High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung's disease.

PURPOSE: Hirschsprung's disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype-phenotype relationship. METHODS: We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance. RESULTS: Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33-50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance. CONCLUSION: We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases.

Penisimplicins A and B: Novel Polyketide-Peptide Hybrid Alkaloids from the Fungus Penicillium simplicissimum JXCC5.

In this study, two previously undescribed nitrogen-containing compounds, penisimplicins A (1) and B (2), were isolated from Penicillium simplicissimum JXCC5. The structures of 1 and 2 were elucidated on the basis of comprehensive spectroscopic data analysis, including 1D and 2D NMR and HRESIMS data. The absolute configuration of 2 was determined by Marfey's method, ECD calculation, and DP4+ analysis. Both structures of 1 and 2 feature an unprecedented manner of amino acid-derivatives attaching to a polyketide moiety by C-C bond. The postulated biosynthetic pathways for 1 and 2 were discussed. Additionally, compound 1 exhibited significant acetylcholinesterase inhibitory activity, with IC50 values of 6.35 µM.

Hypoxia-induced miR-9 expression promotes ovarian cancer progression via activating PI3K/AKT/mTOR/GSK3ß signaling pathway.

Ovarian cancer (OC) is one of the most prevalent malignant tumors affecting women's life and health. Since OC has a poor prognosis due to extensive metastasis, there is a need to explore a new mechanism of OC metastasis. microRNAs (miRs) are single-stranded, non-coding RNAs. miR-9 has been reported to promote cancer and may provide a new strategy for OC diagnosis. The purpose of this study was to examine the function and underlying mechanism of miR-9 in OC. RT-qPCR was used to assess miR-9 expression levels. Transwell assays were used to determine the number of migrating and invading OC cells. The protein expression levels of the PI3K/AKT/mTOR/GSK3ß signaling pathway were examined using western blotting. The results informed that, when compared to normal ovarian tissues, miR-9 was remarkably expressed in OC tissues, and hypoxia might lead to overexpression of miR-9-5p while inhibiting miR-9 notably suppressed the migrating and invading cell numbers in OC cells. In vivo, miR-9-5p knockdown inhibited tumor growth in a subcutaneous nude mice model of SKOV3 cells. Our findings suggest that miR-9 could be an underlying oncogene in OC, opening up new avenues for OC diagnosis and treatment of OC by targeting miR-9.

Diterpenes with bicyclo[2.2.2]octane moieties from the fungicolous fungus Xylaria longipes HFG1018.

Xylarilongipins A (1) and B (2), two diterpenes each with an unusual cage-like bicyclo[2.2.2]octane moiety, along with their biosynthetic precursor hymatoxin L (3), were isolated from the culture broth of the fungicolous fungus Xylaria longipes HFG1018 inhabiting in the medicinal fungus Fomitopsis betulinus. The structures and absolute configurations of the three compounds were established by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Xylarilongipin A (1) displayed moderate inhibitory activity against the cell proliferation of concanavalin A-induced T lymphocytes and lipopolysaccharide-induced B lymphocytes with IC50 values of 13.6 and 22.4 µM, respectively. Additionally, the biosynthetic pathways for compounds 1-3 are discussed. This work not only corroborates the structure of the 9,16-cyclo-(18-nor-)isopimarane skeleton by single-crystal X-ray diffraction analysis for the first time, but also provides new insights into the biosynthetic origin of the unusual diterpene skeletons.

Effects of starting one lung ventilation and applying individualized PEEP right after patients are placed in lateral decubitus position on intraoperative oxygenation for patients undergoing thoracoscopic pulmonary lobectomy: study protocol for a randomized controlled trial.

