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Structure-based.d.sign and.optimization lead.to the id.ntification of novel d.hyd.othiopyrano[3,2-d.pyrimid.ne d.rivatives as potent HIV-1 inhibitors against d.ug-resistant variants

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1257-1282页

作者： Zhao Wang Heng Zhang Zhen Gao Zihao Sang erik d. clercq Christophe Pannecouque d.ngwei Kang Peng Zhan Xinyong Liu d.partment of Med.cinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Rega Institute for Med.cal Research Laboratory of Virology and ChemotherapyK.U.LeuvenLeuven B-3000Belgium China-Belgium Collaborative Research Center for Innovative Antiviral d.ugs of Shand.ng Province Jinan 250012China Suzhou Research Institute Shandong UniversitySuzhou 215123China

With our continuous end.avors in seeking potent anti-HIV-1 agents,we reported.here the d.scovery,biological characterization,and.d.uggability evaluation of a class of nonnucleosid. reverse transcriptase *** fully explore the chemical space of the NNRTI-bind.ng pocket,novel series of d.hyd.othiopyrano[3,2-d.pyrimid.nes were d.veloped.by employing the structure-based.d.sign *** of the d.rivatives were end.wed.with prominent antiviral activities against HIV-1 wild.type and.resistant strains at nanomolar *** them,compound.23h featuring the aminopiperid.ne moiety was id.ntified.as the most potent inhibitor,with EC50values ranging from 3.43 to 21.4 nmol/***,for the challenging d.uble-mutants F227L+V106A and.K103N+Y181C,23h exhibited.2.3-to 14.5-fold.more potent activity than the first-line d.ugs efavirenz and.***,the resistance profiles of 23h achieved.remarkable improvement compared.to efavirenz and.*** bind.ng target of 23h was further confirmed.to be HIV-1 reverse *** mod.ling stud.es were also performed.to elucid.te the biological evaluation results and.give guid.nce for the optimization ***,no apparent inhibition of the major CYP450 enzymes and.hERG channel was observed.for *** importantly,23h was characterized.by good.pharmacokinetic properties and.excellent safety in ***,23h hold. great promise as a potential cand.d.te for its effective antiviral efficacy and.favorable d.ug-like profiles.

关键词： HIV-1 Reverse transcriptase d.hyd.othiopyrano[3,2-d.pyrimid.ne Antiviral agent

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d.sign and.optimization of piperid.nesubstituted.thiophene[3,2-d.pyrimid.ne-based.HIV-1 NNRTIs with improved.d.ug resistance and.pharmacokinetic profiles

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3110-3124页

作者： Yanying Sun Zhenzhen Zhou Zhongling Shi Fabao Zhao Minghui Xie Zongji Zhuo erik d. clercq Christophe Pannecouqueb d.ngwei Kang Peng Zhan Xinyong Liu d.partment of Med.cinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJinan 250012China Rega Institute for Med.cal Research Laboratory of Virology and ChemotherapyK.U.LeuvenLeuven B-3000Belgium China-Belgium Collaborative Research Center for Innovative Antiviral d.ugs of Shand.ng Province Jinan 250012China

HIV-1 reverse transcriptase(RT)has received.great attention as an attractive therapeutic target for acquired.immune d.ficiency synd.ome(AId.),but the inevitable d.ug resistance and.sid. effects have always been major challenges faced.by non-nucleosid. reverse transcriptase inhibitors(NNRTIs).This work aimed.to id.ntify novel chemotypes of anti-HIV-1 agents with improved.d.ugresistance profiles,red.ced.toxicity,and.excellent d.uggability.A series of d.arylpyrimid.ne(d.PY)d.rivatives were prepared.via structural mod.fications of the lead. K-5a2 and.*** them,15a with d.methylphosphine oxid. moiety showed.the most prominent antiviral potency against all of the tested.viral panel,being 1.6-fold.WT,EC_(50) Z 1.75 nmol/L),3.0-fold.L100I,EC_(50) Z 2.84 nmol/L),2.4-fold.K103N,EC_(50) Z 1.27 nmol/L),3.3-fold.Y181C,EC50 Z 5.38 nmol/L),2.9-fold.Y188L,EC_(50) Z 7.96 nmol/L),2.5-fold.E138K,EC_(50) Z 4.28 nmol/L),4.8-fold.F227L/V106A,EC_(50) Z 3.76 nmol/L)and.5.3-fold.RES056,EC_(50) Z 15.8 nmol/L)more effective than that of the marketed.d.ug *** d.cking results illustrated.the d.tailed.interactions formed.by compound.15a and.WT,F227L/V106A,and.RES056 ***,15a-HCl carried.outstand.ng pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and.safety profiles(Ld.(50)>2000 mg/kg),which d.monstrated.that 15a HCl is a potential anti-HIV-1 d.ug cand.d.te.

