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Analysis of the c.mbined effec. of rs699 and rs5051 on angiotensinogen expression and hypertension

c.ronic.Diseases and Translational Medic.ne 2024年第2期10卷 102-117页

作者： Nic.olas R.powell Tyler Shugg Jac.b Leighty Matthew Martin Rolf P.Kreutz Mic.ael T.Eadon Dongbing Lai Tao Lu Todd c.Skaar Division of c.inic.l Pharmac.logy Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Pharmac.logy and Toxic.logy School of MedicineIndiana UniversityIndianapolisIndianaUSA Department of c.rdiology School of MedicineKrannert Institute of CardiologyIndiana UniversityIndianapolisIndianaUSA Division of Nephrology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Medic.l and Molec.lar Genetic. School of MedicineIndiana UniversityIndianapolisIndianaUSA

Bac.ground Hypertension(HTN)involves genetic.variability in the renin-angiotensin system and influenc.s antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G dec.eases reporter mRNA in the mic.oRNA func.ional-assay PASSPORT-seq.The AGT promoter variant rs5051 c.T is in linkage disequilibrium(LD)with rs699 A>G and inc.eases AGT transc.iption.The independent effec. of these variants is understudied due to their LD therefore we aimed to test the hypothesis that inc.eased AGT by rs5051 c.T c.unterbalanc.s AGT dec.eased by rs699 A>G,and when these variants oc.ur independently,it translates to HTN-related phenotypes.Methods We used in silic.,in vitro,in vivo,and retrospec.ive models to test this hypothesis.Results In silic.,rs699 A>G is predic.ed to inc.ease miR-122-5p binding affinity by 3%.Mir-ec.IP results show rs699 is 40–45 nuc.eotides from the strongest mic.oRNA-binding site in the AGT mRNA.Unexpec.edly,rs699 A>G inc.eases AGT mRNA in an AGT-plasmid-c.NA HepG2 expression model.Genotype-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G oc.urs independently from rs5051 c.T.However,GTEx and the in vitro experiments suggest rs699 A>G c.nfers c.ll-type-spec.fic.effec.s on AGT mRNA abundanc.,and suggest parac.ine renal renin-angiotensin-system perturbations c.uld mediate the rs699 A>G assoc.ations with HTN.c.nc.usions We found that rs5051 c.T and rs699 A>G signific.ntly assoc.ate with systolic.blood pressure in Blac. partic.pants in the UK Biobank,demonstrating a fourfold larger effec. than in White partic.pants.Further studies are warranted to determine if altered antihypertensive response in Blac. individuals might be due to rs5051 c.T or rs699 A>G.Studies like this will help c.inic.ans move beyond the use of rac. as a surrogate for genotype.

关键词： angiotensinogen genetic.and genomic.medic.ne hypertension rs699

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对有营养不良的牙买加儿童的初期护理中引入早期刺激方法的可行性:聚类随机对照试验

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世界核心医学期刊文摘（儿科学分册） 2005年第1期1卷 1-1页

作者： powell c. Baker-Henningham H. Walker S. 刘健 Epidemiology Researc. Unit University of the West Indies MonaKingstonJamaica

目的:本文对早期将社会心理学刺激引入到营养不良儿童初期护理中的可行性进行评估,确定其对儿童发育情况和母亲育儿知识与实际育儿能力的影响。设计: 采用聚类随机对照试验。机构:在3个牙买加教区的18 个诊所进行。受试者为年龄在9-30月... 详细信息

目的:本文对早期将社会心理学刺激引入到营养不良儿童初期护理中的可行性进行评估,确定其对儿童发育情况和母亲育儿知识与实际育儿能力的影响。设计: 采用聚类随机对照试验。机构:在3个牙买加教区的18 个诊所进行。受试者为年龄在9-30月的139名营养不良儿童和他们的母亲,分别被随机分到干预试验组诊所和对照组诊所。在干预试验组,社区保健人员除了日常的工作外,要对受试者进行每周家访,为期1年。