BACKGROUND: For patients receiving one lung ventilation in thoracic surgery, numerous studies have proved the superiority of lung protective ventilation of low tidal volume combined with recruitment maneuvers (RM) and individualized PEEP. However, RM may lead to overinflation which aggravates lung injury and intrapulmonary shunt. According to CT results, atelectasis usually forms in gravity dependent lung regions, regardless of body position. So, during anesthesia induction in supine position, atelectasis usually forms in the dorsal parts of lungs, however, when patients are turned into lateral decubitus position, collapsed lung tissue in the dorsal parts would reexpand, while atelectasis would slowly reappear in the lower flank of the lung. We hypothesize that applying sufficient PEEP without RM before the formation of atelectasis in the lower flank of the lung may beas effective to prevent atelectasis and thus improve oxygenation as applying PEEP with RM. METHODS: A total of 84 patients scheduled for elective pulmonary lobe resection necessitating one lung ventilation will be recruited and randomized totwo parallel groups. For all patients, one lung ventilation is initiated the right after patients are turned into lateral decubitus position. For patients in the study group, individualized PEEP titration is started the moment one lung ventilation is started, while patients in the control group will receive a recruitment maneuver followed by individualized PEEP titration after initiation of one lung ventilation. The primary endpoint will be oxygenation index measured at T4. Secondary endpoints will include intrapulmonary shunt, respiratory mechanics, PPCs, and hemodynamic indicators. DISCUSSION: Numerous previous studies compared the effects of individualized PEEP applied alone with that applied in combination with RM on oxygenation index, PPCs, intrapulmonary shunt and respiratory mechanics after atelectasis was formed in patients receiving one lung ventilation during thoracoscopic surgery. In this study, we will apply individualized PEEP before the formation of atelectasis while not performing RM in patients allocated to the study group, and then we're going to observe its effects on the aspects mentioned above. The results of this trial will provide a ventilation strategy that may be conductive to improving intraoperative oxygenation and avoiding the detrimental effects of RM for patients receiving one lung ventilation. TRIAL REGISTRATION: www.Chictr.org.cn ChiCTR2400080682. Registered on February 5, 2024.

Penidaleodiolides A and B, Cage-Like Polyketides with Neurotransmission-Regulating Activity from the Soil Fungus Penicillium daleae L3SO.

Penicillium daleae L3SO is a fungus isolated from the rhizospheric soil of the chloroplast-deficient plant Monotropa uniflora. A chemical study on the rice fermentation of this fungus led to the isolation and identification of two cage-like polyketides, penidaleodiolide A (1) and its biosynthetic-related congener penidaleodiolide B (2). The structures of 1 and 2 were determined by a combination of extensive spectroscopic analysis, biosynthetic consideration, chemical derivatization, and computational methods. Compound 1 harbors an unusual tricyclo[4.3.04,9]nonane scaffold, unprecedented in polyketide natural products. The hypothetical biosynthetic pathways for 1 and 2 were postulated and were supported by CRISPR/Cas9 genome editing results. Penidaleodiolide A (1) showed a significant inhibitory effect on the action potentials of murine hippocampal basket neurons and decreased the frequency of spontaneous excitatory postsynaptic currents in a concentration-dependent manner (the inhibition ratios were 0.30 ± 0.02 for 1 µM, 0.37 ± 0.03 for 10 µM, and 0.50 ± 0.07 for 20 µM) while being devoid of cytotoxicity against the nerve cells.

[Effects of long-term positioning tillage on13C assimilate distribution and grain yield formation in wheat]. / 长期定位耕作模式对小麦13CåŒåŒ–ç‰©åˆ†é å’Œç±½ç²’äº§é‡å½¢æˆçš„å½±å“.

To provide a theoretical basis and technical support for the high-yield and high-efficiency production of wheat, we examined the effects of different tillage patterns on wheat grain yield of Jimai 22 and the physiological mechanisms in an experiment with three treatments: 14 years in rotary tillage (R), minimal and no tillage (S), and minimal and no tillage with a 2-year subsoiling interval (SS). We assessed the light interception by wheat plant canopy, the distribution of photosynthate transport, and grain yield for the three cultivation modes. The results showed that leaf area index was significantly higher for SS treatment than the other treatments at 14-28 days after anthesis. The interception rate and amount of photosynthetically active radiation in the upper and middle layers of wheat canopy were significantly higher for SS treatment than R and S treatments at 21 days after anthesis. The contribution rate of grain assimilation and the distribution proportion of 13C assimilated in grain, and the maximum and average filling rates, were the highest under SS treatment. The 1000-kernel weight for SS treatment increased by 8.7% and 9.6%, and the grain yield increased by 14.2% and 19.4% compared with R and S treatments, respectively. SS treatment significantly improved light energy utilization by wheat canopy, promoted the accumulation and transport of dry matter, increased the grain-filling rate, increased grain weight, which together contributed to the highest grain yield. Therefore, SS was the optimal tillage pattern under the conditions of this experiment.

