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简介：AbstractAlthough whole-exome sequencing and whole-genome sequencing has tremendously improved our understanding of the genetic etiology of human disorders, about half of the patients still do not receive a molecular diagnosis. The high fraction of variants with uncertain significance and the challenges of interpretation of noncoding variants have urged scientists to implement RNA sequencing (RNA-seq) in the diagnostic approach as a high throughput assay to complement genomic data with functional evidence. RNA-seq data can be used to identify aberrantly spliced genes, detect allele-specific expression, and identify gene expression outliers. Amongst eight studies utilizing RNA-seq, a mean diagnostic uplift of 15% has been reported. Here, we provide an overview of how RNA-seq has been implemented to aid in identifying the causal variants of Mendelian disorders.

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简介：Next-generationsequencing(NGS)isanewtechnologyusedforDNAandRNAsequencingandvariant/mutationdetection.NGScansequencehundredsandthousandsofgenesorwholegenomeinashortperiodoftime.Thesequencevariants/mutationsdetectedbyNGShavebeenwidelyusedfordiseasediagnosis,prognosis,therapeuticdecision,andfollowupofpatients.Thecapacityofitsmassiveparallelsequencingoffersnewopportunitiesforpersonalizedprecisionmedicine.

简介：六不同治疗在与变形阉割抵抗的前列腺癌症(mCRPC)指向到病人的阶段III试用表明了改进幸存。为mCRPC的前线的治疗学的选择包括docetaxel，sipuleucel-T，abiraterone和radium-223。Post-docetaxel选择包括cabazitaxel，abiraterone，enzalutamide和radium-223。尽管有最近的年里的许多进步，多是还未知的，争论发生在最佳的治疗选择和序列上。任何一个新代理人都没与对方相比，因此，在今天的实践的医生必须基于非使随机化的比较，毒性考虑和各种各样的假设做选择。Abiraterone现在正在移动直到给最近的规章的赞同的前面线mCRPC空间，enzalutamide将很快列在后面。当时，两个神经质的代理人有更少的毒性与化学疗法的选择和这两个神经质的代理人相比被期望向前在年里在mCRPC病人的一个可观的数字被过去常。很少数据都不为post-abiraterone或post-enzalutamide背景是可得到的。在这评论，当前可得到的定序数据被总结并且解释。生气抵抗是在各种各样的治疗之间的一个潜在的问题，现在是清楚的，特别指向雄激素轴的那些代理人。这评论加亮需要让另外的研究为这些病人优化当前的治疗。

简介：AbstractTargeted sequencing and whole exome sequencing are the most common approaches used to detect causative variants in Mendelian diseases; however, using DNA-based sequencing techniques, the current molecular diagnostic yield is at best 50%. In recent years, RNA sequencing has been shown to be able to provide a genetic diagnosis in patients whose conditions were previously unable to be identified by DNA analysis. RNA sequencing can reveal expression outliers, aberrant splicing events, allele-specific expression, and new pathogenic variants, and as such can complement and expand on the traditional genomic methods used to diagnose Mendelian diseases. Therefore, RNA sequencing is expected to become a routine method for genetic diagnosis in the future. This article reviews the applications and challenges of RNA sequencing in the genetic diagnosis of Mendelian diseases.

简介：TheproblemofpicksequencingintherotaryrackS/Rsystem(PPS-RRS)isinvestigatedwiththeobjectiveofminimizingtheexecutiontime.TherotaryrackS/RsystemconsistsofoneS/Rmachineandmultiplelevelsofcarouselsthatcanrotateindependentlyinbi-directions.Theroutingpolicy,namelythedecisiononthestorageorretrievalsequence,dominatestheefficiencyandthethroughputforsuchS/Rsystems,duetothecomplicatedrelationshipbetweenalllevelsofcarouselsandtheS/Rmachine.ForthepurposeofoptimizingthePPS-RRS,acomputationalmodelisdevelopedintermsofexecutiontimeforpickingmultipleitemsinonetrip.CharacteristicsofthePPS-RRSareanalyzedandalocalsearchheuristicbasedonanewlyproposedneighborhoodispresented.Integratedwiththeproposedlocalsearchprocedureanewhybridgeneticalgorithmisdeveloped.Experimentalresultsdemonstratethestructurecharacteristicsofgoodsequenceandtheefficiencyandeffectivenessoftheproposedsequencingalgorithms.

