Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast-onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast-onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL-0919 may be a powerful/effective antidepressant with fast-onset

Genome-wide identification of the WRKY gene family in Camellia oleifera and expression analysis under phosphorus deficiency

Camellia oleifera Abel. is an economically important woody edible-oil species that is mainly cultivated in hilly areas of South China. The phosphorus (P) deficiency in the acidic soils poses severe challenges for the growth and productivity of C. oleifera. WRKY transcription factors (TFs) have been proven to play important roles in biological processes and plant responses to various biotic/abiotic stresses, including P deficiency tolerance. In this study, 89 WRKY proteins with conserved domain were identified from the C. oleifera diploid genome and divided into three groups, with group II further classified into five subgroups based on the phylogenetic relationships. WRKY variants and mutations were detected in the gene structure and conserved motifs of CoWRKYs. Segmental duplication events were considered as the primary driver in the expanding process of WRKY gene family in C. oleifera. Based on transcriptomic analysis of two C. oleifera varieties characterized with different P deficiency tolerances, 32 CoWRKY genes exhibited divergent expression patterns in response to P deficiency stress. qRT-PCR analysis demonstrated that CoWRKY11, -14, -20, -29 and -56 had higher positive impact on P-efficient CL40 variety compared with P-inefficient CL3 variety. Similar expression trends of these CoWRKY genes were further observed under P deficiency with longer treatment period of 120d. The result indicated the expression sensitivity of CoWRKYs on the P-efficient variety and the C. oleifera cultivar specificity on the P deficiency tolerance. Tissue expression difference showed CoWRKYs may play a crucial role in the transportation and recycling P in leaves by affecting diverse metabolic pathways. The available evidences in the study conclusively shed light on the evolution of the CoWRKY genes in C. oleifera genome and provided a valuable resource for further investigation of functional characterization of WRKY genes involved to enhance the P deficiency tolerance in C. oleifera

Blockade of IL-33 signalling attenuates osteoarthritis.

Objectives:Osteoarthritis (OA) is the most common form of arthritis characterised by cartilage degradation, synovitis and pain. Disease modifying treatments for OA are not available. The critical unmet need is to find therapeutic targets to reduce both disease progression and pain. The cytokine IL-33 and its receptor ST2 have been shown to play a role in immune and inflammatory diseases, but their role in osteoarthritis is unknown. Methods:Non-OA and OA human chondrocytes samples were examined for IL-33 and ST2 expression. Novel inducible cartilage specific knockout mice (IL-33Acan CreERT2) and inducible fibroblast-like synoviocyte knockout mice (IL-33Col1a2 CreERT2) were generated and subjected to an experimental OA model. In addition, wild-type mice were intra-articularly administered with either IL-33- or ST2-neutralising antibodies during experimental OA studies. Results:IL-33 and its receptor ST2 have increased expression in OA patients and a murine disease model. Administering recombinant IL-33 increased OA and pain in vivo. Synovial fibroblast-specific deletion of IL-33 decreased synovitis but did not impact disease outcomes, whilst cartilage-specific deletion of IL-33 improved disease outcomes in vivo. Blocking IL-33 signalling also reduced the release of cartilage-degrading enzymes in human and mouse chondrocytes. Most importantly, we show the use of monoclonal antibodies against IL-33 and ST2 attenuates both OA and pain in vivo. Conclusion:Overall, our data reveal blockade of IL-33 signalling as a viable therapeutic target for OA

Sub-Acute Oral Toxicity of a Novel Derivative of Agomelatine in Rats in a Sex-Dependent Manner

