Hydroxycitric Acid Tripotassium Hydrate Attenuates Monocrotaline and Hypoxia-Induced Pulmonary Hypertension in Rats.

This study investigated the effects of hydroxycitric acid tripotassium hydrate on right ventricular function, myocardial and pulmonary vascular remodeling in rats with pulmonary hypertension, and possible mechanisms. METHODS: Pulmonary hypertension was induced in male Sprague-Dawley rats by a single subcutaneous injection of monocrotaline or hypoxic chamber. In vivo, inflammatory cytokine (including TNF-α, IL-1ß, IL-6, and TGF-ß, the level of SOD) expression, superoxide dismutase and hydrogen peroxide levels, and p-IκBα and p65 expressions were detected. In vitro, pulmonary artery smooth muscle cell proliferation and migration, ROS production, and hypoxia-inducible factor-1 expression were also studied. RESULTS: Hydroxycitric acid tripotassium hydrate decreased right ventricular systolic pressure and reduced right ventricular fibrosis and pulmonary vascular remodeling in rats with two kinds of pulmonary hypertension. Moreover, the expression of both inflammatory and oxidative stress factors was effectively reduced, and the p65 signaling pathway was found to be inhibited in this study. Additionally, hydroxycitric acid tripotassium hydrate inhibited human pulmonary artery smooth cell proliferation and migration in vitro. CONCLUSIONS: This study shows that hydroxycitric acid tripotassium hydrate can alleviate pulmonary hypertension caused by hypoxia and monocycloline in rats, improve remodeling of the right ventricle and pulmonary artery, and inhibit pulmonary artery smooth muscle cell proliferation and migration. The protective effects may be achieved by regulating inflammation and oxidative stress through the p65 signaling pathway.

Impact of heart failure and preoperative platelet count on the postoperative short-term outcome in infective endocarditis patients.

BACKGROUND: Heart failure (HF) and platelet count are often considered risk factors for mortality in patients with infective endocarditis (IE); however, their effects on various complications have not been elucidated. HYPOTHESIS: We speculated that HF and platelet count have significant impact on the short-term outcomes of IE. METHODS: This single-center retrospective study analyzed data from 320 IE patients who underwent surgery. A multivariate Cox proportional hazards model was used to identify the risk factors for adverse outcomes. The effect of the platelet count on the prognosis of patients with HF was determined by subgroup analysis and Kaplan-Meier analysis. RESULTS: The study population was divided into the HF group (n = 102) and the non-HF group (n = 218). The median age of the total population was 44.5 years (31-56 years), of which 227 (70.94%) patients were male. The incidence rates of 1-year all-cause mortality, cardiac outcomes, and composite outcomes were respectively almost sixfold, fourfold, and threefold higher in the HF group than in the non-HF group (all p < 0.001). In multivariate Cox regression analysis, HF was an independent risk factor for 1-year all-cause mortality, cardiac outcomes, cerebral outcomes, and composite outcomes. The Kaplan-Meier survival curves revealed that the patients with both HF and thrombocytopenia demonstrated the worst composite outcomes than the patients of the other groups (log-rank p < 0.001). In the HF group, the platelet count was significantly associated with mortality and composite outcomes. CONCLUSIONS: HF and preoperative platelet count are significantly associated with 1-year all-cause mortality and adverse outcomes postoperatively in IE patients. Patients with HF and thrombocytopenia have the worst short-term prognosis.

Development and validation of a postoperative bleeding complications prediction model in infective endocarditis.

OBJECTIVES: Bleeding complications are one of the most serious postoperative complications after cardiac surgery and are associated with high mortality, especially in patients with infective endocarditis (IE). Our objectives were to identify the risk factors and develop a prediction model for postoperative bleeding complications in IE patients. METHODS: The clinical data of IE patients treated from October 2013 to January 2022 were reviewed. Multivariate logistic regression analysis was used to evaluate independent risk factors for postoperative bleeding complications and develop a prediction model accordingly. The prediction model was verified in a temporal validation cohort. The performance of the model was evaluated in terms of its discrimination power, calibration, precision, and clinical utility. RESULTS: A total of 423 consecutive patients with IE who underwent surgery were included in the final analysis, including 315 and 108 patients in the training cohort and validation cohort, respectively. Four variables were selected for developing a prediction model, including platelet counts, systolic blood pressure, heart failure and vegetations on the mitral and aortic valves. In the training cohort, the model exhibited excellent discrimination power (AUC = 0.883), calibration (Hosmer-Lemeshow test, P = 0.803), and precision (Brier score = 0.037). In addition, the model also demonstrated good discrimination power (AUC = 0.805), calibration (Hosmer-Lemeshow test, P = 0.413), and precision (Brier score = 0.067) in the validation cohort. CONCLUSIONS: We developed and validated a promising risk model with good discrimination power, calibration, and precision for predicting postoperative bleeding complications in IE patients.