[Landscape Pattern Vulnerability and Its Driving Forces in Different Geomorphological Divisions in the Middle Yellow River].

The ecological environment of the middle Yellow River is highly vulnerable. Conducting a scientific assessment of landscape pattern vulnerability holds great significance, as it serves as the basis for the rational construction of the ecological environment in this area. Based on five periods of land use data from the middle Yellow River from 1990 to 2018, the landscape pattern vulnerability index was employed to analyze the spatio-temporal evolution of the landscape pattern vulnerability. Furthermore, the influencing factors for landscape pattern vulnerability in different natural geomorphological divisions were explored using an optimal parameters-based geographical detector model. The results showed that:① From 1990 to 2018, cultivated land (which accounted for 36.96 % to 39.97 % of the area) remained the predominant landscape in the middle Yellow River. Among all landscape types, cultivated land and construction land exhibited the most significant changes. The area of cultivated land decreased by 10 185.00 km2, whereas the area of construction land increased by 7 678.46 km2. ② From 1990 to 2018, the landscape pattern was dominated by low and medium vulnerability and accounted for 70 %-80 % of the total area. The high and higher vulnerability areas were concentrated in the loess hilly and gully region, whereas the lower vulnerability area was concentrated in the valley plain and the earth-rock mountain regions. During this period, landscape pattern vulnerability underwent an incipient decrease, followed by a subsequent increase. From 1990 to 2000 and from 2000 to 2005, the changes in the level of landscape pattern vulnerability were dominated by a "reduction in the degree of vulnerability". However, from 2005 to 2010 and from 2010 to 2018, it was mainly an "increase in the degree of vulnerability". ③ Annual precipitation and NDVI were the main factors influencing the vulnerability of landscape patterns, whereas the influencing factors varied across different natural geomorphological divisions:the loess hilly and gully region and the earth-rock mountain region were dominated by natural factors, with annual precipitation and DEM being the dominant factors, respectively; the loess plateau tableland-gully region, valley plain region, and sandy land and desert region were dominated by human factors, with population density, degree of land use, and distance from roads being the dominant factors, respectively. The interaction results of any two influencing factors were manifested as two-factor enhancement or nonlinear enhancement. Risk detection revealed that high vulnerability areas of landscape patterns in different natural geomorphological divisions were distributed over distinct ranges of their corresponding dominant factors. Therefore, in the practices of ecological management in the middle Yellow River, appropriate management strategies should be implemented based on the vulnerability characteristics of different natural landforms, to further improve the ecological management level of the watershed.

Anti-inflammatory response-based risk assessment in acute type A aortic dissection: A national multicenter cohort study.

Background: Early identification of patients at high risk of operative mortality is important for acute type A aortic dissection (TAAD). We aimed to investigate whether patients with distinct risk stratifications respond differently to anti-inflammatory pharmacotherapy. Methods: From 13 cardiovascular hospitals, 3110 surgically repaired TAAD patients were randomly divided into a training set (70%) and a test set (30%) to develop and validate a risk model to predict operative mortality using extreme gradient boosting. Performance was measured by the area under the receiver operating characteristic curve (AUC). Subgroup analyses were performed by risk stratifications (low versus middle-high risk) and anti-inflammatory pharmacotherapy (absence versus presence of ulinastatin use). Results: A simplified risk model was developed for predicting operative mortality, consisting of the top ten features of importance: platelet-leukocyte ratio, D-dimer, activated partial thromboplastin time, urea nitrogen, glucose, lactate, base excess, hemoglobin, albumin, and creatine kinase-MB, which displayed a superior discrimination ability (AUC: 0.943, 95 % CI 0.928-0.958 and 0.884, 95 % CI 0.836-0.932) in the derivation and validation cohorts, respectively. Ulinastatin use was not associated with decreased risk of operative mortality among each risk stratification, however, ulinastatin use was associated with a shorter mechanical ventilation duration among patients with middle-high risk (defined as risk probability >5.0 %) (ß -1.6 h, 95 % CI [-3.1, -0.1] hours; P = 0.048). Conclusion: This risk model reflecting inflammatory, coagulation, and metabolic pathways achieved acceptable predictive performances of operative mortality following TAAD surgery, which will contribute to individualized anti-inflammatory pharmacotherapy.

