Profilin-1 is involved in macroangiopathy induced by advanced glycation end products via vascular remodeling and inflammation

BACKGROUND The accumulation of advanced glycation end products(AGEs)have been implicated in the development and progression of diabetic vasculopathy.However,the role of profilin-1 as a multifunctional actin-binding protein in AGEs-induced atherosclerosis(AS)is largely unknown.AIM To explore the potential role of profilin-1 in the pathogenesis of AS induced by AGEs,particularly in relation to the Janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STAT3)signaling pathway.METHODS Eighty-nine individuals undergoing coronary angiography were enrolled in the study.Plasma cytokine levels were detected using ELISA kits.Rat aortic vascular smooth muscle cells(RASMCs)were incubated with different compounds for different times.Cell proliferation was determined by performing the MTT assay and EdU staining.An AGEs-induced vascular remodeling model was established in rats and histological and immunohistochemical analyses were performed.The mRNA and protein levels were detected using real-time PCR and Western blot analysis,respectively.In vivo,shRNA transfection was performed to verify the role of profilin-1 in AGEs-induced proatherogenic mediator release and aortic remodeling.Statistical analyses were performed using SPSS 22.0 software.RESULTS Compared with the control group,plasma levels of profilin-1 and receptor for AGEs(RAGE)were significantly increased in patients with coronary artery disease,especially in those complicated with diabetes mellitus(P<0.01).The levels of profilin-1 were positively correlated with the levels of RAGE(P<0.01);additionally,the levels of both molecules were positively associated with the degree of coronary artery stenosis(P<0.01).In vivo,tail vein injections of AGEs induced the release of proatherogenic mediators,such as asymmetric dimethylarginine,intercellular adhesion molecule-1,and the N-terminus of procollagen III peptide,concomitant with apparent aortic morphological changes and significantly upregulated expression of the profilin-1 mRNA and protein in the thoracic aorta(P<0.05 or P<0.01).Downregulation of profilin-1 expression with an shRNA significantly attenuated AGEs-induced proatherogenic mediator release(P<0.05)and aortic remodeling.In vitro,incubation of vascular smooth muscle cells(VSMCs)with AGEs significantly promoted cell proliferation and upregulated the expression of the profilin-1 mRNA and protein(P<0.05).AGEs(200μg/mL,24 h)significantly upregulated the expression of the STAT3 mRNA and protein and JAK2 protein,which was blocked by a JAK2 inhibitor(T3042-1)and/or STAT3 inhibitor(T6308-1)(P<0.05).In addition,pretreatment with T3042-1 or T6308-1 significantly inhibited AGEs-induced RASMC proliferation(P<0.05).CONCLUSION AGEs induce proatherogenic events such as VSMC proliferation,proatherogenic mediator release,and vascular remodeling,changes that can be attenuated by silencing profilin-1 expression.These results suggest a crucial role for profilin-1 in AGEs-induced vasculopathy.

Mechanism of Resveratrol on autophagy mediated by Mst1/Sirt3 signaling pathway in diabetic cardiomyopathy

