Modulation of histone acetylation enables fully mechanized hybrid rice breeding.

Hybrid rice has achieved high grain yield and greatly contributes to food security, but the manual-labour-intensive hybrid seed production process limits fully mechanized hybrid rice breeding. For next-generation hybrid seed production, the use of small-grain male sterile lines to mechanically separate small hybrid seeds from mixed harvest is promising. However, it is difficult to find ideal grain-size genes for breeding ideal small-grain male sterile lines without penalties in the number of hybrid seeds and hybrid rice yield. Here we report that the use of small-grain alleles of the ideal grain-size gene GSE3 in male sterile lines enables fully mechanized hybrid seed production and dramatically increases hybrid seed number in three-line and two-line hybrid rice systems. The GSE3 gene encodes a histone acetyltransferase that binds histones and influences histone acetylation levels. GSE3 is recruited by the transcription factor GS2 to the promoters of their co-regulated grain-size genes and influences the histone acetylation status of their co-regulated genes. Field trials demonstrate that genome editing of GSE3 can be used to immediately improve current elite male sterile lines of hybrid rice for fully mechanized hybrid rice breeding, providing a new perspective for mechanized hybrid breeding in other crops.

EDA2R knockdown alleviates myocardial ischemia/reperfusion injury through inhibiting the activation of the NF-κB signaling pathway.

Ischemia/reperfusion (I/R) is a pathological process that occurs in numerous organs and is often associated with severe cellular damage and death. Ectodysplasin-A2 receptor (EDA2R) is a member of the TNF receptor family that has anti-inflammatory and antioxidant effects. However, to the best of our knowledge, its role in the progression of myocardial I/R injury remains unclear. The present study aimed to investigate the role of EDA2R during myocardial I/R injury and the molecular mechanisms involved. In vitro, dexmedetomidine (DEX) exhibited a protective effect on hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury and downregulated EDA2R expression. Subsequently, EDA2R silencing enhanced cell viability and reduced the apoptosis of cardiomyocytes. Furthermore, knockdown of EDA2R led to an elevated mitochondrial membrane potential (MMP), repressed the release of Cytochrome C and upregulated Bcl-2 expression. EDA2R knockdown also resulted in downregulated expression of Bax, and decreased activity of Caspase-3 and Caspase-9 in cardiomyocytes, reversing the effects of H/R on mitochondria-mediated apoptosis. In addition, knockdown of EDA2R suppressed H/R-induced oxidative stress. Mechanistically, EDA2R knockdown inactivated the NF-κB signaling pathway. Additionally, downregulation of EDA2R weakened myocardial I/R injury in mice, as reflected by improved left ventricular function and reduced infarct size, as well as suppressed apoptosis and oxidative stress. Additionally, EDA2R knockdown repressed the activation of NF-κB signal in vivo. Collectively, knockdown of EDA2R exerted anti-apoptotic and antioxidant effects against I/R injury in vivo and in vitro by suppressing the NF-κB signaling pathway.

Gingival Necrosis Related to Sepsis-Induced Agranulocytosis Due to Pseudomonas aeruginosa Bacteraemia: A Case Report.

Background: There have been no reports of sepsis-induced agranulocytosis causing gingival necrosis in otherwise medically healthy patients to the authors' best knowledge. Even though there are several case reports of gingival necrosis secondary to medication-induced agranulocytosis, they have not systematically described the natural progression of agranulocytosis-related gingival necrosis. Methods: This paper presents a case report of a 29-year-old female Indian patient with generalised gingival necrosis and constitutive signs of intermittent fever, nausea, and vomiting. She also complained of abdominal pains. Blood counts showed agranulocytosis, and the patient was admitted for a workup of the underlying cause. Parenteral broad-spectrum antibiotics were administered, which brought about clinical resolution. Results: Her gingival necrosis was attributed to sepsis-induced agranulocytosis triggered by Pseudomonas aeruginosa bacteraemia, and upon clinical recovery, spontaneous exfoliation left behind exposed bone. Secondary healing over the exposed alveolar bone was noted after a year-long follow-up, albeit with some residual gingival recession. Conclusions: Oral manifestations of gingival necrosis, when present with concomitant constitutive symptoms, could indicate a serious underlying systemic condition that could be potentially life-threatening if left untreated. Dentists should be cognizant of this possibility so that timely intervention is not delayed.

