Numerical simulation of Gurney flap on SFYT15thick airfoil

A two-dimensional steady Reynolds-averaged Navier-Stokes （RANS） equation was solved to investigate the effects of a Gurney flap on SFYT15 thick airfoil aerodynamic performance. This airfoil was designed for flight vehicle operating at 20 km altitude with freestream velocity of 25 m/s, The chord length （C） is 5 m and the Reynolds number based on chord length is Re = 7.76 × 10^5. Gurney flaps with the heights ranging from 0.25%C to 3%C were investigated. The shear stress transport （SST） k-ω turbulence model was used to simulate the flow structure around the airfoil. It is showed that Gurney flap can enhance not only the prestall lift but also lift-to-drag ratio in a certain range of angles of attack. Specially, at cruise angle of attack （ω = 3°）, Gurney flap with 0.5%C height can increase lift-to-drag ratio by 2.7%, and lift coefficient by 12.9%, respectively. Furthermore, the surface pressure distribution, streamlines and trailing-edge flow structure around the airfoil are illustrated, which are helpful to understand the mechanisms of Gurney flap on airfoil aerodynamic performance. Moreover, it is found that the increase of airfoil drag with Gurney flap can be attributed to the increase of pressure drag between the windward and the leeward sides of Gurney flat itself.

Tanshinone Ⅱ-A Attenuates and Stabilizes Atherosclerotic Plaques in Apolipoprotein E Knockout Mice Fed with High Cholesterol Diet

Objective TanshinoneⅡ-A(Tan),a bioactive diterpene isolated fromSalvia miltiorrhiza Bunge(Danshen),possesses anti-oxidant and anti-in-flammatory activities.The present study investigated whether Tan can reduce and stabilize atherosclerotic plaques in Apolipoprotein E knockout(ApoE-/-) mice maintained on a high cholesterol diet(HCD).Methods and Results Six week-old mice challenged with HCD were ran-domly assigned to 4 groups: C57BL/6J,ApoE-/-,ApoE-/-+30 mg/kg.d Tan and ApoE-/-+10 mg/kg.d Tan.After 16 weeks of inter-vention,Tan treated mice showed decreased atherosclerotic lesion size in the aortic sinus and face aorta.Furthermore,immunohistochemical a-nalysis revealed that Tan rendered the lesion composition a more stable phenotype as evidenced by reduced necrotic cores,decreased macrophageinfiltration,increased smooth muscle cell and collagen content.Tan also significantly reduced in situ superoxide anion production,aortic expres-sion of NF-κB,and matrix metalloproteinase-9(MMP-9).In vitro treatment of RAW264.7 macrophages with Tan significantly suppressed oxi-dized LDL-induced reactive oxygen species production,pro-inflammatory cytokine(IL-6,TNF-α,MCP-1) expression,and MMP-9 activity.Conclusions Tan attenuates the development of atherosclerotic lesions and promotes plaque stability in ApoE-/-mice by reducing vascular oxi-dative stress and inflammatory responses.Our findings highlightTan as a potential therapeutic agentto preventatherosclerotic cardiovascular dis-eases.

Wind tunnel tests of stratospheric airship counter rotating propellers

Aerodynamic performance of the high-altitude propeller, especially the counter rotation effects, is ex- perimentally studied. Influences of different configurations on a stratospheric airship, included 2-blade counter-rotating propeller （CRP）, dual 2-blade single rotation propellers （SRPs） and 4-blade SRP, are also indicated. This research indicates that the effect of counter rotation can greatly improve the efficiency. It shows that the CRP configuration results in a higher efficiency than the dual 2-blade SRPs configuration or 4-blade SRP configuration under the same advance ratio, and the CRP configuration also gains the highest efficiency whether under the situation of providing the same trust or absorbing the same power. It con- cludes that, for a stratospheric airship, the CRP configuration is better than the multiple SRPs configuration or a multi-blade SRP one.