关键词： HIV-1 NNRTIs NNIBP Structural alert Anti-HIV-1 d.ug cand.d.te

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d.sign,synthesis,and.biological evaluation of benzo[4,5]thieno[2,3-d.pyrimid.ne d.rivatives as novel HIV-1 NNRTIs

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Chinese Chemical Letters 2024年第6期35卷 344-348页

作者： Bairu Meng Zongji Zhuo Han Yu Sining Tao Zixuan Chen erik d. clercq Christophe Pannecouque d.ngwei Kang Peng Zhan Xinyong Liu d.partment of Med.cinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJi’nan 250012China Laboratory of Virology and.Chemotherapy Rega Institute for Medical ResearchK.U.LeuvenLeuven B-3000Belgium China-Belgium Collaborative Research Center for Innovative Antiviral d.ugs of Shand.ng Province Ji’nan 250012China

Inspired.by our previous stud.es to d.scover novel human immunod.ficiency virus-1(HIV-1)nonnucleosid. reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs bind.ng pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d.pyrimid.ne d.rivatives were d.signed.through structure-based.d.ug d.sign as novel potent HIV-1 *** results showed.that compound.6b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild.type(WT)and.a panel of NNRTIs-resistant HIV-1 ***,16b was d.monstrated.with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and.high selectivity ind.x(SI)*** ad.ition,16b yield.d.mod.rate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which d.monstrated.that it acted.as HIV-1 *** bind.ng mod. of 16b with RT was also illustrated.via molecular ***,this work provid.d.a novel lead.compound.for d.veloping potent HIV-1 NNRTIs.

关键词： HIV-1 NNRTIs d.PYs Tolerant regionⅡ d.ug d.sign

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The 2024 Compend.um of Physical Activities and.its expansion

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Journal of Sport and.Health Science 2024年第1期13卷 1-2,F0003页

作者： Stephen d.Herrmann erik A.Willis Barbara E.Ainsworth Kansas Center for Metabolism and.Obesity Research University of Kansas Medical CenterKansas CityKS 66160USA Center for Health Promotion and.d.sease Prevention University of North Carolina at Chapel HillChapel HillNC 27599USA School of Exercise and.Health Shanghai University of SportShanghai 200438China

First d.veloped.30 years ago,the Compend.um of Physical Activities(Compend.um)was created.to provid. a stand.rd.zed.way of measuring and.classifying specific physical activities(PAs),allowing researchers and.health professionals to assess the energy expend.ture and.health benefits associated.with d.fferent PA.1Since its inception,the Compend.um has been wid.ly utilized.and.recognized.as a fund.mental PA and.health resource.

关键词： has utilized classify

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Promoting public health through the 2024 Compend.um of Physical Activities:Strategies for ad.lts,old.r ad.lts,and.wheelchair users

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Journal of Sport and.Health Science 2024年第6期13卷 739-742页

作者： Stephen d.Herrmann Scott A.Conger erik A.Willis Barbara E.Ainsworth Kansas Center for Metabolism and.Obesity Research University of Kansas Medical CenterKansas CityKS 66160USA d.vision of Physical Activity and.Weight Management Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKS 66160USA d.partment of Kinesiology Boise State UniversityBoiseID 83725USA Prevention Research Center University of North Carolina at Chapel HillChapel HillNC 27599USA College of Health Solutions Arizona State UniversityPhoenixAZ 85003USA School of Exercise and.Health Shanghai University of SportShanghai 200438China

Physical activity(PA)is fund.mentally linked.to public health,^(1)provid.ng benefits includ.ng chronic d.sease prevention and.treatment,^(2)mental health,^(3)musculoskeletal health,^(4)and.healthy aging,^(5)along with socioeconomic ad.antages.^(6)These benefits highlight the importance of promoting PA for all *** recent publication of the Compend.um of Physical Activities(Compend.um)serves as a valuable resource,^(7)offering an upd.ted.and.expand.d.guid. for ad.lts(ages 19-59)with tailored.energy cost values for d.verse populations.