[Effect of gamma-aminobutyric acid treatment on plasma substance P and calcitonin gene-related peptide levels in children with asthma].

OBJECTIVE: To study the changes in plasma substance P (SP) and calcitonin gene-related peptide (CGRP) levels in children with acute asthma before and after gamma-aminobutyric acid (GABA) treatment. METHODS: Seventy-five children with asthma were randomly assigned to GABA treatment (n=36) and control groups (n=39). Both groups were given conventional treatment for asthma. Besides the conventional treatment, the treatment group was administered with oral GABA (25-30 mg/kg•d). Plasma content of SP and CGRP was measured using ELISA before treatment and after remission. RESULTS: There were no significant differences in plasma content of SP and CGRP between the GABA treatment and control groups (P＞0.05) before treatment. Plasma content of SP and CGRP in the GABA treatment group was significantly lower than the control group (SP: 57±15 pg/mL vs 127±12 pg/mL; CGRP: 23±10 pg/mL vs 42±8 pg/mL) after remission (P<0.01). Plasma content of SP and CGRP after remission was significantly lower than before treatment (P<0.01) in both groups. There was a significantly positive correlation between plasma SP and CGRP content in asthmatic children (r=0.792, P<0.01). CONCLUSIONS: GABA can significantly decrease plasma levels of SP and CGRP in children suffering from acute asthma.

METTL3 facilitates immunosurveillance by inhibiting YTHDF2-mediated NLRC5 mRNA degradation in endometrial cancer.

BACKGROUND: N6-methyladenosine (m6A) methylation is the most abundant chemical posttranscriptional modification of mRNA, and it is associated with the regulation of the immune response to tumors. However, the function of m6A modification in the immune response to endometrial cancer (EC) remains unknown. Our study investigated the immunological role of methyltransferase-like 3 (METTL3) in EC and the underlying molecular mechanism. METHODS: We investigated the correlation between the expression of METTL3 and CD8 by using an endometrial tissue microarray cohort. Next, we investigated the role and mechanism of METTL3 in the immune response to EC using a mouse tumor model and a CD8+ T cell-EC cell coculture system after METTL3 overexpression or depletion. Additionally, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were used to investigate the mechanism underlying the function of METTL3 in immunosurveillance of EC. RESULTS: METTL3 levels were downregulated in EC patients, low levels of METTL3 were correlated with poor prognosis in EC patients. There was a positive correlation between METTL3 expression and CD8 expression. Overexpression of METTL3 in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation, migration, and promoted CD8+ T-cell proliferation, and in vivo, METTL3 overexpression increased CD8+ T cell proportions and inhibited EC progression; however, genetic depletion of METTL3 exerted the opposite effects. NLR family CARD domain-containing 5 (NLRC5) was identified as a target of METTL3-mediated m6A modification. The degradation of NLRC5 was increased by YTH domain-containing family 2 (YTHDF2). CONCLUSIONS: Overall, METTL3, YTHDF2, and NLRC5 have potential to be the diagnostic and prognostic biomarkers for EC. METTL3 facilitated the m6A modifications of NLRC5 and inhibited its degradation through a YTHDF2-dependent mechanism in EC. Genetic overexpression of METTL3 attenuated the immune evasion of EC by promoting NLRC5-mediated immunosurveillance, suggesting that the METTL3/YTHDF2/NLRC5 axis is a promising target of immunotherapy in EC.