Polyamines mediate the inhibitory effect of drought stress on nitrogen reallocation and utilization to regulate grain number in wheat.

Drought stress poses a serious threat to grain formation in wheat. Nitrogen (N) plays crucial roles in plant organ development; however, the physiological mechanisms by which drought stress affects plant N availability and mediates the formation of grains in spikes of winter wheat are still unclear. In this study, we determined that pre-reproductive drought stress significantly reduced the number of fertile florets and the number of grains formed. Transcriptome analysis demonstrated that this was related to N metabolism, and in particular, the metabolism pathways of arginine (the main precursor for synthesis of polyamine) and proline. Continuous drought stress restricted plant N accumulation and reallocation rates, and plants preferentially allocated more N to spike development. As the activities of amino acid biosynthesis enzymes and catabolic enzymes were inhibited, more free amino acids accumulated in young spikes. The expression of polyamine synthase genes was down-regulated under drought stress, whilst expression of genes encoding catabolic enzymes was enhanced, resulting in reductions in endogenous spermidine and putrescine. Treatment with exogenous spermidine optimized N allocation in young spikes and leaves, which greatly alleviated the drought-induced reduction in the number of grains per spike. Overall, our results show that pre-reproductive drought stress affects wheat grain numbers by regulating N redistribution and polyamine metabolism.

Advances in the differential diagnosis of transient hyperthyroidism in pregnancy and Graves' disease.

BACKGROUND: The occurrence of thyrotoxicosis during pregnancy is mainly attributed to gestational transient thyrotoxicosis (GTT) and Graves' disease (GD). It is important to distinguish between GTT and Graves' disease because the two diseases are treated very differently. However, a gold standard for the differential diagnosis of the two diseases is currently lacking, and the most common method of differentiation is based on past medical history and clinical presentation combined with thyroid-related antibodies. METHODS: A literature search of the electronic databases PubMed, Embase, Medline, Google Scholar, Cochrane Library, China Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journals Full Text Database and China Biomedical CD-ROM was performed. The search period ranged from journal inception until 2022. We used the following search terms in "All fields": {["thyroid" (common field) OR "thyroid" (subject line)] OR "hyperthyroidism" (common field)} AND {["pregnancy" (title) OR "pregnancy" (title)] AND "one over" (common field)} OR {["pregnancy" (common field) OR "pregnancy" (common field) OR "pregnancy" (subject line)] AND "Graves'" (common field)}. RESULTS: In recent years, some clinical studies at home and abroad have proposed other meaningful differential indicators, such as thyroid stimulating hormone, chorionic gonadotropin, thyroid hormone levels and thyroid ultrasound. CONCLUSION: The differential diagnostic significance of each of these indicators is summarised here with the goal of providing a better reference for the differential diagnosis of hyperthyroidism during pregnancy in clinical practice.

Clinicopathological characteristics, survival outcomes and prognostic factors in the cT1N0M0 pancreatic neuroendocrine tumors: A SEER-based study.

Small nonfunctional pancreatic neuroendocrine tumors ≤2 cm have different biological features, and there is no gold standard treatment for them. This study aimed to assess the risk of malignancy of small non-functional pancreatic neuroendocrine tumors and their outcomes after radical resection. The optimal management of small, incidentally detected pancreatic neuroendocrine tumors is controversial, with the aim of identifying factors predicting survival in patients with clinical stage T1N0M0 (cT1N0M0) pancreatic neuroendocrine tumors and whether surgical treatment improves survival. Using the Surveillance, Epidemiology, and End Results database, we identified 637 patients with cT1N0M0 pancreatic neuroendocrine tumors from 2010 to 2015, including clinicopathological characteristics, treatment modalities, and outcome data. From the surveillance, epidemiology, and end results database of 637 patients with cT1N0M0 PNENs, 564 were treated surgically. Age (P = .000), sex (P < .001), and surgery (P < .001) were independent risk factors affecting survival. Patients who have undergone surgery, women and young adults have a higher overall survival rate. The following independent prognostic predictors for cT1N0M0 pNENs were identified: age, sex, and surgery. At last, we concluded that Surgery can increase the overall survival of pancreatic neuroendocrine tumors in T1N0M0.