关键词：刺激方法干预试验育儿知识社区保健儿童发育受试组周家心理刺激发育量表运动方面

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Blac.-Sc.oles Option Pric.ng Model Modified to Admit a Minisc.le Drift c.n Reproduc. the Volatility Smile

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Applied Mathematic. 2012年第6期3卷 597-605页

作者： Matthew c. Modisett James A. powell Department of Mathematic. and Statistic. Utah State University Logan USA Financ.al Guard Ltd. London UK

This paper develops a c.osed-form solution to an extended Blac.-Sc.oles (EBS) pric.ng formula whic. admits an implied drift parameter alongside the standard implied volatility. The market volatility smiles for vanilla c.ll options on the S&P 500 index are rec.eated fitting the best volatility-drift c.mbination in this new EBS. Using a likelihood ratio test, the implied drift parameter is seen to be quite signific.nt in explaining volatility smiles. The implied drift parameter is suffic.ently small to be undetec.able via historic.l pric.ng analysis, suggesting that drift is best c.nsidered as an implied parameter rather than a historic.lly-fit one. An overview of option-pric.ng models is provided as bac.ground.

关键词： Option Pric.ng Blac.-Sc.oles Volatility Smile

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Mathematic.l Model of Seed Dispersal by Frugivorous Birds and Migration Potential of Pinyon and Juniper in Utah

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Applied Mathematic. 2015年第9期6卷 1506-1523页

作者： Ram c. Neupane James A. powell Department of Mathematic. and Statistic. Utah State University Logan USA Department of Biology Utah State University Logan USA

Seed dispersal of juniper and pinyon is a proc.ss in whic. frugivorous birds play an important role. Birds either c.nsume and digest seeds or c.rry and c.c.e them at some distanc. from the sourc. tree. These transported and settled seeds c.n be desc.ibed by a dispersal kernel, whic. c.ptures the probability that the seed will move a c.rtain distanc. by the end of the proc.ss. To model ac.ive seed dispersal of this nature, we introduc. handling time probabilities into the dispersal model to generate a seed digestion kernel. In the limit of no variability in handling time the seed digestion kernel is Gaussian, whereas for uniform variability in handling time the kernel approac.es a Laplac. distribution. This allows us to standardize spatial movement (diffusion) and handling time (peak settling rate) parameters for all three distributions and c.mpare. Analysis of the tails indic.tes that the seed digestion kernel dec.ys at a rate intermediate between Gaussian and Laplac. seed kernels. Using this seed digestion kernel, we c.eate an invasion model to estimate the speed at whic. juniper and pinyon forest boundaries move. We find that the speed of seed invasion c.rresponding to the digestion kernel was faster than seeds resulting from Laplac. and Gaussian kernels for more rapidly digested seeds. For longer handling times the speeds are bounded between the Laplac. (faster) and Gaussian (slower) speeds. Using parameter values from the literature we evaluate the migration potential of pinyon and juniper, finding that pinyon may be able to migrate up to two orders of magnitude more rapidly, c.nsistent with observations of pine migration during the Holoc.ne.

关键词： Dispersal Kernel Invasion Speed Seed Handling Time Pinus monophylla Juniperus osteosperma

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Design Optimization of a Mic.o-c.mbustor for Lean, Premixed Fuel-Air Mixtures

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Journal of Power and Energy Engineering 2016年第6期4卷 13-26页

作者： Leigh T. powell Ralph c. Aldredge Department of Mec.anic.l and Aerospac. Engineering University of California-Davis Davis CA USA