Objective:To observe the effects of resveratrol on myocardial cell injury and Mst1/Sirt3 signaling pathway mediated autophagy in type 2 diabetic mice. Methods:C57 BL/KSJ db/db mice were allocated to the normal control group,the model group,and the resveratrol group;C57 BL/KSJ db/m mice served as the melbine group,with 10 mice each. The resveratrol group and the melbine group were treated with resveratrol and metformin by gavage,respectively. The normal control group and the model group were treated with equal volume of normal saline by gavage,for 8 consecutive weeks. H & E staining,transmission electron microscopy and immunofluorescence were used to observe the pathological morphology,ultrastructure and apoptosis levels of myocardial tissues,respectively. RT-qPCR method was used to detect the expression levels of apoptosis genes Bax and Bcl-2 in myocardial tissues,and Western-blot method was used to detect the expression levels of autophagy proteins(LC3 and p62),Mst1 and Sirt3 proteins in myocardial tissue. Results:Compared with the model group,resveratrol can significantly reduce the body weight,blood glucose level and serum CK and LDH levels of db/db mice,and the differences were statistically significant(P<0.05;P<0.01). Meanwhile,after resveratrol treatment,myocardial inflammation score,apoptosis rate,Bax mRNA expression level and Bax/Bcl-2 ratio in myocardial tissue were significantly reduced,and Bcl-2 mRNA expression level was significantly increased,and the differences were statistically significant(P<0.01). In addition,compared with the model group,the expression level of p62 and p-Mst1 protein in the myocardial tissue of the resveratrol group was significantly reduced,and the expression level of Sirt3 protein and the ratio of LC3Ⅱ/LC3Ⅰ were significantly increased,and the differences were statistically significant(P<0.01). Conclusion:Resveratrol promotes the autophagy level of cardiomyocytes by activating the Mst1/Sirt3 signaling pathway and inhibits cardiomyocyte apoptosis to play a protective role in diabetic cardiomyopathy.

Laparoscopic combined with thoracoscopic transdiaphragmatic hepatectomy for hepatitis B-related hepatocellular carcinoma located in segment VII or VIII

Laparoscopic hepatectomy(LH)is considered a safe and effective method of treating liver cancer because of its relatively low level of trauma,bleeding,pain,and short hospital stay as compared with traditional open surgery[1].However,this is not ideal for tumors located in segment VII or VIII of the liver as these tumors are difficult to be exposed during laparoscopy,and the conversion rate is relatively high[2].Although it has been reported that the thoracoscopic transdiaphragmatic segment VII or VIII hepatectomy can obtain better visual field and operation space[3]。

CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain

Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms.The circRNAs are mainly enriched in the central nervous system.However,their function in various physiological and pathological conditions have yet to be determined.Here,we identified circFhit,an exon-intron circRNA expressed in GABAergic neurons,which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain.Moreover,we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R^(+) neurons by promoting the expression of its parental gene Fhit in cis.Mechanistically,circFhit was directly bound to the intronic region of Fhit,and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron.In summary,we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R^(+) neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

Systematic analysis of strange single heavy baryons Ξ_(c) and Ξ_(b)

Motivated by the experimental progress in the study of heavy baryons,we investigate the mass spectra of strange single heavy baryons in theλ-mode,using the relativistic quark model and the infinitesimally shifted Gaussian basis function method.We show that experimental results are well captured using the predicted masses.The root mean square radii and radial probability density distributions of the wave functions are analyzed in detail.Meanwhile,the mass spectra allow us to successfully construct the Regge trajectories in the(J,M^(2))plane.We also preliminarily assign quantum numbers to the recently observed baryons,includingΞ_(c)(3055),Ξ_(c)(3080),Ξ_(c)(2930),Ξ_(c)(2923),Ξ_(c)(2939),Ξ_(c)(2965),Ξ_(c)(2970),Ξ_(c)(3123),Ξ_(b)(6100),Ξ_(b)(6227),Ξ_(b)(6327),andΞ_(b)(6333).Finally,the spectral structure of strange single heavy baryons is discussed.Accordingly,we predict several new baryons that may be observed in forthcoming experiments.

A new system for distinguishing native from exotic species in China

Distinguishing between native and exotic species is important for the study of biogeography and taxonomy,species conservation,vegetation management and analysis of flora and fauna(Bean 2007).Although there is a wide range of definitions of indigenous plants in different countries across the world,most people defined indigenous plants as‘taxa that have originated in a given area without human involvement or that have arrived there without intentional or unintentional intervention of humans from an area in which they are native’(Pysek et al.2004).