Antibacterial and ß-amyloid precursor protein-cleaving enzyme 1 inhibitory polyketides from the fungus Aspergillus chevalieri.

One new prenylated benzenoid, (±)-chevalieric acid (1), and four new anthraquinone derivatives, (10S,12S)-, (10S,12R)-, (10R,12S)-, and (10R,12R)-chevalierone (2-5), together with ten previously described compounds (6-15), were isolated from the fungus Aspergillus chevalieri (L. Mangin) Thom and Church. The structures of new compounds were elucidated by extensive 1D and 2D nuclear magnetic resonance (NMR), and HRESIMS spectroscopic analysis. The absolute configurations of 2-5 were determined by experimental and calculated electronic circular dichroism (ECD) and DP4+ analysis. Compound 10 showed weak cytotoxicity against human lung cancer cell line A549 with IC50 39.68 µM. Compounds 2-5 exhibited antibacterial activities against the methicillin-resistant Staphylococcus aureus (MRSA) and opportunistic pathogenic bacterium Pseudomonas aeruginosa. The MIC value for compound 6 against MRSA is 44.02 µM. Additionally, Compounds 8, 10, 11 showed weak to moderate inhibitory activities against the ß-secretase (BACE1), with IC50 values of 36.1, 40.9, 34.9 µM, respectively.

Effects of individualized PEEP obtained by two different titration methods on postoperative atelectasis in obese patients: study protocol for a randomized controlled trial.

BACKGROUND: The incidence of postoperative pulmonary complications (PPCs) is higher in obese patients undergoing general anesthesia and mechanical ventilation due to the reduction of oxygen reserve, functional residual capacity, and lung compliance. Individualized positive end-expiratory pressure (iPEEP) along with other lung-protective strategies is effective in alleviating postoperative atelectasis. Here, we compared the best static lung compliance (Cstat) titration of iPEEP with electrical impedance tomography (EIT) titration to observe their effects on postoperative atelectasis in obese patients undergoing laparoscopic surgery. METHODS: A total number of 140 obese patients with BMI ≥ 32.5kg/m2 undergoing elective laparoscopic gastric volume reduction and at moderate to high risk of developing PPCs will be enrolled and randomized into the optimal static lung compliance-directed iPEEP group and EIT titration iPEEP group. The primary endpoint will be pulmonary atelectasis measured and calculated by EIT immediately after extubation and 2 h after surgery. Secondary endpoints will be intraoperative oxygenation index, organ dysfunction, incidence of PPCs, hospital expenses, and length of hospital stay. DISCUSSION: Many iPEEP titration methods effective for normal weight patients may not be appropriate for obese patients. Although EIT-guided iPEEP titration is effective in obese patients, its high price and complexity limit its application in many clinical facilities. This trial will test the efficacy of iPEEP via the optimal static lung compliance-guided titration procedure by comparing it with EIT-guided PEEP titration. The results of this trial will provide a feasible and convenient method for anesthesiologists to set individualized PEEP for obese patients during laparoscopic surgery. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR2000039144 . Registered on October 19, 2020.

Influence of Multi-Holes on Fatigue Behaviors of Cast Magnesium Alloys Based on In-Situ Scanning Electron Microscope Technology.

The low cycle fatigue tests on the crack initiation and propagation of cast magnesium alloys with two small holes were carried out by using in-situ scanning electron microscope (SEM) observation technology. The fatigue crack propagation behaviors and fatigue life, which are affected by two small artificial through holes, including the distances between two holes and their locations, were discussed in detail based on the experimental results and the finite element analysis (FEA). The results indicated that the fatigue multi-cracks occurred chiefly at the edges of two holes and the main crack propagation was along the weak dendrite boundary with the plastic deformation vestiges on the surface of α-Mg phase of cast AM50 and AM60B alloys. The fatigue cracking characteristics of cast AZ91 alloy depended mainly on the brittle properties of ß-Mg17Al12 phase, in which the multi-cracks occurred still at the edges of two holes and boundaries of ß-Mg17Al12 phase. The fatigue crack initiation position of cast magnesium alloys depends strongly on the radius of curvature of through hole or stress concentration factor at the closed edges of two through holes. In addition, the fatigue multi-cracks were amalgamated for the samples with titled 45° of two small holes of cast Mg-Al alloys when the hole distance is less than 4D (D is the diameter of the small hole).