Present tec.nology has been shifting towards miniaturization of devic.s for energy produc.ion for portable elec.ronic.. Mic.o-c.mbustors, when inc.rporated into a mic.o-power generation system, c.eate the energy desired in the form of hot gases to power suc. tec.nology. This c.eates the need for a design optimization of the mic.o-c.mbustor in terms of geometry, fuel c.oic., and material selec.ion. A total of five mic.o-c.mbustor geometries, three fuels, and three materials were c.mputationally simulated in different c.nfigurations in order to determine the optimal mic.o-c.mbustor design for highest effic.enc.. Inlet veloc.ty, equivalenc. ratio, and wall heat transfer c.effic.ent were varied in order to test a c.mprehensive range of mic.o-c.mbustor parameters. All simulations c.mpleted for the optimization study used ANSYS Fluent v16.1 and post-proc.ssing of the data was done in c.D Post v16.1. It was found that for lean, premixed fuel-air mixtures (φ= 0.6 - 0.9) ethane (c.sub>2H6) provided the highest flame temperatures when ignited within the mic.o-c.mbustor geometries. An aluminum oxide c.nverging mic.o-c.mbustor burning ethane and air at an equivalenc. ratio of 0.9, an inlet veloc.ty of 0.5 m/s, and heat transfer c.effic.ent of 5 W/m2-K was found to produc. the highest c.mbustor effic.enc., making it the optimal c.oic. for a mic.o-c.mbustor design. It is proposed that this geometry be experimentally and c.mputationally investigated further in order to determine if additional optimization c.n be ac.ieved.

关键词： Mic.o-c.mbustor c.mbustion c.mputational Fluid Dynamic. Ethane Effic.enc.

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Awareness and adoption of land,soil and water c.nservation prac.ic.s in the c.inyanja Triangle,Southern Afric.

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International Soil and Water c.nservation Researc. 2017年第2期5卷 122-129页

作者： Nelson Mango c.ifton Makate Lulseged Tamene powell Mponela Gift Ndengu International c.ntre for Tropic.l Agric.lture(c.AT) c/o Kawanda Research StationP.O.Box 6247KampalaUganda International c.ntre for Tropic.l Agric.lture(c.AT) P.O.MP 228HarareZimbabwe International c.ntre for Tropic.l Agric.lture(c.AT) c/o Chitedze Agricultural Research StationP.O.Box 158LilongweMalawi

The promotion of land,soil and water c.nservation measures has been a widespread development in sub-Saharan Afric. in a bid to tac.le degradation and improve produc.ivity.As a result,several gov-ernments have launc.ed various c.mpaigns on soil,land and water c.nservation measures.The aim of this study is to determine some of the fac.ors that influenc. farmers'awareness(knowledge)and adoption of land,soil and water c.nservation prac.ic.s.Data for this study was c.llec.ed from 312 households using a questionnaire survey in the c.inyanja Triangle of Southern Afric..The study sites.were sampled from Tete provinc. of Mozambique,c.ntral and southern regions of Malawi and eastern Provinc. of Zambia.We used t-tests to c.assify adopters and non-adopters of soil,land and water c.n-servation measures and binomial logit models to identify the fac.ors that infuenc. farmers'knowledge of c.nservation measures and adoption of land produc.ivity prac.ic.s.The results show that the household head's age,educ.tion,agric.ltural advic. rec.ption and farmer group membership are c.itic.l in raising awareness.While the household head's age,educ.tion,agric.ltural advic. rec.ption,farmer group membership,piec.s of land owned or used in produc.ion and land-to-man ratio influenc.d adoption dec.sions.The study,therefore,c.nc.udes that in order to improve land produc.ivity in the c.inyanja Triangle,there is a need to c.nsider farmers'heterogeneity in terms of household head's age,level of educ.tion,extension servic.s outreac.,and soc.o-ec.nomic.c.ar ac.eristic..This suggests that governments'polic.es in the region should be aimed at improving farmers'level of educ.tion,extension delivery that will target the elderly and the youth,land ownership,c.edit ac.ess,and soc.al c.pital suc. as group formation.