The Genome of Vitis zhejiang-adstricta Strengthens the Protection and Utilization of the Endangered Ancient Grape Endemic to China.

Vitis zhejiang-adstricta (V. zhejiang-adstricta) is one of the most important and endangered wild grapes. It is a national key protected wild, rare and endangered ancient grape endemic to China and used as a candidate material for resistance breeding owing to its excellent significant disease resistance. Here, we present a high-quality chromosome-level assembly of V. zhejiang-adstricta (IB-VB-01), comprising 506.66 Mb assembled into 19 pseudo-chromosomes. The contig N50 length is 3.91 Mb with 31,196 annotated protein-coding genes. Comparative genome and evolutionary analyses illustrated that V. zhejiang-adstricta has a specific position in the evolution of East Asian Vitis and shared a common ancestor with Vitis vinifera during the divergence of the two species about 10.42 (between 9.34 and 11.12) Mya. The expanded gene families compared with those in plants were related to disease resistance, and constructed gene families were related to plant growth and primary metabolism. With the analysis of gene family expansion and contraction, the evolution of environmental adaptability and especially the NBS-LRR gene family of V. zhejiang-adstricta was elucidated based on the pathways of resistance genes (R genes), unique genes and structural variations. The near-complete and accurate diploid V. zhejiang-adstricta reference genome obtained herein serves as an important complement to wild grape genomes and will provide valuable genomic resources for investigating the genomic architecture of V. zhejiang-adstricta as well as for improving disease resistance breeding strategies in grape.

Clinical efficacy of robotic spine surgery: an updated systematic review of 20 randomized controlled trials.

Purpose: To determine whether using robots in spine surgery results in more clinical advantages and fewer adverse consequences. Methods: Between October 1990 and October 2022, a computer-based search was conducted through the databases of PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, China Biology Medicine, VIP databases, and WAN FANG. The study only included randomized controlled trials (RCTs) comparing the clinical efficacy and safety of robot-assisted surgery with those of conventional spine surgery. The review was conducted following PRISMA 2020, and AMSTAR-2 was used to evaluate the methodological quality. R version 4.2.1 was used in the meta-analysis. The Cochrane Collaboration Tool was used for evaluating the risk of bias. Results: This study analyzed 954 participants from 20 RCTs involving cervical spondylosis, lumbar degenerative disease, scoliosis, etc. The robot-assisted group outperformed the freehand group in terms of intraoperative blood loss, number of screws in grade A position, grade A + B position, radiation dose, and hospital stay. Operation duration, visual analog scale scores of low back pain, Oswestry disability index, and radiation exposure time did not significantly differ between the two groups. Conclusions: Although robotic spine surgery is more accurate in pedicle screw placement than conventional methods, the robot group did not demonstrate an advantage in terms of clinical efficacy. Studies of complications and cost-effectiveness are still very rare.

Risk factors for mortality in surgical patients on combined continuous renal replacement therapy and extracorporeal membrane oxygenation: single-center retrospective study.

OBJECTIVE: In patients receiving extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT) is increasingly being used for renal replacement and fluid management. However, critically ill surgical patients receiving combined ECMO and CRRT tend to have a high mortality rate, and there are limited studies on this population. Therefore, we aimed to investigate the risk factors for mortality in surgical patients receiving combined ECMO and CRRT. METHODS: Data of surgical patients who underwent ECMO between December 2013 and April 2023 were retrospectively reviewed. Univariate and multivariate logistic regression analysis were used to identify the risk variables. Receiver operating characteristic (ROC) curve analysis was used to determine the cutoff value of albumin and age to predict death. RESULTS: A total of 199 patients on ECMO support were screened, of which 105 patients were included in the final analysis. Of 105 patients, 77 (73.33%) were treated with CRRT. Veno-arterial ECMO was performed in 97 cases (92.38%), and the rest were veno-venous ECMO (n = 8, 7.62%). Cardiovascular-related surgery was performed in the main patients (n = 86, 81.90%) and other types of surgery in 19 patients. In surgical patients on ECMO support, the logistic regression analysis showed that CRRT implantation, male sex, and age were the independent risks factors for mortality. Furthermore, the ROC curve analysis showed that age 48.5 years had the highest Youden index. In surgical patients on combined CRRT and ECMO, age, valvular heart disease, and albumin were the independent risk factors for prognosis. Albumin had the highest Youden index at a cutoff value of 39.95 g/L for predicting mortality, though the overall predictive value was modest (area under ROC 0.704). Age had the highest Youden index at a cutoff value of 48.5 years for predicting mortality. CONCLUSIONS: In our cohort of surgical patients requiring ECMO, which consisted mostly of patients undergoing cardiovascular surgery requiring VA-ECMO, the need for CRRT was an independent risk factor for mortality. In the subset of patients on combined CRRT and ECMO, independent risk factors for mortality included higher age, lack of valvular heart disease, and lower serum albumin.