Should we stop dual anti-platelet therapy for dental extractions? An umbrella review for this dental dilemma.

OBJECTIVES: Dual Anti-platelet Therapy (DAPT) are prescribed to patients who had or are at risk of cerebrovascular or cardiovascular ischemic events. This umbrella review appraises existing systematic reviews on the risk of bleeding related complications during and after dental extractions for patients on DAPT. STUDY DATA AND SOURCES: This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered to the PROSPERO (International prospective register of systematic reviews) database. A systematic electronic literature search was conducted according to the PRISMA guidelines, via PubMed, Ovid, Cochrane and Embase. STUDY SELECTION: Four systematic reviews met the inclusion criteria and were included the analysis. They show DAPT increases the risk of bleeding related complications after dental extractions, but the differences may not be clinically significant as local haemostatic measures were adequate in controlling bleeding. CONCLUSION: Despite the increased risk of bleeding after dental extractions in patients on DAPT, it may not be necessary to interrupt the anti-platelet therapy. Local haemostatic agents may be sufficient in controlling both the primary or secondary bleeding. On the other hand, the complications of discontinuing DAPT may be more severe and fatal.

Species Sensitivity Distributions of Benthic Macroinvertebrates in Fludioxonil-Spiked Sediment Toxicity Tests.

The fungicide fludioxonil, given its physicochemical properties, potentially accumulates and persists in sediments. Fludioxonil has a widespread agricultural use to control various fungal diseases. Its residues may cause toxic effects to benthic aquatic fauna, thereby impacting ecosystem service functions of aquatic ecosystems. To assess the potential environmental effects of fludioxonil in the sediment compartment of edge-of-field surface waters, sediment-spiked single-species toxicity tests with benthic macroinvertebrates were performed. In all experiments artificial sediment was used with an organic carbon content of 2.43% on dry weight basis. The single-species tests were conducted with 8 benthic macroinvertebrates covering different taxonomic groups typical for the Yangtze River Delta, China. The 28d-EC10 and 28-LC10 values thus obtained were used to construct species sensitivity distributions (SSDs). In addition, our dataset was supplemented with 28d-EC10 and 28-LC10 values for 8 different benthic invertebrates from a study in the Netherlands that used field-collected sediment. Based on SSDs constructed with 28d-EC10 or 28d-LC10 values hazardous concentrations to 5% of the species tested (HC5's) were obtained. The HC5 values based on the toxicity tests from China were lower than those from the Netherlands, although 95% confidence bands overlapped. The HC5 values derived from the separate datasets from China and the Netherlands, as well as from the combined dataset, were compared to the Tier-3 Regulatory Acceptable Concentrations (RAC) for fludioxonil and the benthic invertebrate community derived from a sediment-spiked outdoor microcosm experiment conducted in the Netherlands. The HC5 values obtained appeared to be lower than this Tier-3 RAC when expressed in terms of total sediment concentration, but not always when expressed in terms of pore water concentrations.

Spontaneous osteonecrosis of the jaw in a ß-Thalassemia intermedia patient.

The resultant anemia in hemoglobinopathies like thalassemia can lead to expansion of the bone marrow cavities due to compensatory hyperplasia. This article reports a case of spontaneous osteonecrosis of the left maxillary alveolus in a patient with ß-Thalassemia intermedia. The area affected presented as areas of osteosclerosis on the radiographic examination and sequestrectomy of the left maxillary alveolus was performed after consultation with his hematologist. The exact pathogenesis for the osteonecrosis is unclear. One possible postulation for the cause of osteonecrosis in our case could be that the alveolar bone suffered ischemic infarction secondary to occlusion of the microvasculature within the expanded cancellous bone.