Seasonal Variations of Soil Enzyme Activity on Rocky Hillsides Continuously Planted with Vitis heyneana Roem.et Schult

[Objectives]This study was conducted to investigate the effects of Vitis heyneana cultivation on rocky hillsides on the variation of soil fertility,so as to provide theoretical support for economic development and the control of rocky desertification in the Dashi mountainous area.[Methods]Taking V.heyneana planting base in Luocheng County,Hechi City,Guangxi Province as the research object,the methods of field investigation,regular sampling and experimental analysis were used to analyze seasonal variations of soil urease,sucrase and soil alkaline phosphatase activity of 15 different sample plots surveyed,and their correlation with soil physical and chemical properties was analyzed.[Results]①In general,sucrase,urease and alkaline phosphatase were lower in summer and autumn,and higher in spring and winter,and the performance of the activity of the three enzymes was inconsistent.Among them,the activity of sucrase was in order of spring>autumn>summer>winter,and the activity of urease and alkaline phosphatase showed an order of winter>spring>summer>autumn.②The seasonal variations of soil fertility in different sample plots were affected by various factors such as human disturbance,climate change,vegetation coverage,topography and landforms,cultivation and management measures,and although the change laws in different sample plots were different,the seasonal differences in soil fertility in the same place were extremely significant.③If the influence of artificial fertilization factors is excluded,the planting of V.heyneana on rocky hillsides will cause a significant decrease in soil enzyme activity,that is,a significant decrease in soil fertility.[Conclusions]Related issues such as the effects of planting V.heyneana on the variation of soil fertility in rocky hillsides should arouse necessary attention of management departments and producers.

Numerical study of the influence of spoiler deflection on high-lift configuration

This paper numerically studies the influence of the downward spoiler deflection on the boundary layer flow of a high-lift two-element airfoil consisting of a droop nose, a main wing, a downward deflecting spoiler and a single slotted flap. Both of the boundary layer of the upper surface of the spoiler and the confluent boundary layer of the upper surface of the flap become thicker, as the downward spoiler deflection increases. Compared to the attached flow at the angle of attack of 10°, the flow of the upper surface of the spoiler becomes separated at the angle of attack of 16° when the spoiler deflection is large enough, which corresponds to the boundary layer flow reversal in velocity profiles.

The Experimental Investigation of Recirculation of Air-Cooled System for a Large Power Plant

The paper introduces thermal buoyancy effects to experimental investigation of wind tunnel simulation on direct air-cooled condenser for a large power plant. In order to get thermal flow field of air-cooled tower, PIV experiments are carried out and recirculation ratio of each condition is calculated. Results show that the thermal flow field of the cooling tower has great influence on the recirculation under the cooling tower. Ameliorating the thermal flow field of the cooling tower can reduce the recirculation under the cooling tower and improve the efficiency of air-cooled condenser also.

Characteristics and Mortality Risk Factors of Influenza-Associated Encephalopathy/Encephalitis in Children in a Tertiary Pediatric Hospital in China, 2016-2019

Background: Seasonal influenza associated neurological complications had high mortality and morbidity rates in children. In this study, we aimed to investigate the clinical characteristics and mortality risk factors in children with influenza-associated encephalopathy. Methods: Retrospectively analyze the clinical data, laboratory tests, and imaging examinations of 68 children diagnosed with influenza-associated encephalopathy from January 2016 to December 2019 at Guangzhou Women and Children’s Medical Center, and the cases were divided into survival and non-survival groups by disease outcome and analyzed between two groups. Chi-square test or Mann-Whitney rank sum test was used for comparison between groups, and multivariate Logistic regression analysis was used for the analysis of risk factors for death. Results: Among the 68 children with influenza-associated encephalopathy, 40 were male, and 28 were female, aged from 3 months to 13 years, of which 66.18% (45/68) were under 5 years old. Pathogenetic tests showed that influenza virus type A accounted for 63.24% (43/68), and influenza virus type B accounted for 36.76% (25/68). Typical brain MRI changes in childhood influenza-associated encephalopathy were bilateral symmetrical lesions of the thalamus, basal ganglia, brainstem, and cerebellum. 68 patients had a mortality rate of 20.59% (14/68), with a significantly higher proportion of fever peak > 39°C, Acute Disturbance of Consciousness (ADOC), and cardiac arrest in the non-survival group than in the survival group (P < 0.05). Laboratory tests showed significantly higher in Alanine Aminotransferase (ALT), Aspartate Transaminase (AST), Creatinine Kinase (CK), Lactate Dehydrogenase (LDH), lactate, and C-Reactive Protein (CRP). And CSF protein levels in the non-survival group compared with the survivor (P < 0.05), among them, elevated ALT, AST, LDH, and CSF protein were independent high-risk factors for death from influenza-associated encephalopathy. Conclusions: Children under 5 years of age with influenza are prone to combine neurological complications and have a higher mortality rate. Significant elevations in ALT, AST, LDH, and CSF proteins predict death from influenza-associated encephalopathy in children.