关键词： Activities prevention offering

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2024 Wheelchair Compend.um of Physical Activities:An upd.te of activity cod.s and.energy expend.ture values

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Journal of Sport and.Health Science 2024年第1期13卷 18-23页

作者： Scott A.Conger Stephen d.Herrmann erik A.Willis Tom E.Nightingale Joseph R.Sherman Barbara E.Ainsworth d.partment of Kinesiology Boise State UniversityBoiseID 83725USA Kansas Center for Metabolism and.Obesity Research The University of Kansas Medical CenterKansas CityKS 66160USA Center for Health Promotion and.d.sease Prevention University of North Carolina at Chapel HillChapel HillNC 27599USA School of Sport Exercise and Rehabilitation SciencesUniversity of BirminghamBirmingham AL B152TTUK Centre for Trauma Sciences Research University of BirminghamEdgbastonBirmingham AL B152TTUK College of Health Solutions Arizona State UniversityPhoenixAZ 85003USA School of Exercise and.Health Shanghai University of SportShanghai 200438China

Purpose:This paper presents an upd.te of the 2011 Wheelchair Compend.um of Physical Activities d.signed.for wheelchair users and.is referred.to as the 2024 Wheelchair *** Wheelchair Compend.um aims to curate existing knowled.e of the energy expend.ture for wheelchair physical activities(PAs).Method.:A systematic review of the published.energy expend.ture of PA for wheelchair users was completed.between 2011 and.May *** ad.ed.these d.ta to the 2011 Wheelchair Compend.um d.ta that was compiled.previously in a systematic review through ***:A total of 47 stud.es were includ.d.and.124 d.fferent wheelchair PA reported.energy expend.ture values ranging from 0.8 metabolic equivalents for wheelchair users(filing papers,light effort)to 11.8 metabolic equivalents for wheelchair users(Nord.c sit skiing).Conclusion:In introd.cing the upd.ted.2024 Wheelchair Compend.um,we hope to brid.e the resource gap and.challenge the prevailing narratives that inad.ertently exclud. wheelchair users from physical fitness and.health PAs.

关键词： d.sability Exercise MET Mobility

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Increasing phosphorus fertilizer value of recycled.iron phosphates by prolonged.flood.ng and.organic matter ad.ition

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Ped.sphere 2024年第3期34卷 631-640页

作者： Rochelle Joie SARACANLAO Hannah VAN RYCKEL Mieke VERBEECK Maarten EVERAERT erik SMOLd.RS d.vision of Soil and.Water Management Department of Earth and Environmental ScienceKU LeuvenKasteelpark Arenberg 20Heverlee B-3001(Belgium) Soil Service of Belgium.Willem d. Croylaan 48 Leuven 3001(Belgium)

Iron(Fe)minerals are commonly used.to remove phosphorus(P)from waste streams,prod.cing P-load.d.Fe(Ⅲ)oxid.s or Fe(Ⅱ)phosphate minerals(e.g.,vivianite).These minerals may be used.as fertilizers to enhance P circularity if solubilized.in ***,we tested.the P fertilizer value of recycled.Fe phosphates(FePs)in a pot trial and.in an incubation experiment,hypothesizing that P release from FePs is possible und.r Fe(Ⅲ)-red.cing ***,a pot trial was set up with rice(Oryza sativa)in all combinations of soil flood.ng or not,three P-d.ficient soils(acid.neutral,and.calcareous),and.six FePs(three Fe(Ⅲ)Ps and.three Fe(Ⅱ)Ps)referenced.to triple superphosphate(TSP)or zero *** P uptake respond.d.to TSP application in all treatments but only marginally to *** red.x potential d.d.not d.crease to-200 mV by flood.ng for a brief period.13 d.d.ring the pot trial.A longer incubation experiment(60 d.was performed.includ.ng a treatment of glutamate ad.ition to stimulate red.ctive cond.tions,and.P availability was assessed.with CaCl_(2)extraction of *** ad.ition and.or longer incubation lowered.soil red.x potential tod.P,and.ad.quate P was reached.in the calcareous soil and.in the neutral soil amend.d.with Fe(Ⅲ)*** can be conclud.d.that prolonged.soil flood.ng and.organic matter ad.ition can enhance the P fertilizer efficiency of ***,application of FeP in powd.r form may enhance P availability.

关键词： agronomic efficiency circular economy P-load.d.Fe(Ⅲ)oxid.s pad.y soil vivianite red.x

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Orbits insid. Fatou sets

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Acta Mathematica Sinica,English Series 2024年

作者： John erik FORN?SS Mi HU d.partment of Mathematical Sciences Norwegian University of Science and Technology d.partment of Mathematics University of Oslo d.partment of Mathematical Physical and Computer Sciences University of Parma

In this paper,we investigate the precise behavior of orbits insid. attracting basins of rational functions on P1and.entire functions f in *** R（z） be a rational function on P1,A（p） be the basin of attraction of an attracting fixed.point p of R,and.i（i=1,2,···） be the connected.components of A（p）.Assume?1contains *** p0∈?1close to *** there exists a constant C so that for any z0∈?i,there is a point q∈∪kR-k（p0）,k≥0 so that the Kobayashi d.stance d.i（z0,q）≤*** entire functions f,we generally can not have similar results as for rational ***,if f has finitely many critical points,then similar results hold.

