摘要：Purpose Skin pigmentation disorders,such as vitiligo and melasma,are difficult to diagnose in the early stages,but abnor-mal tyrosinase levels and tyrosinase activity are potential *** resorufin-based fluorescence probes(RBFPs)have been designed to detect tyrosinase in tumors,but they have not been used in skin pigmentation *** this study,one of these RBFPs(synthesized by resorufin salt coupled with 3-(bromomethyl)phenol)was evaluated *** The RBFP was tested in different kinds of mouse and human skin cells,as well as in in vivo models,including zebrafish,guinea pigs,and Sprague-Dawley *** addition,small interfering RNAs(siRNAs),kojic acid,and 1-phenyl-2-thiourea(PTU)were used to inhibit tyrosinase levels or tyrosinase *** This probe successfully detected tyrosinase and emitted red fluorescence in melanoma cells and *** was also observable in zebrafish and on the skin of guinea pigs when using the *** mouse and human cells,the RBFP showed good selectivity to ***,in the case of decreased tyrosinase levels or activity caused by siRNAs,kojic acid,or PTU,the probe was sensitive to these ***,the RBFP showed no toxic effects at concentrations of<20μmol/L,both in vitro and in *** Our findings indicate the value and limitations of the RBFP in tyrosinase detection,but suggest the need for further improvement of fluorescent probes in the diagnosis of skin pigmentation disorders.

摘要：Dear Editor,Since the declaration of COVID-19 as a global pandemic on March 11,2020,this pandemic has been circulating for 17 months throughout the world,leading to more than 200 million infections and nearly 4A million deaths as of August 15,*** pathogen of COVID-19 is a novel coronavirus named SARS-CoV-2,which shares ～79％ genome sequence identity with SARS-CoV.1 At the early stage of the COVID-19 outbreak,SARS-CoV-2 caused great panic in the hardest-hit areas due to its high transmissibility and *** fight the COVID-19 crisis,drug repurposing was immediately pursued in order to find potential *** now,though some treatment options are available,there still lack effective antiviral *** is considered as the best way to control this global pandemic,but the emerging SARS-CoV-2 variants pose a great challenge to the protective efficacy of the existing ***,in the long run,finding an effective antiviral medication against the SARS-CoV-2 infection is a pressing need.

摘要：Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol(LDL-C).A novel series of tetrahydroprotoberberine derivatives(THPBs)were designed,synthesized,and evaluated as PCSK9 modulators for the treatment of *** them,eight compounds exhibited excellent activities in downregulatinghepatic PCSK9 expression better than berberine in HepG2 *** addition,five compounds 15,18,22,(R)-22,and(S)-22 showed better performance in the low-density lipoprotein,labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethyl-indocarbocyanine perchlorate(Dil-LDL)uptake assay,compared with berberine at the same *** 22,selected for in vivo evaluation,demonstrated significant reductions of total cholesterol(TC)and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic *** exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 *** results of human ether-ago-go related gene(hERG)inhibition assay indicated the potential druggability for compound 22,which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.

摘要：The imaging mass spectrometry（IMS） technology has experienced a rapid development in recent years.A new IMS technology which is based on air flow assisted ionization（AFAI） was *** allows for the convenient pretreatment of the samples and can image a large area of sample in a single measurement with high *** AFAI in DESI mode was used as the ion source in this *** new IMS method is named *** adoption of assisted air flow makes the sample pretreatment easy and *** optimization of the distance between the ion transport tube and MS orifice increases the sensitivity of the *** data processing,a program based on MATLAB with the function of numerical analysis was developed.A theoretical imaging resolution of a few hundred microns can be *** composite AFAI-IMS images of different target analytes were imaged with high sensitivity.A typical AFAI-IMS image of the whole-body section of a rat was obtained in a single analytical *** ability to image a large area for relevant samples in a single measurement with high sensitivity and repeatability is a significant *** method has enormous potentials in the MS imaging of large and complicated samples.

摘要：This paper presents DDGrid, a novel grid computing system for drug discovery and design. By utilizing the idle resources donated by the clusters that scatter over the Intemet, DDGrid can implement efficient data-intensive biologic applications. P2P high-level resource management framework with a GridP2P hybrid architecture is described. With P2P technologies, some problems which are inevitable in the master-slave model can be avoided, such as single point of failure or performance bottleneck. Then an agent-based resource scheduling algorithm is presented. With this scheduling algorithm, the idle computational resources are dynamically scheduled according to the real-time working load on each execution node. Thus DDGrid can hold an excellent load balance state. Furthermore, the framework is introduced into the practical protein molecules docking applications. Solid experimental results show the load balance and robustness of the proposed system, which can greatly speed up the process of protein molecules docking.