Separation and characterization of impurity P in azithromycin product.

Azithromycin is a macrolide antibiotic which is used to treat a wide variety of bacterial infections. Impurity P is one of the impurities in azithromycin product, which is registered in Pharmacopoeias of Europe and USA. However, to date, the structure of this impurity has still not been elucidated. In this work, we separated impurity P from azithromycin product using preparative chromatography and successfully identified its chemical structure using multiple analytical techniques. First, high-resolution ion trap-time-of-flight mass spectrometry (IT-TOF MS) was used to determine the accurate molecular mass ([M+H]+m/z 777.5121) and the chemical formula (C39H72N2O13) of the impurity. Second, Fourier transforming infrared spectroscopy (FT-IR), ultraviolet-visible absorption spectroscopy (UV-vis) and tandem mass spectrometry (MS/MS) analyses were performed to probe into the key functional groups of the impurity to aid the NMR analysis. Finally, the structure of the impurity was successfully resolved using multidimensional NMR. In addition, a mechanism for the formation of this impurity was proposed.

Intramolecular benzyl cation transfer in the gas-phase fragmentation of protonated benzyl phenyl sulfones.

In this study, the gas-phase fragmentations of protonated benzyl phenyl sulfones were investigated by electrospray ionization tandem mass spectrometry (ESI-MSn ). Upon collisional activation, several characteristic fragment ions were observed, and the similar results occurred with different substituted benzyl phenyl sulfones. A mechanism involving an intramolecular benzyl cation transfer and the formation of intermediate ion was proposed and further identified by density functional theory (DFT) calculations. In addition, a reference compound, benzenesulfinic acid benzyl ester, has been synthesized, and its protonated ion has the same gas-phase behavior as compared to the protonated benzyl phenyl sulfone. This work provides access to some insight into the intramolecular benzyl-transfer reactions of benzyl phenyl sulfones in the gas phase and orients the characteristic peaks in collision-induced dissociation spectrometry (CID-MS).

Establishing Standardized Biomedical Laboratory Technician Education for the Development of Biotechnology Research in China.

Chinese scientists have been actively engaged in biotechnology research since the mid-20th century. However, biotechnology education, especially biomedical laboratory technology education, is relatively scarce in China. More and more cutting-edge equipment and techniques have been introduced into biomedical laboratories in China, but there is a lack of high-quality technicians to apply these advancements to scientific research. In addition, the traditional education and apprenticeship systems have been demonstrated little progress. To address this gap, West China Hospital of Sichuan University established a 2-year educational program for laboratory technology in 2006 based on the residency training program. The project integrates scientific methods into the research laboratory technician training in relevant disciplines, and has developed a systematic, scientific, and effective standardized training system to cultivate high-level and stable experimental technician team for the need of advanced laboratories, which has been demonstrated greatly improve the efficiency of biomedical researchers and laboratory facilities. In this article, we introduce the practical experience in establishment and development of a standardized training system for biomedical laboratory technicians to ensure the sustainable development of medical researches.

Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway.

Fuziline, an aminoalcohol-diterpenoid alkaloid derived from Aconiti lateralis radix preparata, has been reported to have a cardioprotective activity in vitro. However, the potential mechanism of fuziline on myocardial protection remains unknown. In this study, we aimed to explore the efficacy and mechanism of fuziline on isoproterenol (ISO)-induced myocardial injury in vitro and in vivo. As a result, fuziline effectively increased cell viability and alleviated ISO-induced apoptosis. Meanwhile, fuziline significantly decreased the production of ROS, maintained mitochondrial membrane potential (MMP) and blocked the release of cytochrome C, suggesting that fuziline could play the cardioprotective role through restoring the mitochondrial function. Fuziline also could suppress ISO-induced endoplasmic reticulum (ER) stress via the PERK/eIF2α/ATF4/Chop pathway. In addition, using ROS scavenger NAC could decrease ISO-induced apoptosis and block ISO-induced ER stress, while PERK inhibitor GSK2606414 did not reduce the production of ROS, indicating that excess production of ROS induced by ISO triggered ER stress. And fuziline protected against ISO-induced myocardial injury by inhibiting ROS-triggered ER stress. Furthermore, fuziline effectively improved cardiac function on ISO-induced myocardial injury in rats. Western blot analysis also showed that fuziline reduced ER stress-induced apoptosis in vivo. Above these results demonstrated that fuziline could reduce ISO-induced myocardial injury in vitro and in vivo by inhibiting ROS-triggered ER stress via the PERK/eIF2α/ATF4/Chop pathway.