简介：技术显著地改进了定序产量并且减少的下一代的定序的出现(NGS)花费。然而，短读的长度，副本读并且数据的巨大的体积使处理的数据比归化为美国人的定序技术更困难、复杂。尽管有包裹开发了估计数据质量的某软件，那些包裹任何一个不对用户容易可得到或要求生物信息学技巧和计算机资源。而且，当前可得到的几乎所有优秀评价软件当在NGS数据处理副本评价时，考虑定序的错误。这里，我们在场一个新用户友好的优秀评价软件包裹叫了BIGpre，它为Illumina和454个平台工作。BIGpre包含另外的优秀评价软件的所有函数，例如关联在之间前面、反向读，读GC内容分发，和基础N质量。更重要地，BIGpre合并联系程序检测并且搬迁副本在订定序错误进报道并且整修低质量以后读也从未加工的数据读。BIGpre首先在Perl被写并且从统计包裹R集成图形的能力。这个包裹为从Illumina和454个平台定序数据集生产数据质量的平坦、图形的摘要。处理几百百万在分钟以内读，这个包裹提供立即的诊断信息让用户操作为下游的分析定序数据。BIGpre在http://bigpre.sourceforge.net是自由地可得到的。

简介：AbstractDrug resistance via drug-resistant mutations in the human immunodeficiency virus (HIV) genome is the primary cause of antiviral therapy failure. Consequently, HIV drug resistance genotyping has become a critical approach in HIV prevention and control. Compared to the Sanger sequencing technology, high-throughput sequencing (HTS) technology has superior sensitivity and timeliness, with strong detection capabilities for low-frequency mutations. With the continued advancement of HTS technologies, their prominence in HIV drug resistance detection techniques has increased accordingly. This article will review the latest developments in HTS technology and its applications in HIV drug resistance testing.

简介：Next-generationsequencing(NGS)hasbeenrapidlyintegratedintomolecularpathology,dramaticallyincreasingthebreadthgenomicofinformationavailabletooncologistsandtheirpatients.Thisreviewwillexplorethewaysinwhichthisnewtechnologyiscurrentlyappliedtobolstercareforpatientswithsolidtumorsandhematologicalmalignancies,focusingonpracticesandguidelinesforassessingthetechnicalvalidityandclinicalutilityofDNAvariantsidentifiedduringclinicalNGSoncologytesting.

简介：Precisionmedicineaimstoidentifytherightdrug,fortherightpatient,attherightdose,attherighttime,whichisparticularlyimportantincancertherapy.Problemssuchasthevariabilityoftreatmentresponseandresistancetomedicationhavebeenlongstandingchallengesinoncology,especiallyfordevelopmentofnewmedications.Solidtumors,unlikehematologicmalignanciesorbraintumors,areremarkablydiverseintheircellularoriginsanddevelopmentaltiming.Theabilityofnext-generationsequencing(NGS)toanalyzethecomprehensivelandscapeofgeneticalterationsbringspromisestodiseasesthathaveahighlycomplexandheterogeneousgeneticcompositionsuchascancer.HereweprovideanoverviewofhowNGSisabletofacilitateprecisionmedicineandchangetheparadigmofcancertherapy,especiallyforsolidtumors,throughtechnicaladvancements,moleculardiagnosis,responsemonitoringandclinicaltrials.

简介：Inordertoanalyzethenucleoprotein(NP)geneofCrimean-Congohemorrhagicfevervirus(CCHFV),viralRNAwasamplifiedbyRT-PCRbyusingtheproof-readingDNApolymerasetoproducethecompleteNPgene.ThePCRproductwassequenced,analyzedforphylogenesisandclonedintotheexpressionvectorpE132aandtherecombinantplasmidexpressedinE.coilBL-21withhighyield.Theprimarilypurifiedfusedprotein.wasusedtocoatELISAplatesforthedetectantibodies.ItwasfoundthesimilaritiesbetweenNPgeneofBA88166andotherXHFVsinnucleotidelevelandaminoacidcontentswereverysignificant,andtheNPgeneofBA88166encodedanucleoproteinwith482aminoacidandadeducedmolecularweight(MW)of54kDa.Westernblotassayshowedthatthefusionproteinexpressedinbacteriapossessedgoodantigenicity.TheresultswithELISAforthedetectionofthehumanandanimalseracollectedinendemicareaswerefoundtobeingoodaccordancetotheclinicaldiagnosis.ItconcludedthattherelationsofNPgenesofXHFVBA88166andotherXHFVsappearedtobeevolutionallyclose.Themethodologiesestablishedinthisstudywereaccurate,specific,rapidandreproduciblefortheclinicalexaminationsandepidemiologicalsurvey.