Efficient genome editing in grapevine using CRISPR/LbCas12a system.

Clustered regularly interspaced short palindromic repeats (CRISPR) /Cas12a system, also known as CRISPR/Cpf1, has been successfully harnessed for genome engineering in many plants, but not in grapevine yet. Here we developed and demonstrated the efficacy of CRISPR/Cas12a from Lachnospiraceae bacterium ND2006 (LbCas12a) in inducing targeted mutagenesis by targeting the tonoplastic monosaccharide transporter1 (TMT1) and dihydroflavonol-4-reductase 1 (DFR1) genes in 41B cells. Knockout of DFR1 gene altered flavonoid accumulation in dfr1 mutant cells. Heat treatment (34℃) improved the editing efficiencies of CRISPR/LbCas12a system, and the editing efficiencies of TMT1-crRNA1 and TMT1-crRNA2 increased from 35.3% to 44.6% and 29.9% to 37.3% after heat treatment, respectively. Moreover, the sequences of crRNAs were found to be predominant factor affecting editing efficiencies irrespective of the positions within the crRNA array designed for multiplex genome editing. In addition, genome editing with truncated crRNAs (trucrRNAs) showed that trucrRNAs with 20 nt guide sequences were as effective as original crRNAs with 24 nt guides in generating targeted mutagenesis, whereas trucrRNAs with shorter regions of target complementarity ≤ 18 nt in length may not induce detectable mutations in 41B cells. All these results provide evidence for further applications of CRISPR/LbCas12a system in grapevine as a powerful tool for genome engineering.

Evolution, coronary artery bypass surgery and outcomes of right ventricular dysfunction in ischaemic cardiomyopathy.

OBJECTIVES: Whether the presence or evolution of right ventricular dysfunction (RVD) affects the prognosis and the therapeutic choice between coronary artery bypass grafting (CABG) or medical therapy alone in patients with ischaemic cardiomyopathy (ICM) remains unclear. We investigate the prognostic and therapeutic implications of RVD in patients with ICM. METHODS: Patients with baseline echocardiographic right ventricular (RV) assessment were included from the Surgical Treatment of Ischaemic Heart Failure trial. The primary outcome was all-cause mortality. RESULTS: Of 1212 patients enrolled in the Surgical Treatment of Ischaemic Heart Failure trial, 1042 patients were included, with 143 (13.7%) mild RVD and 142 (13.6%) moderate-to-severe RVD. After a median follow-up of 9.8 years, compared with patients with normal RV function, patients with RVD had a higher risk of mortality [mild RVD: adjusted hazard ratio (aHR) 1.32; 95% confidence interval (CI) 1.06-1.65; moderate-to-severe RVD: aHR, 1.75; 95% CI 1.40-2.19]. Among patients with moderate-to-severe RVD, CABG provided no additional survival benefits compared to medical therapy alone (aHR: 0.98; 95% CI: 0.67-1.43). Among 746 patients with pre- and post-therapeutic RV assessment, a gradient risk for death increased from patients with consistent normal RV function, to patients with recovery from RVD, new-onset RVD and persistent RVD. CONCLUSIONS: RVD was associated with a worse prognosis in patients with ICM, and CABG provided no additional survival benefits to patients with moderate-to-severe RVD. The evolution of RV function had important prognostic implications, which emphasized the importance of both pre- and post-therapeutic RV assessment.

Mode-tunable, micro/nanoscale electrohydrodynamic deposition techniques for optoelectronic device fabrication.