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries.Preclinical studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease models.Of clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia stroke.Here,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy.We highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and others.Finally,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis

The clinical utilization of doxorubicin(Dox)in various malignancies is restrained by its major adverse effect:irreversible cardiomyopathy.Extensive studies have been done to explore the prevention of Dox cardiomyopathy.Currently,ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy.Sorting Nexin 3(SNX3),the retromer-associated cargo binding protein with important physiological functions,was identified as a potent therapeutic target for cardiac hypertrophy in our previous study.However,few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy.In this study,a decreased level of SNX3 in Dox-induced cardiomyopathy was observed.Cardiac-specific Snx3 knockout(Snx3-cKO)significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly.SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro,and cardiac-specific Snx3 transgenic(Snx3-cTg)mice were more susceptible to Dox-induced feroptosis and cardiomyopathy.Mechanistically,SNX3 facilitated the recycling of transferrin 1 receptor(TFRC)via direct interaction,disrupting iron homeostasis,increasing the accumulation of iron,triggering ferroptosis,and eventually exacerbating Dox-induced cardiomyopathy.Overall,these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRCdependentferroptosis.

Diagnostic value of ACR TI-RADS combined with three-dimensional shear wave elastography in ACR TI-RADS 4 and 5 thyroid nodules

Background:Three-dimensional shear wave elastography(3D-SWE)is a promising method in distinguishing benign and malignant thyroid nodules.By combining with conventional method,it may further improve the diagnostic value.The study aimed to assess the diagnostic value of American College of Radiology(ACR)thyroid imaging reporting and data system(TI-RADS)combined with 3D-SWE in ACR TI-RADS 4 and 5 thyroid nodules.Methods:All nodules were examined by conventional ultrasonography,ACR TI-RADS classification,and 3D-SWE examination.Conventional ultrasonography was used to observe the location,size,shape,margin,echogenicity,taller-than-wide sign,microcalcification,and blood flow of thyroid nodules,and then ACR TI-RADS classification was performed.The Young’s modulus values(3D-C-Emax,3D-C-Emean,and elastography standard deviation[3D-C-Esd])were measured on the reconstructed coronal plane images.According to the receiver operating characteristic(ROC)curve,the best diagnostic efficiency among 3D-C-Emax,3D-C-Emean,and 3D-C-Esd was selected and the cut-off threshold was calculated.According to the surgical pathology,they were divided into benign group and malignant group.And appropriate statistical methods such as t-test and Mann-Whitney U test were used to compare the difference between the two groups.On this basis,3D-SWE combined with conventional ACR TI-RADS was reclassified as combined ACR TI-RADS to determine benign or malignant thyroid nodules.Results:Of the 112 thyroid nodules,62 were malignant and 50 were benign.The optimal cut-off value of three-dimensional maximum Young’s modulus in coronal plane(3D-C-Emax)was 51.5 kPa and the area under the curve(AUC)was 0.798.The AUC,sensitivity,specificity,and accuracy of conventional ACR TI-RADS were 0.828,83.9%,66.0%,and 75.9%,respectively.The AUC,sensitivity,specificity,and accuracy of combined ACR TI-RADS were 0.845,90.3%,66.0%,and 79.5%,respectively.The difference between the two AUC values was statistically significant.Conclusions:Combined ACR TI-RADS has higher diagnostic efficiency than conventional ACR TI-RADS.The sensitivity and accuracy of combined ACR TI-RADS showed significant improvements.It can be used as an effective method in the diagnosis of thyroid nodules.

Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression

As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin(Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor(30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.

Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation

The clinical application of doxorubicin(DOX) in cancer chemotherapy is limited by its lifethreatening cardiotoxic effects. Chrysophanol(CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes.However, the effects of CHR’s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9 C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide(3 AB)and ABT888. Ectopic expression of PARP1 effectively blocked this CHR’s cardioprotection against DOX-induced cardiomyocyte injury in H9 C2 cells. Furthermore, pre-administration with both CHR and 3 AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague–Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.

MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B

Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.