摘要：Objective：Although chondroprotective activities have been documented for polysaccharides,the potential target of different polysaccharide may *** study was aimed to explore the effect of glucan HBP-A in chondrocyte monolayer culture and chondrocytes-alginate hydrogel constructs in vivo,especially on the expression of type Ⅱ ***：Chondrocytes isolated from rabbit articular cartilage were cultured and verified by immunocytochemical staining of type Ⅱ *** viability was assessed after being treated with HBP-A in different *** status of chondrocytes-alginate hydrogel constructs in vitro was observed by scanning electron microscope（SEM）.The constructs were treated with HBP-A and then injected to nude mice *** weeks after transplantation,the specimens were observed through transmission electron microscopy（TEM）.The mRNA expressions of disintegrin and metalloproteinase with thrombospondin motifs 5（ADAMTs-5）,aggrecan and type Ⅱ collagen in both monolayer culture and constructs were determined by real time polymerase chain reaction（PCR）.The expression of typeⅡ collagen and matrix metalloproteinases-3（MMP-3） in chondrocyte monolayer culture was also tested through Western blot and enzyme linked immunosorbent assay（ELISA）,***：MMP-3 secretion and ADAMTs-5 mRNA expression in vitro were inhibited by HBP-A at 0.3 mg/mL *** morphological study,there were significant appearance of collagen in those constructs treated by ***,in both chondrocyte monolayer culture and chondrocytes-alginate hydrogel constructs,the expression of type Ⅱcollagen was increased significantly in HBP-A group when compared with control group（P〈0.001）.Conclusions：The study documented that the potential pharmacological target of glucan HBP-A in chondrocytes monolayer culture and tissue engineered cartilage in vivo may be concerned with the inhibition of catabolic enzymes MMP-3,ADAMTs-5,and increas

摘要：A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.

摘要：The research and development （R＆D） process of chinese medicine, with one notable feature, clinical application based, is significantly different from which of chemical and biological medicine, from laboratory research to clinics. Besides, compound prescription is another character. Therefore, according to different R＆D theories between chinese and Western medicine, we put forward a new strategy in drug design of chinese medicine, which focuses on ＂combination- activity relationship （CAR）＂, taking prescription discovery, component identification and formula optimization as three key points to identify the drugs of high efficacy and low toxicity. The method of drug design of chinese medicine includes： new prescription discovery based on clinical data and literature information, component identification based on computing and experimental research, as well as formula optimization based on system modeling. This paper puts forward the concept,research framework and techniques of drug design of chinese medicine, which embodies the R＆D model of chinese medicine, hoping to support the drug design of chinese medicine theoretically and technologically.

摘要：To discover novel strobilurins analogues with good and broad spectrum activity,a series of nove 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides-based strobilurins was designed,synthesized,and tested agains various phytopathogenic *** *** 7k exhibited substantial and broad spectrum antifungal activities against the tested phytopathogenic fungi,especially compound 7b,which showed 100%,80%,90%,and 90%antifungal activity(in virto)against Erysiphe graminis(***),Puccinia sorghi Schw:(P sorghi Schw.)Colletotrichum lagenarium(***),and Pseudoperonospora cubensis(P cubensis)at 300 ug/mL,*** or comparable to the positive control ***,compound 7b exhibited 85%greenhouse *** activity(in vivo)against *** even at 0.2μg/mL,equal to azoxystrobin(90%)and trifloxystrobin(90%)Meanwhile,compound 7b against P cubensis displayed 70%and 55%greenhouse inhibition activity(in vivo)at 1.56 and 0.2μg/mL,respectively,much better than those of azoxystrobin and trifloxystrobin(both 0%at 1.56 and 0.2 ug/mL).Therefore,compound 7b could be considered as the most promising fungicidal candidate for furthe ***,based on the effective concentration(ECso)against ***,the built CoMSIA model provided the useful reference for the further structural optimization design.

摘要：The secretion of melatonin(MT)is obviously different in the younger and the senior sectors of the population,and the maximum plasma concentration of seniors is only half of that in the younger population *** exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system(DDS),an improved therapeutic effect and reduced side effects can be *** upon this hypothesis,the pharmacokinetic parameters of MT,namely,the absorption rate constant(ka),the elimination rate constant(ke),and the ratio of absorption rate(F)to the apparent volume of distribution(V)were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger *** dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system(DDS)to generate plasma MT profiles similar to the physiological level-time *** in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates,namely,4.919μg/h during 0-4 h(r=0.9992),and 11.097μg/h during 4-12 h(r=0.9886),*** the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors,an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger *** high similarity between the experimental drug release profiles and the theoretical profiles(similarity factor f_(2)>50)and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles(r=0.9366,0.9163,0.9264)ind