The rapid development of fascinating new optoelectronic materials and devices calls for the innovative production of micro/nanostructures in a high-resolution, large-scale, low-cost fashion, preferably compatible with flexible/wearable applications. Powerful electrohydrodynamic (EHD) deposition techniques, which generate micro/nanostructures using high electrical forces, exhibit unique advantages in high printing resolution (<1 µm), tunable printing modes (electrospray for films, electrospinning for fibers and EHD jet printing for dots), and wide material applicability (viscosity 1-10 000 cps), making them attractive in the fabrication of high-density and high-tech optoelectronic devices. This review highlights recent advances related to EHD-deposited optoelectronics, ranging from solar cells, photodetectors, and light-emitting diodes, to transparent electrodes, with detailed descriptions of the EHD-based jetting mechanism, ink formulation requirements and corresponding jetting modes to obtain functional micro/nanostructures. Finally, a brief summary and an outlook on the future perspectives are proposed.

Perovskite Dimensional Evolution Through Cations Engineering to Tailor the Detection Limit in Hard X-ray Response.

Halide perovskites with various compositions are potential candidates in low-dosage X-ray detection due to their large sensitivity and tunable optoelectronic properties. Here, cations engineering induced dimensional evolution of halide perovskites between 0D, 2D, and 3D is reported. Centimeter-sized 2D lead-free perovskite single-crystal of 4-fluorophenethylammonium antimony iodide (FPEA3 SbI6 ) is synthesized. In contrast to the 0D phenethylammonium antimony iodide (PEA3 Sb2 I9 ), face-shared [Sb2 I9 ]3- of the bi-octahedral structure of PEA3 Sb2 I9 is split into corner-shared [SbI6 ]3- by intermolecular interactions and steric hindrance of FPEA+ ions in 2D FPEA3 SbI6 . Two Sb3+ ions share three octahedral [SbI6 ]3- , leaving one-third of Sb3+ vacancies in the framework of FPEA3 SbI6 . Furthermore, Sn2+ ions can be filled into the vacancies to form continuous 2D frameworks to tune the anisotropic conductivity and device sensitivity to hard X-rays. The dimensional evolution of perovskite single-crystals from 3D to 2D or 0D to 2D maximizes the signal/noise ratio to facilize the adjustability of detection limit in hard X-ray detection, which is determined by both device sensitivity and device noise current. A record low detection limit coefficient of 0.65 is achieved in the 2D FPEA3 SbSn0.5 I7 single-crystal sample, which results from selective charges collection over mobile ions/noise current in the 2D perovskite structure.

Notopterol Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rat.

Introduction: Current targeted pulmonary arterial hypertension (PAH) therapies have improved lung hemodynamics, cardiac function, and quality of life; however, none of these have reversed the ongoing remodeling of blood vessels. Considering notopterol, a linear furocoumarin extracted from the root of traditional Chinese medicine Qiang-Huo (Notopterygium incisum), had shown the antiproliferative and anti-inflammatory properties in previous studies, we hypothesized that it could play a role in ameliorating PAH. Methods: In vivo, we conducted monocrotaline (MCT) induced PAH rats and treated them with notopterol for 3 weeks. Then, the rats were examined by echocardiography and RV catheterization. The heart and lung specimens were harvested for the detection of gross examination, histological examination and expression of inflammatory molecules. In vitro, human pulmonary arterial smooth muscle cells (HPASMCs) were treated with notopterol after hypoxia; then, cell proliferation was assessed by cell counting kit-8 and Edu assay, and cell migration was detected by wound healing assays. Results: We found that notopterol improved mortality rate and RV function while reducing right ventricular systolic pressure in MCT-induced PAH rats. Furthermore, notopterol reduced right ventricular hypertrophy and fibrosis, and it also eased pulmonary vascular remodeling and MCT-induced muscularization. In addition, notopterol attenuated the pro-inflammatory factor (IL-1ß, IL-6) and PCNA in the lungs of PAH rats. For the cultured HPASMCs subjected to hypoxia, we found that notopterol can inhibit the proliferation and migration of HPASMCs. Conclusion: Our studies show that notopterol exerts anti-inflammatory and anti-proliferative effects in the pulmonary arteries, which may contribute to prevention of PAH.

Machine Learning-Based Risk Model for Predicting Early Mortality After Surgery for Infective Endocarditis.