Agomelatine (AGO) is a new type of antidepressant with demonstrated antidepressant effects and a unique modulating circadian rhythm action. However, AGO has hepatotoxicity, which limits its clinical application. In order to develop new drugs that cause less liver injury than AGO, a series of derivatives were synthesized; compound GW117 was screened from derivatives due to its high receptor affinity. This study will investigate its sub-acute oral toxicity profile in rats in a sex-dependent manner. GW117 and AGO was administrated by gavage (200, 400, or 800 mg/kg/day) for 28 days. Hematological, biochemical tests, organ weights, histopathological examinations were carried out, the results showed that AGO and GW117 had adverse effects on platelet, liver and kidney, and had sex-differences in some indicators. Hematological tests showed that AGO and GW117 reduced the platelet count in male animals but had no effect in females. AGO increased plasma alanine aminotransferase (ALT) and total bilirubin in male animals, and GW117 had no effect on these two indicators. For females, AGO moderately elevated ALT, alkaline phosphatase (ALP), and total bilirubin, while GW117 only elevated ALP slightly. Two drugs could increase liver weight and coefficient, and cause liver pathological injury, including hepatic sinusoidal dilatation, hepatocyte fatty deposition and dotted cell necrosis in two genders. AGO caused mild to moderate hepatocyte and hepatobiliary injury in both genders, while only a mild hepatobiliary injury was caused by GW117 in females. Renal function tests showed that both drugs can increase blood urea nitrogen levels in males, while AGO, but not GW117, can slightly increase blood creatinine and urea nitrogen in females. The kidney weight and coefficient could be significantly increased by two drugs in males, and by AGO medium and GW117 high and low doses in females. The kidney pathological damage was mainly characterized by tubule dilatation, a thinning of the renal cortex. Kidney damage caused by GW117 was less than that of AGO, and there was no sex-difference. In summary, GW117 can cause mild liver and kidney damage in both genders, as well as mild platelets reduction in males, while degree of damage is less severe than AGO. Therefore, as an excellent derivative, GW117 deserves further development as an antidepressant

Probiotics fortify intestinal barrier function: a systematic review and meta-analysis of randomized trials

BackgroundProbiotics play a vital role in treating immune and inflammatory diseases by improving intestinal barrier function; however, a comprehensive evaluation is missing. The present study aimed to explore the impact of probiotics on the intestinal barrier and related immune function, inflammation, and microbiota composition. A systematic review and meta-analyses were conducted.MethodsFour major databases (PubMed, Science Citation Index Expanded, CENTRAL, and Embase) were thoroughly searched. Weighted mean differences were calculated for continuous outcomes with corresponding 95% confidence intervals (CIs), heterogeneity among studies was evaluated utilizing I2 statistic (Chi-Square test), and data were pooled using random effects meta-analyses.ResultsMeta-analysis of data from a total of 26 RCTs (n = 1891) indicated that probiotics significantly improved gut barrier function measured by levels of TER (MD, 5.27, 95% CI, 3.82 to 6.72, P < 0.00001), serum zonulin (SMD, -1.58, 95% CI, -2.49 to -0.66, P = 0.0007), endotoxin (SMD, -3.20, 95% CI, -5.41 to -0.98, P = 0.005), and LPS (SMD, -0.47, 95% CI, -0.85 to -0.09, P = 0.02). Furthermore, probiotic groups demonstrated better efficacy over control groups in reducing inflammatory factors, including CRP, TNF-α, and IL-6. Probiotics can also modulate the gut microbiota structure by boosting the enrichment of Bifidobacterium and Lactobacillus.ConclusionThe present work revealed that probiotics could improve intestinal barrier function, and alleviate inflammation and microbial dysbiosis. Further high-quality RCTs are warranted to achieve a more definitive conclusion.Clinical trial registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=281822, identifier CRD42021281822

Proceedings of Insert Conference Abbreviation: ASMEPVP2005 2005 ASME Pressure Vessels and Piping Conference PVP2005-71501 FATIGUE CRACK GROWTH PROPERTIES OF 16MNR AND 316L STEELS AT HIGH TEMPERATURE