Transonic buffet control research with two types of shock control bump based on RAE2822 airfoil

Current research shows that the traditional shock control bump（SCB） can weaken the intensity of shock and better the transonic buffet performance. The author finds that when SCB is placed downstream of the shock, it can decrease the adverse pressure gradient. This may prevent the shock foot separation bubble to merge with the trailing edge separation and finally improve the buffet performance. Based on RAE2822 airfoil, two types of SCB are designed according to the two different mechanisms. By using Reynolds-averaged Navier-Stokes（RANS） and unsteady Reynolds-averaged Navier-Stokes（URANS） methods to analyze the properties of RAE2822 airfoil with and without SCB, the results show that the downstream SCB can better the buffet performance under a wide range of freestream Mach number and the steady aerodynamics characteristic is similar to that of RAE2822 airfoil. The traditional SCB can only weaken the intensity of the shock under the design condition. Under the off-design conditions, the SCB does not do much to or even worsen the buffet performance. Indeed, the use of backward bump can flatten the leeward side of the airfoil, and this is similar to the mechanism that supercritical airfoil can weaken the recompression of shock wave.

Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

Targeting castration-resistant prostate cancer with a novel RORγ antagonist elaiophylin

Prostate cancer(PCa)patients who progress to metastatic castration-resistant PCa(mCRPC)mostly have poor outcomes due to the lack of effective therapies.Our recent study established the orphan nuclear receptor RORγas a novel therapeutic target for CRPC.Here,we reveal that elaiophylin(Elai),an antibiotic from Actinomycete streptomyces,is a novel RORy antagonist and showed potent antitumor activity against CRPC in vitro and in vivo.We demonstrated that Elai selectively binded to RORy protein and potently blocked RORγtranscriptional regulation activities.Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions.Furthermore,Elai markedly reduced the recruitment of RORγto its genomic DNA response element(RORE),suppressed the expression of RORγtarget genes AR and AR variants,and significantly inhibited PCa cell growth.Importantly,Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models.Taken together,these results suggest that Elai is novel therapeutic RORγinhibitor that can be used as a drug candidate for the treatment of human CRPC.

Aerodynamic optimization and mechanism design of flexible variable camber trailing-edge flap

Trailing-edge flap is traditionally used to improve the takeoff and landing aerodynamic performance of aircraft.In order to improve flight efficiency during takeoff,cruise and landing states,the flexible variable camber trailing-edge flap is introduced,capable of changing its shape smoothly from 50% flap chord to the rear of the flap.Using a numerical simulation method for the case of the GA（W）-2 airfoil,the multi-objective optimization of the overlap,gap,deflection angle,and bending angle of the flap under takeoff and landing configurations is studied.The optimization results show that under takeoff configuration,the variable camber trailing-edge flap can increase lift coefficient by about 8% and lift-to-drag ratio by about 7% compared with the traditional flap at a takeoff angle of 8°.Under landing configuration,the flap can improve the lift coefficient at a stall angle of attack about 1.3%.Under cruise state,the flap helps to improve the lift-todrag ratio over a wide range of lift coefficients,and the maximum increment is about 30%.Finally,a corrugated structure–eccentric beam combination bending mechanism is introduced in this paper to bend the flap by rotating the eccentric beam.

A one-step specific assay for continuous detection of sirtuin 2 activity

Sirtuins(SIRTs)are nicotinamide adenine dinucleotide(NAD^+)-dependent histone deacetylases with diverse physiological functions.A variety of small molecules have been developed to interrogate the physiological function of SIRTs.Therefore,it is desirable to establish efficient and convenient assays to screen SIRTs modulators.In this study,we designed a series of fluorescent nonapeptide probes derived from substrates of SIRTI-SIRT3.Fluorescence increment of these probes is based on SIRT-mediated removal of the acyl side chain with fluorophore,which makes this system free of lysine-recognizing protease.Comparing the reaction of these fluorescent nonapeptide substrates with SIRT1-SIRT3 and SIRT6,it was confirmed that this assessment system was the most suitable for SIRT2activity detection.Thus,SIRT2 was used to modify substrates by truncating the amino acids or lysine side chain of nonapeptide.Finally,two specific and efficient fluorescent probes for SIRT2,ne-D9 and ne-K4a,were developed.Evaluation of the results revealed that ne-K4a based assay was more suitable for modulators screening in vitro,while the other specific substrate ne-D9 was stable in cell lysate and could detect the activity of SIRT2 in the same.In summary,this study presents a novel strategy for detecting SIRT2 activity in vitro and in cell lysate.

The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy

The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.