Background The early mortality after surgery for infective endocarditis is high. Although risk models help identify patients at high risk, most current scoring systems are inaccurate or inconvenient. The objective of this study was to construct an accurate and easy-to-use prediction model to identify patients at high risk of early mortality after surgery for infective endocarditis. Methods and Results A total of 476 consecutive patients with infective endocarditis who underwent surgery at 2 centers were included. The development cohort consisted of 276 patients. Eight variables were selected from 89 potential predictors as input of the XGBoost model to train the prediction model, including platelet count, serum albumin, current heart failure, urine occult blood ≥(++), diastolic dysfunction, multiple valve involvement, tricuspid valve involvement, and vegetation >10 mm. The completed prediction model was tested in 2 separate cohorts for internal and external validation. The internal test cohort consisted of 125 patients independent of the development cohort, and the external test cohort consisted of 75 patients from another center. In the internal test cohort, the area under the curve was 0.813 (95% CI, 0.670-0.933) and in the external test cohort the area under the curve was 0.812 (95% CI, 0.606-0.956). The area under the curve was significantly higher than that of other ensemble learning models, logistic regression model, and European System for Cardiac Operative Risk Evaluation II (all, P<0.01). This model was used to develop an online, open-access calculator (http://42.240.140.58:1808/). Conclusions We constructed and validated an accurate and robust machine learning-based risk model to predict early mortality after surgery for infective endocarditis, which may help clinical decision-making and improve outcomes.

Belumosudil, ROCK2-specific inhibitor, alleviates cardiac fibrosis by inhibiting cardiac fibroblasts activation.

Cardiac fibrosis is thought to be the hallmark of pathological hypertrophic remodeling, of which the myofibroblast transdifferentiation is the key cell biological event. However, there is still no specific and effective therapeutic agent approved for cardiac fibrosis. To investigate the effects of belumosudil, the first ρ-associated kinase-2 (ROCK2)-specific inhibitor, on cardiac hypertrophy, fibrosis, and dysfunction induced by pressure overload, the transverse aortic constriction (TAC) or sham operation was carried out on wild-type C57BL/6 mice (male, 6-8 wk old) under pentobarbital anesthesia. After that, mice were randomly divided into three groups: sham operation + vehicle, TAC + vehicle, TAC + 50 mg·kg-1·day-1 belumosudil. We found that belumosudil effectively ameliorated cardiac hypertrophy, fibrosis, and dysfunction in TAC mice. To elucidate the underlying mechanism, we inhibited the expression of ROCK2 in vitro by either belumosudil or siRNA. We showed that the inhibition of ROCK2 by either belumosudil or knockdown suppressed cardiac fibroblasts activation and proliferation significantly induced by transforming growth factor-ß1 (TGF-ß1). Furthermore, our study confirmed ROCK2 mediates cardiac fibrosis by interacting with TGF-ß1/mothers against decapentaplegic homolog 2 (Smad2) pathway. Taken together, we demonstrated that belumosudil ameliorates cardiac hypertrophy and fibrosis induced by TAC via inhibiting cardiac fibroblasts activation. In conclusion, belumosudil may be a promising therapeutic drug for cardiac hypertrophy and fibrosis induced by myocardial pressure overload.NEW & NOTEWORTHY Although ρ-associated kinase-2 (ROCK2) is the main isoform of ρ-associated kinases (ROCKs) in the heart and more important in cardiac hypertrophy and fibrosis than ρ-associated kinase-1 (ROCK1), there has not been any pharmacological approach to inhibit ROCK2 selectively. Our study demonstrates for the first time that belumosudil, the first ROCK2-specific inhibitor, effectively ameliorates cardiac hypertrophy, fibrosis, and dysfunction induced by TAC via inhibiting cardiac fibroblasts activation.

A chromosome-level genome of Syringa oblata provides new insights into chromosome formation in Oleaceae and evolutionary history of lilacs.