Inhibition of Ageratina adenophora on Spore Germination and Gametophyte Development of Macrothelypteris torresiana

Allelopathy of Ageratina adenophora plays an important role in its invasion. However, we have little knowledge of its allelpathic effects on ferns. In Petri dish bioassays, the inhibitory potential of aqueous leachates from roots, stems and leaves of A. adenophora was studied on the spore germination and gametophyte development of Macrothelypteris torresiana. All leachatss inhibited the spore germination and growth of the first rhizoid of M. torresiana and inhibitory effects increased with increasing leachate concentrations. Root leachates proved most inhibitory. Gametophyte rhizoids of M. torresiana treated with stem and leaf leachates of A. adenophora were erect, which was similar to those of the control. However, gametophyte rhizoids of M. torresiana treated with root leachates of A. adenophora were erect, but also curving or swollen. Moreover, curving and swollen rhizoids increased with increasing concentrations. As time went by, rhizoids treated with root leachates were not so curved and the swelling almost disappeared. Possible causes are discussed in the present study. The increasing concentrations of leaf leachates also delayed the stages of gametophyte development. With the treatment of root leachates, the delay was more obvious. Thus A. adenophora inhibited the spore germination and gametophyte development of M. torresiana and the root leachates were most inhibitory.

Exploiting the Community Structure of Fraudulent Keywords for Fraud Detection in Web Search

Internet users heavily rely on web search engines for their intended information.The major revenue of search engines is advertisements(or ads).However,the search advertising suffers from fraud.Fraudsters generate fake traffic which does not reach the intended audience,and increases the cost of the advertisers.Therefore,it is critical to detect fraud in web search.Previous studies solve this problem through fraudster detection(especially bots)by leveraging fraudsters'unique behaviors.However,they may fail to detect new means of fraud,such as crowdsourcing fraud,since crowd workers behave in part like normal users.To this end,this paper proposes an approach to detecting fraud in web search from the perspective of fraudulent keywords.We begin by using a unique dataset of 150 million web search logs to examine the discriminating features of fraudulent keywords.Specifically,we model the temporal correlation of fraudulent keywords as a graph,which reveals a very well-connected community structure.Next,we design DFW(detection of fraudulent keywords)that mines the temporal correlations between candidate fraudulent keywords and a given list of seeds.In particular,DFW leverages several refinements to filter out non-fraudulent keywords that co-occur with seeds occasionally.The evaluation using the search logs shows that DFW achieves high fraud detection precision(99%)and accuracy(93%).A further analysis reveals several typical temporal evolution patterns of fraudulent keywords and the co-existence of both bots and crowd workers as fraudsters for web search fraud.

Cross-section measurement for the ^(93)Nb(n,2n)^(92g)Nb reaction at the neutron energy of 14.6 MeV by the AMS method

The cross-section for the 93Nb（n, 2n）92gNb reaction has been measured at the neutron energy of 14.6 MeV using neutron activation and accelerator mass spectrometry （AMS） determination of the long-lived product nuclide 92gNb. The neutron energy was generated from the D＋T neutron source at the China Institute of Atomic Energy （CIAE）. The neutron flux was monitored by measuring the activity of 92mNb produced in the competing reaction channel of 93Nb（n, 2n）92mNb. At the neutron energy of 14.6 MeV, the 93Nb（n, 2n）92gNb reaction cross-section of （736±220） mb was obtained for the first time.

Orbit design and mission planning for global observation of Jupiter

This paper presents the method created by the National University of Defense Technology(NUDT)team in the 10th China Trajectory Optimization Competition,which entails a 3-year observation mission of 180 regions on Jupiter.The proposed method can be divided into three steps.First,a preliminary analysis and evaluation via an analytical method is undertaken to decide whether the third subtask of the mission,i.e.,exploring the Galilean moons,should be ignored.Second,a near-optimal orbit for magnetic field observation is designed by solving an analytical equation.Third,a set of observation windows and their sequence are optimized using a customized genetic algorithm.The final index obtained is 354.505,ranking second out of all teams partaking in the competition.