospital MAE and thus can be used as a useful prognostic biomarker before the surgery.