Lilacs (Syringa L.), a group of well-known ornamental and aromatic woody plants, have long been used for gardening, essential oils and medicine purposes in East Asia and Europe. The lack of knowledge about the complete genome of Syringa not only hampers effort to better understand its evolutionary history, but also prevents genome-based functional gene mining that can help in the variety improvement and medicine development. Here, a chromosome-level genome of Syringa oblata is presented, which has a size of 1.12 Gb including 53 944 protein coding genes. Synteny analysis revealed that a recent duplication event and parallel evolution of two subgenomes formed the current karyotype. Evolutionary analysis, transcriptomics and metabolic profiling showed that segment and tandem duplications contributed to scent formation in the woody aromatic species. Moreover, phylogenetic analysis indicated that S. oblata shared a common ancestor with Osmanthus fragrans and Olea europaea approximately 27.61 million years ago (Mya). Biogeographic reconstruction based on a resequenced data set of 26 species suggested that Syringa originated in the northern part of East Asia during the Miocene (approximately 14.73 Mya) and that the five Syringa groups initially formed before the Late Miocene (approximately 9.97 Mya). Furthermore, multidirectional dispersals accompanied by gene introgression among Syringa species from Northern China during the Miocene were detected by biogeographic reconstruction. Taken together, the results showed that complex gene introgression, which occurred during speciation history, greatly contributed to Syringa diversity.

The genome of Prunus humilis provides new insights to drought adaption and population diversity.

Prunus humilis (2n = 2x = 16) is a dwarf shrub fruit tree native to China and distributed widely in the cold and arid northern region. In this study, we obtained the whole genome sequences of P. humilis by combining Illumina, PacBio and HiC sequencing technologies. This genome was 254.38 Mb long and encodes 28,301 putative proteins. Phylogenetic analysis indicated that P. humilis shares the same ancestor with Prunus mume and Prunus armeniaca at ∼ 29.03 Mya. Gene expansion analysis implied that the expansion of WAX-related and LEA genes might be associated with high drought tolerance of P. humilis and LTR maybe one of the driver factors for the drought adaption by increase the copy number of LEAs. Population diversity analysis among 20 P. humilis accessions found that the genetic diversity of P. humilis populations was limited, only 1.40% base pairs were different with each other, and more wild resources need to be collected and utilized in the breeding and improvement. This study provides new insights to the drought adaption and population diversity of P. humilis that could be used as a potential model plant for horticultural research.

Overexpression of grape ABA receptor gene VaPYL4 enhances tolerance to multiple abiotic stresses in Arabidopsis.

BACKGROUND: Abscisic acid (ABA) plays a crucial role in abiotic stress responses. The pyrabactin resistance (PYR)/PYR-like (PYL)/regulatory component of ABA receptor (RCAR) proteins that have been characterized as ABA receptors function as the core components in ABA signaling pathway. However, the functions of grape PYL genes in response to different abiotic stresses, particularly cold stress, remain less studied. RESULTS: In this study, we investigated the expression profiles of grape PYL genes upon cold treatment and isolated the VaPYL4 gene from Vitis amurensis, a cold-hardy grape species. Overexpression of VaPYL4 gene in grape calli and Arabidopsis resulted in enhanced cold tolerance. Moreover, plant resistance to drought and salt stress was also improved by overexpressing VaPYL4 in Arabidopsis. More importantly, we evaluated the contribution of VaPYL4 to plant growth and development after the treatment with cold, salt and drought stress simultaneously. The transgenic plants showed higher survival rates, earlier flowering phenotype, and heavier fresh weight of seedlings and siliques when compared with wild-type plants. Physiological analyses showed that transgenic plants had much lower content of malondialdehyde (MDA) and higher peroxidase (POD) activity. Stress-responsive genes such as RD29A (Responsive to desiccation 29A), COR15A (Cold responsive 15A) and KIN2 (Kinase 2) were also significantly up-regulated in VaPYL4-overexpressing Arabidopsis plants. CONCLUSIONS: Our results show that overexpression of VaPYL4 could improve plant performance upon different abiotic stresses, which therefore provides a useful strategy for engineering future crops to deal with adverse environments.

Celastrol attenuates the remodeling of pulmonary vascular and right ventricular in monocrotaline-induced pulmonary arterial hypertension in rats.