Influences of the alternation of wet-dry periods on the variability of chromophoric dissolved organic matter in the water level fluctuation zone of the Three Gorges Reservoir area, China.

Dissolved organic matter (DOM) is a crucial driver of various biogeochemical processes in aquatic systems. Thus, many lakes and streams have been investigated in the past several decades. However, fewer studies have sought to understand the changes in DOM characteristics in the waters of the Three Gorges Reservoir (TGR) areas, which are the largest artificial reservoir areas in the world. Thus, a field investigation of dissolved organic carbon (DOC) concentrations and of chromophoric dissolved organic matter (CDOM) properties was conducted from 2013 to 2015 to track the spatial-temporal variability of DOM properties in the TGR areas. The results showed that the alternations of wet and dry periods due to hydrological management have a substantial effect on the quantity and quality of aquatic DOM in TGR areas. Increases in DOC concentrations in the wet period show an apparent "dilution effect" that decreases CDOM compounds with relatively lower aromaticity (i.e., SUVA254) and molecular weight (i.e., SR). In contrast to the obvious temporal variations of DOM, significant spatial variability was not observed in this study. Additionally, DOM showed more terrigenous characteristics in the dry period but weak terrigenous characteristics in the wet period. Furthermore, the positive correlation between SUVA254 and CDOM suggests that the aromatic component controls the CDOM dynamics in TGR areas. The first attempt to investigate the DOM dynamics in TGR areas since the Three Gorges Dam was conducted in 2012, and the unique patterns of spatial-temporal variations in DOM that are highlighted in this study might provide a new insight for understanding the role of DOM in the fates of contaminants and may help in the further management of flow loads and water quality in the TGR area.

The cardiovascular toxicity of triadimefon in early life stage of zebrafish and potential implications to human health.

The health risk of triadimefon (TF) to cardiovascular system of human is still unclear, especially to pesticide suicides population, occupational population (farmers, retailers and pharmaceutical workers), and special population (young children and infants, pregnant women, older people, and those with compromised immune systems) who are at a greater risk. Therefore, firstly we explored the toxic effects and possible mechanism of cardiovascular toxicity induced by TF using zebrafish model. Zebrafish at stage of 48 h post fertilization (hpf) exposed to TF for 24 h exhibited morphological malformations which were further confirmed by histopathologic examination, including pericardial edema, circulation abnormalities, serious venous thrombosis and increased distance between the sinus venosus (SV) and bulbus arteriosus (BA) regions of the heart. In addition to morphological changes, TF induced functional deficits in the heart of zebrafish, including bradycardia and a significant reduced cardiac output that became more serious at higher concentrations. To better understand the possible molecular mechanisms underlying cardiovascular toxicity in zebrafish, we investigated the transcriptional level of genes related to calcium signaling pathway and cardiac muscle contraction. Q-PCR (quantitative real-time polymerase chain reaction) results demonstrated that the expression level of genes related to ATPase (atp2a1l, atp1b2b, atp1a3b), calcium channel (cacna1ab, cacna1da) and cardiac troponin C (tnnc1a) were significantly decreased after TF exposure. For the first time, the present study revealed that TF exposure had observable morphological and functional negative impacts on cardiovascular system of zebrafish. Mechanistically, this toxicity might result from the pressure of down-regulation of genes associated with calcium signaling pathway and cardiac muscle contraction following TF exposure. These findings generated here can provide information for better pesticide poisoning treatments, occupational disease prevention, and providing theoretical foundation for risk management measures.

Design, Synthesis, and Fungicidal Evaluation of Novel Pyrazole-furan and Pyrazole-pyrrole Carboxamide as Succinate Dehydrogenase Inhibitors.

