简介：AbstractPsoriatic arthritis (PsA) is a type of chronic inflammatory arthritis which is associated with psoriasis. The early recognition and treatment for PsA are of critical importance. Janus kinase (JAK) inhibitors, as a kind of orally small molecules, have emerged as an encouraging class of drug in PsA treatment. This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA. There are three JAK inhibitors approved for use in autoimmune diseases, for example, tofacitinib, baricitinib, and upadacitinib, and only tofacitinib has been approved in PsA treatment. The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing. The efficacy and safety of these agents were briefly discussed. Although there are still issues in terms of their efficacy and safety currently, JAK inhibitors are expected to benefit more PsA patients in future.

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简介：Cancerevadeshostimmunesurveillancebyusingimmunecheckpoints,whichareinhibitorypathwayscrucialformaintainingself-tolerance1.Tumorcellsexpressmultipleinhibitoryligands,andtumor-infiltratinglymphocytes(TIL)expressavarietyofinhibitoryreceptors.InhibitoryreceptorscytotoxicT-lymphocyte-associatedprotein4(CTLA-4)andprogrammeddeath-1

简介：摘要目的系统评价Janus kinase(JAK)抑制剂治疗新型冠状病毒肺炎(Coronavirus Disease 2019, COVID-19)的临床疗效和不良反应。方法对符合纳入标准的19篇文献进行JAK抑制剂治疗COVID-19的临床疗效和不良反应的Meta分析，分析内容包括异质性检验、相对危险度(relative risk, RR)、均数差(mean difference, MD)和发表偏倚。结果19项研究中的JAK抑制剂组与对照组相比，临床疗效方面，病死率、临床恶化、恢复率的RR及其95%置信区间(95% confidence interval, 95%CI)分别为0.52(95%CI: 0.44~0.62)、0.45(95%CI: 0.25~0.83)、1.21(95%CI: 1.03~1.43)，恢复时间的MD及其95%CI为－0.96(95%CI: －1.13~－0.79)；不良反应方面(包含严重不良反应、感染、栓塞、深静脉血栓、肺栓塞、肝功能障碍、精神障碍、肾脏和泌尿系统疾病)，只有严重不良反应的P值具有统计学意义，P＝0.010，其RR及95%CI为0.83(95%CI: 0.72~0.97)。结论JAK抑制剂有助于降低COVID-19住院患者的病死率，改善临床结果，且不良反应的风险不增加。

简介：Polymer/metalcompositesegmentalJanusnanoparticles(NPs)aresynthesizedbysequentialgrowthagainstpoly(4-vinylpyridine)(P4VP)crosslinkedcP4VP-PSJanusNPs.AJanusclusterofpoly(4-vinylpyridine)-block-polystyrene(P4VPb-PS)diblockcopolymerisself-organizedafterabsorptionontoasilicapatchysphereviahydrogenbonding.SelectivecrosslinkingofP4VPleadstotheformationofrobustcP4VP-PSJanusNPs.WithinthecP4VPdomain,functionalspeciessuchasmetalsarepreferentiallygrownbyinsitureduction.Otherthiol-cappedpolymers,forexample,thiol-cappedpoly(Nisopropylacrylamide)(PNIPAM-SH),canbeconjugatedontotheoppositesidetoformpolymer/metaltriplesegmentalJanusNPs.ThehyperthermiaeffectofAuNPofPNIPAM-Au@cP4VP-PSbynearinfrared(NIR)irradiationcantriggerafasttransitionfromamphiphilictohydrophobicoftheJanusNPsatlowsurroundingtemperature.De-stabilizationoftheemulsionisNIRtriggeredalthoughthesystemtemperatureisbelowLCST(~32°C).