Background: Pulmonary arterial hypertension is a progressive angio-proliferative disease associated with high morbidity and mortality rates. Although the histopathology of pulmonary arterial hypertension is well described, its therapeutic option remains unsatisfactory. This study investigated the effect of celastrol treatment on right ventricular dysfunction, remodeling, and pulmonary vascular remodeling in pulmonary arterial hypertension rats as well as its possible mechanisms. Methods: Pulmonary arterial hypertension was induced in male Sprague-Dawley rats by a single subcutaneously injection of monocrotaline. After daily delivery of celastrol (1 mg/kg) or vehicle via intraperitoneal injection for 4 weeks, the effects of celastrol on right ventricular function, fibrosis, and pulmonary vascular remodeling were assessed. The infiltration of macrophages, the expression of inflammatory cytokines, including MCP-1, IL-1ß, IL-6, and IL-10, and the expression of NF-κB signaling pathway-associated proteins, IκBα, p-IKKα/ß and p65 were further detected. Finally, the effect of celastrol on human pulmonary artery smooth cells proliferation under hypoxia was studied in vitro. Results: Rats with pulmonary arterial hypertension had decreased right ventricular function, increased right ventricular fibrosis and pulmonary arteries with interstitial thickening and prominent media hypertrophy. Treatment with celastrol improved right ventricular function, attenuated right ventricular fibrosis and pulmonary vascular remodeling. Significantly decreased macrophage infiltration, reduced levels of pro-inflammatory cytokines, increased level of anti-inflammatory cytokine and inhibited NF-κB signaling pathway were observed in the lung tissues of rats treated with celastrol. Moreover, celastrol significantly suppressed the proliferation of human pulmonary artery smooth cells under hypoxia. Conclusions: We showed that in rats with pulmonary arterial hypertension, celastrol could improve right ventricular function, attenuate right ventricular and pulmonary vascular remodeling, and inhibit human pulmonary artery smooth cells proliferation under hypoxia. Suppression of the nuclear factor-κB (NF-κB) signaling pathway may be a part of the protective mechanism.

Highly efficient activation of endogenous gene in grape using CRISPR/dCas9-based transcriptional activators.

Overexpression and knockout (or knockdown) of gene of interest are two commonly used strategies for gene functional study. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system-mediated gene knockout had been applied in most plant species, including grapevine. However, CRISPR/dCas9 (deactivated Cas9)-based transcriptional activation is still unreported in fruit crops, although a few studies had been documented in Arabidopsis and rice. Here, we tested two transcriptional activators VP64 and TV for transcriptional activation of endogenous genes in grape. Both the dCas9-VP64 and dCas9-TV systems are efficient enough for transcriptional activation of the UDP-glucose flavonoid glycosyltransferases (UFGT) gene in grape cells. The effectiveness of the dCas9-VP64 system in UFGT activation was about 1.6- to 5.6-fold, while the efficiency of the dCas9-TV system was around 5.7- to 7.2-fold. Moreover, in grapevine plants, highly efficient activation of the cold-responsive transcription factor gene CBF4 was achieved by using the dCas9-TV system. The expression of CBF4 was increased 3.7- to 42.3-fold in transgenic plants. Compared with the wild-type plants, the CBF4-activated plants exhibited lower electrolyte leakage after cold treatment. Our results demonstrate the effectiveness of the dCas9-VP64 and dCas9-TV system in gene activation in grape, which will facilitate application of transcriptional activation in this economically important species.

Neutrophil Gelatinase-associated Lipocalin: A Potential Predictor of Embolic Events in Endocarditis.

BACKGROUND: As the complication of infective endocarditis (IE), embolic events are associated with increased mortality and morbidity. However, there are no reliable indicators to predict embolism. The aim of this study was to evaluate neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker to identify IE patients at high risk of embolism. METHODS: We conducted a prospective observational study of IE patients from January 2018 to December 2020. Plasma NGAL levels were measured in 88 IE patients (37 patients with embolic events and 51 patients without embolic events), 91 noninfectious heart valve disease patients, and 20 healthy blood donors by enzyme-linked immunosorbent assay. Native valve tissue was obtained from 16 IE patients and 16 noninfectious heart valve disease patients. Western blot and immunohistochemical staining were performed to detect NGAL and matrix metalloproteinase-9. RESULTS: Higher levels of NGAL were observed in IE patients than in noninfectious heart valve disease patients (P < .001) or healthy blood donors (P < .01). In addition, NGAL levels were higher in IE patients with embolic events compared with patients not having embolic events (P < .001). Receiver-operating characteristics analysis demonstrated that NGAL acted as a potential embolic events predictor with the cutoff value of 166.78 ng/mL. The IE patients with higher NGAL levels had significantly more severe native valve morphologic changes. The NGAL was colocalized with matrix metalloproteinase-9, and their expression in the valves of IE patients was higher than in those of noninfectious heart valve disease patients. CONCLUSIONS: Neutrophil gelatinase-associated lipocalin is a potential predictor of embolic events in IE. That may be attributed to its potency of increasing the proteolytic activity of matrix metalloproteinase-9, which leads to valve morphologic impairment.