Developing transmission line equations of oxygen transport for predicting oxygen distribution in the arterial system.

The oxygen content in the arterial system plays a significant role in determining the physiological status of a human body. Understanding the oxygen concentration distribution in the arterial system is beneficial for the prevention and intervention of vascular disease. However, the oxygen concentration in the arteries could not be noninvasively monitored in clinical research. Although the oxygen concentration distribution in a vessel could be obtained from a three-dimensional (3D) numerical simulation of blood flow coupled with oxygen transport, a 3D numerical simulation of the systemic arterial tree is complicated and requires considerable computational resources and time. However, the lumped parameter model of oxygen transport derived from transmission line equations of oxygen transport requires fewer computational resources and less time to numerically predict the oxygen concentration distribution in the systemic arterial tree. In this study, transmission line equations of oxygen transport are developed according to the theory of oxygen transport in the vessel, and fluid transmission line equations are used as the theoretical reference for the development. The transmission line equations of oxygen transport could also be regarded as the theoretical basis for developing lumped parameter models of other substances in blood.

Experimental Study on Fatigue Behaviour of Shot-Peened Open-Hole Steel Plates.

This paper presents an experimental study on the fatigue behaviour of shot-peened open-hole plates with Q345 steel. The beneficial effects induced by shot peening on the fatigue life improvement are highlighted. The characteristic fatigue crack initiation and propagation modes of open-hole details under fatigue loading are revealed. The surface hardening effect brought by the shot peening is analyzed from the aspects of in-depth micro-hardness and compressive residual stress. The fatigue life results are evaluated and related design suggestions are made as a comparison with codified detail categories. In particular, a fracture mechanics theory-based method is proposed and demonstrated its validity in predicting the fatigue life of studied shot-peened open-hole details.

NADPH oxidase inhibitor improves outcome of mechanical reperfusion by suppressing hemorrhagic transformation.

BACKGROUND: Severe hemorrhagic transformation (HT) after mechanical thrombectomy predicts a poor clinical outcome in acute ischemic stroke. To better understand the mechanism of HT, we investigated the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in HT after reperfusion during acute stroke and whether NOX2/4 inhibitor VAS2870 reduces reperfusion-induced HT after mechanical recanalization. METHODS: A model of reperfusion-induced HT was established in rats (n=182) with hyperglycemic challenge and 5 h middle cerebral artery occlusion followed by 19 h reperfusion. NOX inhibitor VAS2870 was delivered intravenously 30 min before reperfusion. Infarct volume, brain water content, HT, neurological score, mortality rate, blood-brain barrier (BBB) damage, neuronal apoptosis, and reactive oxygen species were determined at 24 h after cerebral ischemia. The expressions of NOX1, NOX2, NOX4, and BBB-associated proteins were measured. RESULTS: NOX2 and NOX4 upregulation and severe HT were observed in hyperglycemic rats after cerebral ischemia/reperfusion. VAS2870 suppressed oxidative stress, neuronal apoptosis, and NOX2/4 upregulation in the ischemic hemisphere. VAS2870 reduced infarct volume (17.2±5.3% vs 37.4±9.2%, p<0.01) and the frequency of reperfusion-induced parenchymal hematoma (29.7% vs 59.5%, p<0.05) at 24 h after ischemia compared with the ischemia/reperfusion group. VAS2870 attenuated brain edema and reduced reperfusion-induced BBB breakdown, resulting in improved neurological outcome (neurological deficit score 1.43±0.50 vs 2.43±0.93, p<0.001) and reduced mortality (11.9% vs 64.1%, p<0.001). CONCLUSIONS: NOX2 and NOX4 may mediate HT in rats with large vessel stroke after mechanical reperfusion. Infusion of NOX inhibitor VAS2870 before mechanical thrombectomy represents a novel adjunctive therapeutic strategy to prevent reperfusion-induced HT and improve outcome of acute stroke treatment.