简介：AbstractBackground:Developing effective spinal cord repair strategies for spinal cord injury (SCI) is of great importance. Emerging evidence suggests that microRNAs (miRNAs) are closely linked to SCI recovery. This study aimed to investigate the function of miR-34c in the neuronal recovery in rats with SCI.Methods:A rat model with SCI was established. Differentially expressed miRNAs were identified by a microarray analysis. MiR-34c expression in rats was measured by reverse transcription quantitative polymerase chain reaction. Altered expression of miR-34c or C-X-C motif ligand 14 (CXCL14) was introduced in SCI rats to measure their roles in neuronal recovery. Western blot analysis was performed to determine the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription-3 (STAT3). Neuronal apoptosis in rat spinal cord tissues was detected. The concentrations of SCI recovery-related proteins thyrotropin releasing hormone (TRH), prostacyclin (PGI2), and ganglioside (GM) were evaluated by enzyme-linked immunosorbent assay. Data were analyzed using a t-test with a one-way or two-way analysis of variance.Results:Rats with SCI presented decreased grip strength (112.03 ± 10.64 vs. 17.32 ± 1.49 g, P < 0.01), decreased miR-34c expression (7 days: 3.78 ± 0.44 vs. 0.95 ± 0.10, P < 0.05), and increased CXCL14 expression (7 days: 0.61 ± 0.06 vs. 2.91 ± 0.27, P < 0.01). MiR-34c was found to directly bind to CXCL14. Overexpression of miR-34c increased grip strength (11.23 ± 1.08 vs. 31.26 ± 2.99 g, P < 0.01) and reduced neuronal apoptosis in spinal cord tissues (53.61% ± 6.07% vs. 24.59% ± 3.32%, P < 0.01), and silencing of CXCL14 also increased the grip strength (12.76 ± 1.13 vs. 29.77 ± 2.75 g, P < 0.01) and reduced apoptosis in spinal cord tissues (55.74% ± 6.24% vs. 26.75% ± 2.84%, P < 0.01). In addition, miR-34c upregulation or CXCL14 downregulation increased the concentrations of TRH, PGI2, and GM, and reduced phosphorylation of JAK2 and STAT3 in rats with SCI (all P < 0.01).Conclusion:The study provided evidence that miR-34c could promote neuronal recovery in rats with SCI through inhibiting CXCL14 expression and inactivating the JAK2/STAT3 pathway. This study may offer new insights into SCI treatment.

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简介：HDAC和帽子是哪个的二种酶catalysedeacetylation和在优核质的histone的acetylation，其动态平衡在DNA为基因抄写和优核质的基因表示有精确规定水平。他们的Disbalance能在正常房间带增长和区别的混乱，然后导致肿瘤的开始。他们的异常功能是直接与各种各样的肿瘤的开始和前进有关例如promyelocytic白血病，Hodgkin淋巴瘤，结肠的癌症和gastral癌症。HDAC的禁止者被用于肿瘤的治疗。他们能制止HDAC的活动并且堵住deacetylation的混乱引起的基因表示的抑制。它的主要生物效果在导致肿瘤房间的区别躺着，逮捕在G0/G1的房间圆，激活房间apoptosis基因，提高化学治疗和放射性的治疗的敏感。到目前为止HDAC是在anticancer药research.Cellular与分子的免疫学的重要目标酶。2006；3(4):285-290。

简介：EfficientactivationofTlymphocytesthroughTcellreceptor(TCR)dependsontwosignals．Thefirstsignal(signalone)isderivedfromTCRinteractingwiththeMHC／antigenicpeptidecomplex，whichconfersantigenicspecificitytotheimmuneresponse．Thesecondsignal(signaltwo)isprovidedbytheengagementofTcellsurfacereceptorswiththeirspecificligandsonantigenpresentingcell(APC)[1]．Asthereisgrowingevidenceforbidirectionalcommunicationsandsocalled“reversesignaling”fortraditionallydefinedligands，thedistinctionbetweenreceptorsandligandsbecomeslessclear．Thesepairsofmoleculesshouldbeviewedascosignalingmoleculesfunctioningincellswhichwouldexpresseitherthereceptorsortheligands.