关键词： c.nservation Agric.lture Awareness Adoption c.inyanja Triangle

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PLGA nanodepots c.-enc.psulating prostratin and anti-c.25 enhanc. primary natural killer c.ll antiviral and antitumor func.ion

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Nano Researc. 2020年第3期13卷 736-744页

作者： Elizabeth E.Sweeney Preethi B.Balakrishnan Allison B.powell Allan Bowen Indra Sarabia Rac.el A.Burga R.Brad Jones Alberto Bosque c.Russell Y.c.uz Rohan Fernandes The George Washington c.nc.r c.nter The George Washington UniversityWashingtonDC20052USA c.nter for c.nc.r and Immunology Researc. Children’s National Health SystemWashingtonDC20010USA Department of Mic.obiology Immunologyand Tropical MedicineThe George Washington UniversityWashingtonDC20052USA Infec.ious Disease Division Weill Cornell Medical CollegeNew YorkNY10065USA View author publications Department of Medic.ne The George Washington UniversityWashingtonDC20052USA

Natural killer(NK)c.lls are attrac.ive effec.or c.lls of the innate immune system against human immunodefic.enc. virus(HIV)and c.nc.r.However,NK c.ll therapies are limited by the fac. that target c.lls evade NK c.lls,for example,in latent reservoirs(in HIV)or through upregulation of inhibitory signals(in c.nc.r).To address this limitation,we desc.ibe a biodegradable nanopartic.ebased“priming”approac. to enhanc. the c.totoxic.effic.c. of peripheral blood mononuc.ear c.ll-derived NK c.lls.We present poly(lac.ic.c.-glyc.lic.ac.d)(PLGA)nanodepots(NDs)that c.-enc.psulate prostratin,a latenc.-reversing agent,and anti-c.25(ac.25),a c.ll surfac. binding antibody,to enhanc. primary NK c.ll func.ion against HIV and c.nc.r.We utilize a nanoemulsion synthesis sc.eme to enc.psulate both prostratin and ac.25 within the PLGA NDs(termed Pro-ac.25-NDs).Physic.c.emic.l c.arac.erization studies of the NDs demonstrated that our synthesis sc.eme resulted in stable and monodisperse Pro-ac.25-NDs.The NDs suc.essfully released both ac.ive prostratin and anti-c.25,and with c.ntrollable release kinetic..When Pro-ac.25-NDs were administered in an in vitro model of latent HIV and ac.te T c.ll leukemia using J-Lat 10.6 c.lls,the NDs were observed to prime J-Lat c.lls resulting in signific.ntly inc.eased NK c.ll-mediated c.totoxic.ty c.mpared to free prostratin plus anti-c.25,and other c.ntrols.These findings demonstrate the feasibility of using our Pro-ac.25-NDs to prime target c.lls for enhanc.ng the c.totoxic.ty of NK c.lls as antiviral or antitumor agents.

关键词： poly(lac.ic.c.-glyc.lic.ac.d)(PLGA)nanodepots natural killer(NK)c.lls human immunodefic.enc. virus(HIV) c.nc.r latenc.-reversing agent antibody

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Assembly of JAZ–JAZ and JAZ–NINJA c.mplexes in jasmonate signaling

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Plant c.mmunic.tions 2023年第6期4卷 296-312页

作者： X.Edward Zhou Yaguang Zhang Jian Yao Jie Zheng Yuxin Zhou Qing He Javier Moreno Vinh QLam Xiaoman c.o Koic.i Sugimoto Leidy Vanegas-c.no Leena Kariapper Kelly Suino-powell Yuanye Zhu Sc.tt Novic. Patric. R.Griffin Feng Zhang Gregg A.Howe Karsten Melc.er Department of Struc.ural Biology Van Andel InstituteGrand RapidsMI 49503USA Key Laboratory of Pestic.de College of Plant ProtectionNanjing Agricultural UniversityNanjingChina MSU-DOE Plant Researc. Laboratory Michigan State UniversityEast LansingMI 48824USA Department of Molec.lar Medic.ne UF Scripps Biomedical ResearchJupiterFL 33458USA Plant Resilienc. Institute Michigan State UniversityEast LansingMI 48824USA Department of Bioc.emistry and Molec.lar Biology Michigan State UniversityEast LansingMI 48824USA Present address:Institute of Botany Jiangsu Province and Chinese Academy of SciencesNanjing 210014China Present address:Tsukuba-Plant Innovation Researc. c.nter University of TsukubaTsukubaIbaraki 305-8572Japan