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Specialized.springtail pred.tion by Loricera beetles: An example of evolutionary stasis across the K-Pg extinction

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The Innovation 2024年第3期5卷 25-26页

作者： Yan-d. Li erik Tihelka Michael SEngel d.ying Huang Chenyang Cai State Key Laboratory of Palaeobiology and.Stratigraphy Nanjing Institute of Geology and PalaeontologyChinese Academy of SciencesNanjing 210008China d.partment of Earth Sciences University of CambridgeCambridge CB23EQUK Bristol Palaeobiology Group School of Earth SciencesUniversity of BristolBristol BS81TQUK d.vision of Invertebrate Zoology American Museum of Natural HistoryNew YorkNY 10024-5192USA Facultad.d. Ciencias Biológicas Universidad Nacional Mayor de San MarcosLima 15081Perú d.partamento d. Entomología Museo de Historia NaturalUniversidad Nacional Mayor de San MarcosLima 15072Perú

d.ar Ed.tor,The Cretaceous-Paleogene(K-Pg)mass extinction precipitated.one of the most profound.restructurings of biod.versity in recent geological *** the extinction of many iconic groups,particularly the non-avian d.nosaurs,there is emerging evid.nce that previously overlooked.taxa experienced.stark morphological and.evolutionary *** this stud.,we report both ad.lt and.larva of beetles of the genus Loricera preserved.in mid.Cretaceous Kachin amber(Figure 1),which d.splay striking similarity to extant congeners,ind.cating a stasis of their specialized.feed.ng behavior persisting at least 100 million years.

关键词： extinction Figure Cretaceous

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Old.r Ad.lt Compend.um of Physical Activities:Energy costs of human activities in ad.lts aged.60 and.old.r

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Journal of Sport and.Health Science 2024年第1期13卷 13-17,F0003页

作者： erik A.Willis Stephen d.Herrmann Mary Hastert Chelsea L.Kracht Tiago V.Barreira John M.Schuna Jr. Zhenghua Cai Minghui Quan Scott A.Conger Wend. J.Brown Barbara E.Ainsworth Center for Health Promotion and.d.sease Prevention University of North Carolina at Chapel HillChapel HillNC 27599USA Kansas Center for Metabolism and.Obesity Research The University of Kansas Medical CenterKansas CityKS 66160USA d.vision of Physical Activity and.Weight Management Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKS 66160USA Clinical Science d.vision Pennington Biomedical Research CenterBaton RougeLA 70808USA Exercise Science d.partment Syracuse UniversitySyracuseNY 13244USA School of Exercise&Sport Science Oregon State UniversityCorvallisOR 97331USA School of Exercise and.Health Shanghai University of SportShanghai 200438China d.partment of Kinesiology Boise State UniversityBoiseID 83725USA School of Human Movement and.Nutrition Sciences The University of QueenslandSt.LuciaQLD 4072Australia Faculty of Health Sciences and.Med.cine Bond UniversityGold CoastQLD 4229Australia College of Health Solutions Arizona State UniversityPhoenixAZ 85003USA

Purpose:To d.scribe the d.velopment of a Compend.um for estimating the energy costs of activities in ad.lts>60 years(OA Compend.um).Method.:Physical activities(PAs)and.their metabolic equivalent of task(MET)values were obtained.from a systematic search of stud.es published.in 4 sport and.exercise d.tabases(PubMed.Embase,SPORTd.scus(EBSCOhost),and.Scopus)and.a review of articles includ.d.in the 2011 Ad.lt Compend.um that measured.PA in old.r *** values were computed.as the oxygen cost(VO_(2),mL/kg/min)d.ring PA d.vid.d.by 2.7 m L/kg/min(MET_(60+))to account for the lower resting metabolic rate in old.r ***:We id.ntified.68 articles and.extracted.energy expend.ture d.ta on 427 *** these,we d.rived.99 unique Specific Activity cod.s with correspond.ng MET_(60+)values for old.r *** d.veloped.a website to present the OA Compend.um MET_(60+)values:https://***:The OA Compend.um uses d.ta collected.from ad.lts>60 years for more accurate estimation of the energy cost of PAs in old.r *** is an accessible resource that will allow researchers,ed.cators,and.practitioners to find.MET_(60+)values for old.r ad.lts for use in PA research and.practice.

关键词： Energy expend.ture Exercise MET Old.r ad.lts

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