The identification of novel succinate dehydrogenase (SDH) inhibitors represents one of the most attractive directions in the field of fungicide research and development. During our continuous efforts to pursue inhibitors belonging to this class, some structurally novel pyrazole-furan carboxamide and pyrazole-pyrrole carboxamide derivatives have been discovered via the introduction of scaffold hopping and bioisosterism to compound 1, a remarkably potent lead obtained by pharmacophore-based virtual screening. As a result of the evaluation against three destructive fungi, including Sclerotinia sclerotiorum, Rhizoctonia solani, and Pyricularia grisea, a majority of them displayed potent fungicidal activities. In particular, compounds 12I-i, 12III-f, and 12III-o exhibited excellent fungicidal activity against S. sclerotiorum and R. solani comparable to that of commercial SDHI thifluzamide and 1.

Effects of multi-environmental factors on physiological and biochemical responses of large yellow croaker, Larimichthys crocea.

Land-based recirculating aquaculture systems (RAS) and cage culture are important methods of Larimichthys crocea production. The effects of environmental factors on physiological and biochemical aspects of L. crocea require clarification. Temperature and salinity are controlled in RAS and directly affect L. crocea growth and survival. To explore optimal parameters, the oxygen consumption rate (RO), ammonium excretion rate (RN), and O/N ratio at different temperatures (8, 14, 20, 26, and 32 °C) and salinities (5, 15, 25, and 35‰) were determined. RO, RN, and O/N first increased and then decreased with elevated temperature and salinity, peaking at 26 °C and 25‰, respectively. This suggests that the metabolism of L. crocea was maximal at 26 °C and 25‰ salinity, which promote its growth and survival. Additionally, hypoxia affects cage culture, and has significant effects on enzymatic activities and stress-inducible gene expression. To accelerate the selective breeding of hypoxia-tolerant L. crocea in cage culture, we measured adenosine triphosphatase (ATPase), lactate dehydrogenase (LDH), and succinate dehydrogenase (SDH) activities, and hypoxia-inducing factor 1 (HIF-1) mRNA expression in the myocardium under hypoxia (2.5, 3.5, and 4.5 mg L-1). ATPase and SDH activities first decreased and then increased under hypoxia, whereas LDH activity and HIF-1α expression first increased and then decreased. Thus, under hypoxia, the myocardial mitochondria switched from being susceptible to being resistant to injury induced by energy metabolism, and respiration in L. crocea likely converted from aerobic to anaerobic during adaptation. Furthermore, the upregulation of HIF-1α mRNA suggests it has an active role in protection against anoxic damage.

Effects of azocyclotin on gene transcription and steroid metabolome of hypothalamic-pituitary-gonad axis, and their consequences on reproduction in zebrafish (Danio rerio).

The widely used organotins have the potential to disrupt the endocrine system, but little is known of underlying mechanisms of azocyclotin toxicity in fish. The objective of the present study was to investigate the impact of azocyclotin on reproduction in zebrafish. Adult zebrafish were exposed to 0.09 and 0.45µg/L azocyclotin for 21days, and effects on steroid hormones and mRNA expression of the genes belonging to the hypothalamic-pituitary-gonad (HPG) axis were investigated. Mass spectrometry methodology was developed to profile steroids within the metabolome of the gonads. They were disrupted as a result of azocyclotin exposure. Alterations in the expression of key genes associated with reproductive endocrine pathways in the pituitary (lhß), gonad (cyp19a1a, cyp17a1 and 17ß-hsd3), and liver (vtg1, vtg2, cyp1a1, comt, ugt1a and gstp1) were correlated with significant reductions in estrogen in both sexes and increased testosterone in females. Azocyclotin-induced down-regulation of cyp19a1a in males suggested a reduction in the rate of estrogen biosynthesis, while up-regulation of hepatic cyp1a1 and comt in both sexes suggested an increase in estrogen biotransformation and clearance. Azocyclotin also induced change in the expression of 17ß-hsd3, suggesting increased bioavailability of 11-ketotestosterone (11-KT) in the blood. Furthermore, the down-regulation of lhß expression in the brains of azocyclotin-exposed fish was associated with inhibition of oocyte maturation in females and retarded spermatogenesis in males. As a histological finding, retarded development of the ovaries was found to be an important cause for decreased fecundity, with down-regulation of vtg suspected to be a likely underlying mechanism. Additionally, relatively high concentrations of azocyclotin in the gonads may have directly caused toxicity, thereby impairing gametogenesis and reproduction. Embryonic or larval abnormalities occurred in the F1 generation along with accumulated burdens of azocyclotin in F1 eggs, following parental exposure. Overall, our results indicate that exposure to azocyclotin can impair reproduction in fish, and induce toxicity related abnormalities in non-exposed offspring.