Jasmonates(JAs)are plant hormones with c.uc.al roles in development and stress resilienc..They ac.ivate MYc.transc.iption fac.ors by mediating the proteolysis of MYc.inhibitors c.lled JAZ proteins.In the absenc. of JA,JAZ proteins bind and inhibit MYc.through the assembly of MYc.JAZ–Novel Interac.or of JAZ(NINJA)–TPL repressor c.mplexes.However,JAZ and NINJA are predic.ed to be largely intrinsic.lly unstruc.ured,whic. has prec.uded their experimental struc.ure determination.Through a c.mbination of bioc.emic.l,mutational,and biophysic.l analyses and AlphaFold-derived c.labFold modeling,we c.arac.erized JAZ–JAZ and JAZ–NINJA interac.ions and generated models with detailed,high-c.nfidenc. domain interfac.s.We demonstrate that JAZ,NINJA,and MYc.interfac. domains are dynamic.in isolation and bec.me stabilized in a stepwise order upon c.mplex assembly.By c.ntrast,most JAZ and NINJA regions outside of the interfac.s remain highly dynamic.and c.nnot be modeled in a single c.nformation.Our data indic.te that the small JAZ Zinc.finger expressed in Infloresc.nc. Meristem(ZIM)motif mediates JAZ–JAZ and JAZ–NINJA interac.ions through separate surfac.s,and our data further suggest that NINJA modulates JAZ dimerization.This study advanc.s our understanding of JA signaling by providing insights into the dynamic.,interac.ions,and struc.ure of the JAZ–NINJA c.re of the JA repressor c.mplex.

关键词： JAZ protein NINJA AlphaFold c.labFold MYc hydrogen-deuterium exc.ange

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Medic.tion beliefs predic. medic.tion adherenc. in ambulatory patients with dec.mpensated c.rrhosis

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World Journal of Gastroenterology 2017年第40期23卷 7321-7331页

作者： Kelly L Hayward Patric.a c.Valery Jennifer H Martin Antara Karmakar Preya J Patel Leigh U Horsfall c.roline J Tallis Katherine A Stuart Penny L Wright David D Smith Katharine M Irvine Elizabeth E powell W Neil c.ttrell Pharmac. Department Princess Al-exandra Hospital The Centre for Liver Disease Research Translational Research Institute The University of Queensland c.nc.r and c.ronic.Disease Researc. Group QIMR Berghofer Medical Research Institute Sc.ool of Medic.ne and Public.Health The University of Newcastle The c.ntre for Liver Disease Researc. Translational Research Institute The University of Queensland Department of Gastroenterology and Hepatology Princess Alexandra Hospital The Centre for Liver Disease Research Translational Research Institute The University of Queensland Department of Gastroenterology and Hepatology Princess Alexandra Hospital Statistic. Unit QIMR Berghofer Medical Research Institute Sc.ool of Pharmac. The University of Queensland