ABSTRACT Fatigue failures often take place in high temperature pressure vessels and equipment because of fluctuation of pressure and temperature. Fatigue crack growth properties of materials at high temperatures are very important for safety assessment of high temperature equipment. A series of fatigue crack growth tests were carried out, and fatigue crack growth rates were determined at 25~500℃ for typical steels 316L and 16MnR. The laws of fatigue crack growth of two materials at different temperatures and the effect of temperature on fatigue crack growth rates were studied. The results show that the crack growth rates increase with temperature for 316L steel. Both the exponent n and constant C for Paris law change with temperature. The fatigue cracks of 16MnR propagate at 150℃ and 300℃ more slowly than at room temperature and 425℃. The fatigue crack growth rate at 425 ℃ is the highest for temperature range of 25-425℃

Enhancement of Turbulent Convective Heat Transfer using a Microparticle Multiphase Flow

The turbulent heat transfer enhancement of microfluid as a heat transfer medium in a tube was investigated. Within the Reynolds number ranging from 7000 to 23,000, heat transfer, friction loss and thermal performance characteristics of graphite, Al2O3 and CuO microfluid with the particle volume fraction of 0.25%–1.0% and particle size of 5 μm have been respectively tested. The results showed that the thermal performance of microfluids was better than water. In addition, the graphite microfluid had the best turbulent convective heat transfer effect among several microfluids. To further investigate the effect of graphite particle size on thermal performance, the heat transfer characteristics of the graphite microfluid with the size of 1 μm was also tested. The results showed that the thermal performance of the particle size of 1 μm was better than that of 5 μm. Within the investigated range, the maximum value of the thermal performance of graphite microfluid was found at a 1.0% volume fraction, a Reynolds number around 7500 and a size of 1 μm. In addition, the simulation results showed that the increase of equivalent thermal conductivity of the microfluid and the turbulent kinetic energy near the tube wall, by adding the microparticles, caused the enhancement of heat transfer; therefore, the microfluid can be potentially used to enhance turbulent convective heat transfer

PVP2005-71502 STUDY ON TUBE PULLING APART LOAD IN TUBULAR HEAT EXCHANGERS WITH FEA METHOD

ABSTRACT Tube pulling apart loads of tube-and-shell heat exchangers are very complicated, because these loads are affected by many factors, such as, tube to tubesheet joint structure, pressure, and temperatures. The tubes may break or be fouled during the service, which will result in change of tube metal temperatures and affect pulling loads. Some tubes may be pulled out from the tubesheet because of too much high tube pulling apart loads and the heat exchanger cannot be operated normally. Depending on the different flow passes of the fluid and the temperature change in the service, the tube pulling loads for several cases with different temperature distribution are calculated and analyzed for a heat exchanger using finite element (FE) method. The results show that the pulling loads of different tubes are different obviously. The pulling loads of the heat exchanger are assessed with ASME Code. The maximum pulling load is over the allowable force. FE method is a good technique to assess the distribution of the pulling loads and the location of the maximum pulling load. So it is useful and important to use FE method for forecasting the break and leak of the tubes

Eyes absent tyrosine phosphatase activity is not required for Drosophila development or survival.

Eyes absent (Eya) is an evolutionarily conserved transcriptional coactivator and protein phosphatase that regulates multiple developmental processes throughout the metazoans. Drosophila eya is necessary for survival as well as for the formation of the adult eye. Eya contains a tyrosine phosphatase domain, and mutations altering presumptive active-site residues lead to strongly reduced activities in ectopic eye induction, in vivo genetic rescue using the Gal4-UAS system, and in vitro phosphatase assays. However, these mutations have not been analyzed during normal development with the correct levels, timing, and patterns of endogenous eya expression. To investigate whether the tyrosine phosphatase activity of Eya plays a role in Drosophila survival or normal eye formation, we generated three eya genomic rescue (eyaGR) constructs that alter key active-site residues and tested them in vivo. In striking contrast to previous studies, all eyaGR constructs fully restore eye formation as well as viability in an eya null mutant background. We conclude that the tyrosine phosphatase activity of Eya is not required for normal eye development or survival in Drosophila. Our study suggests the need for a re-evaluation of the mechanism of Eya action and underscores the importance of studying genes in their native context