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简介：AbstractBackground:Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers without effective therapy. To explore potential molecular targets in ESCC, we quantified the mutation spectrum and explored the relationship between gene mutation and clinicopathological characteristics and programmed death-ligand 1 (PD-L1) expression.Methods:Between 2015 and 2019, 29 surgically resected ESCC tissues and adjacent normal tissues from the Fourth Hospital of Hebei Medical University were subjected to targeted next-generation sequencing. The expression levels of PD-L1 were detected by immunohistochemistry. Mutational signatures were extracted from the mutation count matrix by using non-negative matrix factorization. The relationship between detected genomic alterations and clinicopathological characteristics and PD-L1 expression was estimated by Spearman rank correlation analysis.Results:The most frequently mutated gene was TP53 (96.6%, 28/29), followed by NOTCH1 (27.6%, 8/29), EP300 (17.2%, 5/29), and KMT2C (17.2%, 5/29). The most frequently copy number amplified and deleted genes were CCND1/FGF3/FGF4/FGF19 (41.4%, 12/29) and CDKN2A/2B (10.3%, 3/29). By quantifying the contribution of the mutational signatures to the mutation spectrum, we found that the contribution of signature 1, signature 2, signature 10, signature 12, signature 13, and signature 17 was relatively high. Further analysis revealed genetic variants associated with cell cycle, chromatin modification, Notch, and Janus kinase-signal transducer and activator of transcription signaling pathways, which may be key pathways in the development and progression of ESCC. Evaluation of PD-L1 expression in samples showed that 13.8% (4/29) of samples had tumor proportion score ≥1%. 17.2% (5/29) of patients had tumor mutation burden (TMB) above 10 mut/Mb. All samples exhibited microsatellite stability. TMB was significantly associated with lymph node metastasis (r = 0.468, P = 0.010), but not significantly associated with PD-L1 expression (r = 0.246, P = 0.198). There was no significant correlation between PD-L1 expression and detected gene mutations (all P > 0.05).Conclusion:Our research initially constructed gene mutation profile related to surgically resected ESCC in high-incidence areas to explore the mechanism underlying ESCC development and potential therapeutic targets.

简介：Theintroductionofnext-generationsequencing(NGS)technologyintestingforhereditarycancersusceptibilityallowstestingofmultiplecancersusceptibilitygenessimultaneously.Whiletherearemanypotentialbenefitstoutilizingthistechnologyinthehereditarycancerclinic,includingefficiencyoftimeandcost,therearealsoimportantlimitationsthatmustbeconsidered.Thebestpanelforthegivenclinicalsituationshouldbeselectedtominimizethenumberofvariantsofunknownsignificance.Theinclusioninpanelsoflowpenetranceornewlyidentifiedgeneswithoutspecificactionabilitycanbeproblematicforinterpretation.Geneticcounselorsareanessentialpartofthehereditarycancerriskassessmentteam,helpingthemedicalteamselectthemostappropriatetestandinterprettheoftencomplexresults.Geneticcounselorsobtainanextendedfamilyhistory,counselpatientsontheavailabletestsandthepotentialimplicationsofresultsforthemselvesandtheirfamilymembers(pre-testcounseling),explaintopatientstheimplicationsofthetestresults(post-testcounseling),andassistintestingfamilymembersatrisk.