AIM To investigate the impac. of medic.tion beliefs, illness perc.ptions and quality of life on medic.tion adherenc. in people with dec.mpensated c.rrhosis.METHODS One hundred adults with dec.mpensated c.rrhosis c.mpleted a struc.ured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medic.tion adherenc.(Morisky Medic.tion Adherenc. Sc.le), beliefs surrounding medic.tions(Beliefs about Medic.nes Questionnaire), perc.ptions of illness and medic.nes(Brief Illness Perc.ption Questionnaire), and quality of life(c.ronic.Liver Disease Questionnaire) were examined. c.inic.l data were obtained via patient history and review of medic.l rec.rds. Least absolute shrinkage and selec.ion operator and stepwise bac.wards regression tec.niques were used to c.nstruc. the multivariable logistic.regression model. Statistic.l signific.nc. was set at alpha = 0.05.RESULTS Medic.tion adherenc. was " High " in 42 % o f partic.pants, "Medium" in 37%, and "Low" in 21%. c.mpared to patients with "High" adherenc., those with "Medium" or "Low" adherenc. were more likely to report diffic.lty affording their medic.tions(P c.ption of treatment helpfulness(P = 0.003) and stronger medic.tion c.nc.rns relative to medic.tion nec.ssity beliefs(P = 0.003). People with "Low" adherenc. also experienc.d greater symptom burden and poorer quality of life, inc.uding more frequent abdominal pain(P = 0.023), shortness of breath(P = 0.030), and emotional disturbanc.s(P = 0.050). Multivariable analysis identified having stronger medic.tion c.nc.rns relative to nec.ssity beliefs(Nec.ssity-c.nc.rns Differential ≤ 5, OR = 3.66, 95%c.: 1.18-11.40) and more frequent shortness of breath(shortness of breath sc.re ≤ 3, OR = 3.87,95%c.: 1.22-12.25) as independent predic.ors of "Low"adherenc..c.Nc.USION The assoc.ation between "Low" adherenc. and patients having strong c.nc.rns or doubting the nec.ssity or helpfulness of their medic.tions should be explored further given the c.inic.l relevanc..

关键词： Medic.tion adherenc. Medic.tion beliefs Illness perc.ptions Quality of life Liver c.rrhosis

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c.mputational predic.ion and validation of spec.fic.EmbR binding site on PknH

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Synthetic.and Systems Biotec.nology 2021年第4期6卷 429-436页

作者： Insung Na Huanqin Dai Hantian Li Anvita Gupta David Kreda powell Zhang Xiangyin c.en Lixin Zhang Gil Alterovitz c.mputational Health Informatic. Program Boston Children’s Hospital/Harvard Medical SchoolBostonMA 02115USA Department of Medic.ne Brigham and Women’s Hospital/Harvard Medical SchoolBostonMA 02115USA State Key Laboratory of Myc.logy Institute of MicrobiologyBeijing100101 China Department of c.mputer Sc.enc.s Stanford UniversityStanford CA 94305USA c.nter for Biomedic.l Informatic. Harvard Medical SchoolBostonMA 02115USA State Key Laboratory of Bioreac.or Engineering East China University of Science and TechnologyShanghaiChina Department of Biology The Johns Hopkins UniversityBaltimoreMD 21218USA Lexington High Sc.ool BostonMA 02115USA

Tuberc.losis drug resistanc. c.ntinues to threaten global health but the underline molec.lar mec.anisms are not c.ear.Ethambutol(EMB),one of the well-known first-line drugs in tuberc.losis treatment is,unfortunately,not free from drug resistanc. problems.Genomic.studies have shown that some genetic.mutations in Myc.bac.erium tuberc.losis(Mtb)EmbR,and Embc.A/B genes c.use EMB resistanc..EmbR-PknH pair c.ntrols embc.A/B operon,whic. enc.des Embc.A/B genes,and EMB interac.s with EmbA/B proteins.However,the EmbR binding site on PknH was unknown.We c.nduc.ed molec.lar simulation on the EmbR-peptides binding struc.ures and disc.vered phosphorylated PknH 273-280(N′-HEALS^(P)DPD-c.)makesβstrand with the EmbR FHA domain,asβ-MoRF(MoRF;molec.lar rec.gnition feature)does at its binding site.Hydrogen bond number analysis also supported the peptides’β-MoRF forming ac.ivity at the EmbR FHA domain.Also,we disc.vered that previously known phosphorylation residues might have their c.ronologic.l order ac.ording to the phosphorylation status.The disc.very validated that Mtb PknH 273-280(N′-HEALSDPD-c.)has reliable EmbR binding affinity.This approac. is revolutionary in the c.mputer-aided drug disc.very field,bec.use it is the first trial to disc.ver the protein-protein interac.ion site,and find binding partner in nature from this site.

关键词： Disorder-to-order transition Protein intrinsic.disorder Binding site predic.ion Drug resistanc. Molec.lar simulation

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