Competitive antagonists facilitate the recovery from desensitization of α1ß2γ2 GABAA receptors expressed in Xenopus oocytes.

AIM: The continuous presence of an agonist drives its receptor into a refractory state, termed desensitization. In this study, we tested the hypothesis that a competitive antagonist, SR95531, could facilitate the recovery of α1ß2γ2 GABAA receptor from functional desensitization. METHODS: α1ß2γ2 GABAA receptors were expressed in Xenopus oocytes. GABA-evoked currents were recorded using two-electrode voltage-clamp technique. Drugs were applied through perfusion. RESULTS: Long application of GABA (100 µmol/L) evoked a large peak current followed by a small amplitude steady-state current (desensitization). Co-application of SR95531 during the desensitization caused a larger rebound of GABA current after removal of SR95531. Furthermore, application of SR95531 after removal of GABA increased the rate of receptor recovery from desensitization, and the recovery time constant was decreased from 59±3.2 s to 33±1.6 s. SR95531-facilitated receptor recovery from desensitization was dependent on the perfusion duration of SR95531. It was also dependent on the concentration of SR95531, and the curve fitting with Hill equation revealed two potency components, which were similar to the two potency components in inhibition of the steady-state current by SR95531. Bicuculline caused similar facilitation of desensitization recovery. CONCLUSION: SR95531 facilitates α1ß2γ2 GABAA receptor recovery from desensitization, possibly through two mechanisms: binding to the desensitized receptor and converting it to the non-desensitized state, and binding to the resting state receptor and preventing re-desensitization.

Budesonide ameliorates lung injury induced by large volume ventilation.

BACKGROUND: Ventilation-induced lung injury (VILI) is a health problem for patients with acute respiratory dysfunction syndrome. The aim of this study was to investigate the effectiveness of budesonide in treating VILI. METHODS: Twenty-four rats were randomized to three groups: a ventilation group, ventilation/budesonide group, and sham group were ventilated with 30 ml/kg tidal volume or only anesthesia for 4 hor saline or budesonide airway instillation immediately after ventilation. The PaO2/FiO2and wet-to-dry weight ratios, protein concentration, neutrophil count, and neutrophil elastase levels in bronchoalveolar lavage fluid (BALF) and the levels of inflammation-related factors were examined. Histological evaluation of and apoptosis measurement inthe lung were conducted. RESULTS: Compared with that in the ventilation group, the PaO2/FiO2 ratio was significantly increased by treatment with budesonide. The lung wet-to-dry weight ratio, total protein, neutrophil elastase level, and neutrophilcount in BALF were decreased in the budesonide group. The BALF and plasma tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, intercellular adhesion molecule (ICAM)-1, and macrophage inflammatory protein (MIP)-2 levels were decreased, whereas the IL-10 level was increased in the budesonide group. The phosphorylated nuclear factor (NF)-kBlevels in lung tissue were inhibited by budesonide. The histological changes in the lung and apoptosis were reduced by budesonide treatment. Bax, caspase-3, and cleaved caspase-3 were down-regulated, and Bcl-2 was up-regulated by budesonide. CONCLUSIONS: Budesonide ameliorated lung injury induced by large volume ventilation, likely by improving epithelial permeability, decreasing edema, inhibiting local and systemic inflammation, and reducing apoptosis in VILI.