简介：Thispaperstudiesatwostagesupplychainwithadominantupstreampartner.ManufactureristhedominantpartnerandoperatesinaJust-in-Timeenvironment.Productionisdoneinasinglemanufacturinglinecapableofproducingtwoproductswithoutstoppingtheproductionforswitchingfromoneproducttotheother.Themanufacturerimposesconstraintsonthedistributorbyadheringtohisfavorableproductionschedulewhichminimizeshismanufacturingcost.Distributorontheotherhandcaterstoretailers'orderswithoutincurringanyshortagesandisresponsibleformanagingtheinventoryoffinishedgoods.Adheringtomanufacturer'sschedulemayleadtohighinventorycarryingcostsforthedistributor.Distributor'sproblem,whichistofindanoptimaldistributionsequencewhichminimizesthedistributor'sinventorycostundertheconstraintimposedbythemanufacturerisprovedNP-HardbyManojetal.(2008).Therefore,solvinglargesizeproblemsrequireefficientheuristics.Wedevelopalgorithmsforthedistributionproblembyexploitingitsstructuralproperties.Weproposetwoheuristicsandusetheirsolutionsintheinitialpopulationofageneticalgorithmtoarriveatsolutionswithanaveragedeviationoflessthan3.5%fromtheoptimalsolutionforpracticalsizeproblems.

简介：Denovosequencingisoneofthemostpromisingproteomicstechniquesforidentificationofproteinposttranslationmodifications(PTMs)instudyingproteinregulationsandfunctions.WehavedevelopedacomputertoolPRIMEforidentificationofbandyionsintandemmassspectra,akeychallengingproblemindenovosequencing.PRIMEutilizesafeaturethationsofthesameanddifferenttypesfollowdifferentmass-differencedistributionstoseparatebfromyionscorrectly.Wehaveformulatedtheproblemasagraphpartitionproblem.Alinearinteger-programmingalgorithmhasbeenimplementedtosolvethegraphpartitionproblemrigorouslyandefficiently.TheperformanceofPRIMEhasbeendemonstratedonalargeamountofsimulatedtandemmassspectraderivedfromYeastgenomeanditspowerofdetectingPTMshasbeentestedon216simulatedphosphopeptides.

简介：AbstractSFTS virus (SFTSV) is a novel bunyavirus, which was discovered as the etiological agent of severe fever with thrombocytopenia syndrome (SFTS) in China in 2009, and was now prevalent in at least 25 provinces in China. SFTS was subsequently identified in South Korea and Japan in 2012. To explore the molecular evolution and genetic characteristics of this newly identified pathogen, we reported 72 whole genome sequences of SFTSV, and built a dataset of SFTSV genome sequences containing 292 L-segment, 302 M-segment and 502 S-segment. We clearly divided SFTSV into six genotypes, Genotype A-F. It was found that genotype F was the dominant epidemic genotype of Japan, South Korea, and Zhejiang province of China. The coalescent analysis supported that SFTSV originated in the early 18th century from Zhejiang province, and Genotype F was the most primitive one. Henan, Hubei, and Anhui provinces which are located in Dabie Mountain area were mainly epidemic of Genotype A, which emerged relatively late but distributed widely. A total of 37 recombination events were identified, making SFTSV with a high recombination frequency (L segment 5.1%, M segment 3.6%, S segment 0.8%) among negative-strand segmented RNA viruses. It was identified that 19 reassortant strains belonged to 12 reassortment forms of SFTSV genome containing 6 newly identified forms. The reassortment virus and recombination in tick were both found for the first time. We also found many of genotype-specific mutation sites, 7 of which could be considered as potential molecular marker for genotype classification. This study promoted a more comprehensive understanding of the phylogeny and origin, and the genetic diversity of SFTSV, and it could help the studies of other newly discovered tick-borne bunyavirus as reference data and research ideas.

简介：前列腺癌症是全球癌症相关的死亡的一个领先的原因，但是试图改善诊断并且开发新奇治疗被重要耐心的异质惊讶。在最近的年里，到几百个前列腺瘤的下一代的定序的应用程序定义新奇分子的子类型并且描绘了位于疾病开始和前进下面的广泛的genomic错误。在诊所观察的异质是由与复杂性流行的一处分子的风景的underpinned，现在是清楚的，在genomic重新整理和稀罕变化联合放大transcriptomic差异的地方。这评论把我们前列腺癌症‘的当前的理解；omic的包括拷贝数字变化的哨兵角色，oncogenic熔化基因，chromothripsis的潜在的影响，和在定义联系变化的子类型的突破的成长光谱。增加的证据建议损害经常在特定的细胞的功能和发信号的小径上集成的那genomic，还周期性的基因错误显得稀罕。因此，我们继续定义单个瘤染色体，是批评的，特别在他们的表示transcriptome的上下文。仅仅通过到瘤可变性罐头的瘤的改进描述，我们前进到精确治疗和个性化的肿瘤学的年龄。

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