NADPH oxidase inhibitor regulates microRNAs with improved outcome after mechanical reperfusion.

BACKGROUND: Inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) pathway improves the neurological outcome in the transient middle cerebral artery occlusion (tMCAO) animal model. In this study we analyzed the microRNAs profile targeting NOX2 and NOX4 genes and its response to NOX2/4 inhibitor VAS2870 to understand the mechanisms of this protective effect. METHODS: The intraluminal filament tMCAO model was established in hyperglycemic rats (n=106) with 5 hours ischemia followed by 19 hours reperfusion. NOX inhibitor VAS2870 was delivered intravenously before reperfusion. Infarct volume, hemorrhagic transformation, and mortality were determined at 24 hours after cerebral ischemia. MicroRNAs profile targeting NOX2 and NOX4 genes were predicted by microRNA databases and further evaluated by microRNA microarray and quantitative RT-PCR. RESULTS: Ten microRNAs potentially targeting NOX2 and NOX4 genes (including microRNA-29a, microRNA-29c, microRNA-126a, microRNA-132, microRNA-136, microRNA-138, microRNA-139, microRNA-153, microRNA-337, and microRNA-376a) were significantly downregulated in the ischemic hemisphere in the tMCAO group compared with the sham-operated group, as shown by microRNA microarray and quantitative RT-PCR (all p<0.05). Intravenous treatment with NOX inhibitor VAS2870 before reperfusion increased the expression of microRNA-29a, microRNA-29c, microRNA-126a, and microRNA-132 compared with the tMCAO group (all p<0.05). CONCLUSIONS: Several microRNAs potentially targeting NOX2 and NOX4 genes displayed altered levels in hyperglycemic rats with the tMCAO model, suggesting their regulatory roles and targeting potentials for acute ischemic stroke treatment. Targeting specific microRNAs may represent a novel intervention opportunity to improve outcome and reduce hemorrhagic transformation after mechanical reperfusion for acute ischemic stroke.

Fatigue Property of Open-Hole Steel Plates Influenced by Bolted Clamp-up and Hole Fabrication Methods.

Steel plates with open holes are commonly used in structural assemblies. The fatigue properties of such details are influenced by bolted clamp-up and hole fabrication methods. The fracture surface, stiffness degradation and fatigue life of test specimens are investigated in detail and compared with the contemporary test data. The analysis results show that the presence of draglines greatly influences the fatigue crack initiation at the open-hole cut by laser. The bolted clamp-up condition greatly enhances the stiffness and the fatigue life of the open-hole details. A discussion is also made from a comparison with the referred fatigue life of hole fabrication details, such as the influence of plate thickness and plasma cutting, drilling and oxy-fuel gas cutting, with the details studied herein. This work could enhance the understanding of the fatigue property and design of such details.

A preliminary study on epigenetic regulation of Acanthopanax senticosus in leukemia cell lines.

Conventional chemotherapy for leukemia inevitably causes systemic toxicity. Acanthopanax senticosus, a naturally occurring herb used in traditional Chinese medicine, has been found to be a multipotent bioflavonoid with great potential in the prevention and treatment of malignant diseases. However, the mechanism underlying the action of A. senticosus in epigenetic regulation is poorly understood. In the study described here, we focused on the efficacy of A. senticosus in inducing apoptosis of leukemia cells and a possible mechanism. By evaluating the inhibition ratio and morphologic changes, we found that A. senticosus can inhibit growth and induce apoptosis of human leukemia HL-60 and HL60/ADM cells in a dose- and time-dependent manner. Furthermore, A. senticosus induced Fas ligand (FasL) expression and blocked the cell cycle in S phase. In addition, A. senticosus exhibited a potential for inhibition of histone deacetylase (HADC), which contributes to histone acetylation. It possibly resulted in the promotion of the expression of FasL. It is suggested that A. senticosus could be recognized as a new HDAC inhibitor which was able to reactivate aberrantly silenced genes. We discuss the clinical aspects of using A. senticosus for treatment of leukemia.