简介：AbstractEpigenetic regulation includes changes of DNA methylation and modifications of histone proteins and is essential for normal physiologic functions, especially for controlling gene expression. Epigenetic dysregulation plays a key role in disease pathogenesis and progression of some malignancies, including acute myeloid leukemia (AML). Epigenetic therapies, including hypomethylating agents (HMAs) and histone deacetylase (HDAC) inhibitors, were developed to reprogram the epigenetic abnormalities in AML. However, the molecular mechanisms and therapeutic effects of the two agents alone or their combination remain unknown. An overview of these epigenetic therapies is given here. A literature search was conducted through PubMed database, looking for important biological or clinical studies related to the epigenetic regimens in the treatment of AML until October 15th, 2019. Various types of articles, including original research and reviews, were assessed, identified, and eventually summarized as a collection of data pertaining the mechanisms and clinical effects of HMAs and HDAC inhibitors in AML patients. We provided here an overview of the current understanding of the mechanisms and clinical therapeutic effects involved in the treatment with HMAs and HDAC inhibitors alone, the combination of epigenetic therapies with intensive chemotherapy, and the combination of both types of epigenetic therapies. Relevant clinical trials were also discussed. Generally speaking, the large number of studies and their varied outcomes demonstrate that effects of epigenetic therapies are heterogeneous, and that HMAs combination regimens probably contribute to significant response rates. However, more research is needed to explore therapeutic effects of HDAC inhibitors and various combinations of HMAs and HDAC inhibitors.

简介：AbstractWith the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.

简介：Sixnovelbenzoylphenylureachitininhibitorderivativesweresynthesizedintheyieldsof30%-50%fromthereadilyavailablestartingmaterialchlorothalonil1viasequentialfluorineexchange,aminolysis,hydrolysisandacylationreactions.

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简介：INTRODUCTIONItisaninterestingresearchareausingureaseinhibitorstocurbureaseactivityinsoil,todecreasetherateofureahydrolysisandtoincreasetherecoveryofureanitrogen(Zhou,1984;Guan,1985).Fewstudieshavebeenconductedontherelationshipbetweentheeffectivenessoftheinhibitorsappliedtoriceandtheenvironmentalconditionsandits

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简介：IAPs(inhibitorsofapoptosis)areafamilyofproteinscontainingoneormorecharacteristicBIRdomains.Theseproteinshavemultiplebiologicalactivitiesthatincludebindingandinhibitingcaspases,regulatingcellcycleprogression,andmodulatingreceptor-mediatedsignaltransduction.OurrecentstudiesfoundtheIAPfamilymembersXIAPandc-IAP1areubiquitinatedanddegradedinproteasomesinresponsetoapoptoticstimuliinTcells,andtheirdegradationappearstobeimportantforTcellstocommittodeath.InadditiontothreeBIRdomains,eachoftheseIAPsalsocontainsaRINGfingerdomain.Wefoundthisregionconfersubiquitinproteaseligase(E3)activitytoIAPs,andisresponsiblefortheauto-ubiquitinationanddegradationofIAPsafteranapoptoticstimulus.GiventhefactthatIAPscanbindavarietyofproteins,suchascaspasesandTRAFs,itwillbeofinteresttocharacterizepotentialsubstratesoftheE3activityofIAPsandtheeffectsofubiquitinationbyIAPsonsignaltransduction,cellcycle,andapoptosis.

简介：SulfatecanbeactivatedbyATPsulfurylaseandadenosine5-phosphosulfatekinase(APSK)invivo.RecentstudiessuggestedthatAPSKinArabidopsisthalianaregulatedthepartitionbetweenAPSreductionandphosphorylationanditsactivitycanbemodulatedbycellularredoxstatus.InordertostudyregulationofAPSKinrice(OsAPSK),OsAPSKIgenewasclonedanditsactivitywasanalyzed.OsAPSKIC36andC69werefoundtobetheconservedcounterpartsofC86andC119,whichinvolvedindisulfideformationinAtAPSK.C36A/C69AOsAPSK1doublemutationwasmadebysitedirectedmutagenesis.OsAPSKanditsmutantwereprokaryoticallyover-expressedandpurified,andthenassayedforAPSphosphorylationactivity.OsAPSK1activitywasdepressedbyoxidizedglutathione,whiletheactivityofitsmutantwasnot.Furtherstudiesinthecasethatoxidativestresswillfluctuateinvivo3'-phosphoadenosine-5'-phosphosulfatecontent,andallAPSKisoenzymeshavesimilarregulationpatternsarenecessarytobeperformed.

简介：Brassinosteroids(BR)是植物激素的一个主要的组调整植物生长和开发。BRI1，对质膜局部性的蛋白质，当BR受体和它被建议了，工作它的kinase活动在调整BR的植物生长和开发有一个必要角色。这里，我们报导隔离和bri1的新等位基因的分子的描述，bri1-301，哪个表演中等词法显型和减少的回答到在正常生长条件下面的BR。顺序分析从GG识别了二底的改变到，导致到在BRI1kinase领域的989I的989G的变换在。kinase活动的试管内试金证明bri1-301不向BRI1底层TTL和BAK1举办可检测的autophosphorylation活动或磷酸化活动。而且，我们的结果建议甚至与极其损害的kinase活动，bri1-301仍然在调整植物生长和开发保留部分功能，它提出BRI1kinase活动是否在高等植物为调停BR的生长和开发是必要的问题。

简介：Humanpolymorphonuclearleukocytes(PMN)havebeenreportedtocompletelylackofDNA-dependentproteinkinase(DNA-PK)whichiscomposedofKuproteinandthecatalyticsubunitDNA-PKcs,neededfornonhomologousend-joining(NHEJ)ofDNAdouble-strandbreaks.PromyelocyticHL-60cellsexpressavariantformofKuresultinginenhancedradiationsensitivity.ThisraisesthequestioniflowefficiencyofNHEJ,instrumentalforthecellularrepairofoxidativedamage,isanormalcharacteristicofmyeloiddifferentiation.HereweconfirmedthecompletelackofDNAPKinPMNproteinextracts,andtheexpressionofthetruncatedKu86variantforminHL-60.However,thisdegradationofDNA-PKwasshowntobeduetoaDNA-PK-degradingproteaseinPMNandHL-60.Inaddition,byusingaprotease-resistantwholecellassay,bothKu86andDNA-PKcscouldbedemonstratedinPMN,suggestingthepreviouslyreportedabsenceinPMNofDNA-PKtobeanartefact.ThelevelsofKu86andDNA-PKcsweremuchreducedinPMN,ascomparedwiththatofthelymphocytes,whereasHL-60displayedamarkedlyelevatedDNA-PKconcentration.Inconclusion,ourfindingsprovideevidenceofreduced,notdepletedexpressionofDNA-PKduringthematurestagesofmyeloiddifferentiation.

简介：SulfatecanbeactivatedbyATPsulfurylaseandadenosine5’-phosphosulfatekinase(APSK)invivo.RecentstudiessuggestedthatAPSKinArabidopsisthalianaregulatedthepartitionbetweenAPSreductionandphosphorylationanditsactivitycanbemodulatedbycellularredoxstatus.InordertostudyregulationofAPSKinrice(OsAPSK),OsAPSK1genewasclonedanditsactivitywasanalyzed.OsAPSK1C36andC69werefoundtobetheconservedcounterpartsofC86andC119,whichinvolvedindisulfideformationinAtAPSK.C36A/C69AOsAPSK1doublemutationwasmadebysitedirectedmutagenesis.OsAPSK1anditsmutantwereprokaryoticallyover-expressedandpurified,andthenassayedforAPSphosphorylationactivity.OsAPSK1activitywasdepressedbyoxidizedglutathione,whiletheactivityofitsmutantwasnot.Furtherstudiesinthecasethatoxidativestresswillfluctuateinvivo3’-phosphoadenosine-5’-phosphosulfatecontent,andallAPSKisoenzymeshavesimilarregulationpatternsarenecessarytobeperformed.