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Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism:WLB-73502,an analgesic with improved efficacy and safety profile compared to strong opioids

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Acta Pharmaceutica Sinica B 2023年第1期13卷 82-99页

作者： Alba Vidal-Torres Begoña Fernández-Pastor Mónica García Eva Ayet Anna Cabot javier Burgueño Xavier Monroy Bertrand Aubel Xavier Codony Luz Romero Rosalía Pascual Maria Teresa Serafini Gregorio Encina Carmen Almansa Daniel Zamanillo Manuel Merlos JoséMiguel vela WeLab Barcelona Parc Cientific de BarcelonaBarcelona 08028Spain

Opioids are the most effective painkillers,but their benefit-risk balance often hinder their therapeutic ***-73502 is a dual,bispecific compound that binds sigma-1(S1R)and mu-opioid(MOR)***-73502 is an antagonist at the *** behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificantβ-arrestin-2 recruitment,thus demonstrating low intrinsic efficacy on MOR at both signalling *** its partial MOR agonism,WLB-73502exerted full antinociceptive efficacy,with potency superior to morphine and similar to oxycodone against nociceptive,inflammatory and osteoarthritis pain,and superior to both morphine and oxycodone against neuropathic ***-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive *** to morphine and oxycodone,tolerance to its antinociceptive effect did not develop after repeated 4-week ***,contrary to opioid comparators,WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy,and it was devoid of proemetic effect(retching and vomiting)in ferrets at potentially effective ***-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

关键词： WLB-73502 Sigma-1 receptor Mu-opioid receptor Biased agonist Analgesic activity Chronic pain Neuropathic pain Safety

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Animal models used to study direct peripheral nerve repair: a systematic review

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Neural Regeneration Research 2020年第3期15卷 491-502页

作者： fran.isco javier vela Guadalupe Martínez-Chacón Alberto Ballestín JoséLuis Campos fran.isco Miguel Sánchez-Margallo Elena Abellán Department of Microsurgery Jesús Usón Minimally Invasive Surgery CentreCáceresSpain Scientific Director Jesús Usón Minimally Invasive Surgery CentreCáceresSpain

Objective:Peripheral nerve repair is required after traumatic *** common condition represents a major public health problem *** after nerve repair depends on several factors,including the severity of the injury,the nerve involved,and the surgeon’s technical *** the precise microsurgical repair of nerve lesions,adequate functional recovery is not always achieved and,therefore,the regeneration process and surgical techniques are still being ***-clinical animal models are essential for this research and,for this reason,the focus of the present systematic review(according to the PRISMA statement)was to analyze the different animal models used in pre-clinical peripheral nerve repair *** sources:Original articles,published in English from 2000 to 2018,were collected using the Web of Science,Scopus,and PubMed *** selection:Only preclinical trials on direct nerve repair were included in this *** articles were evaluated by the first two authors,in accordance with predefined data *** measures:The primary outcomes included functional motor abilities,daily activity and regeneration *** outcomes included coaptation technique and animal ***:This review yielded 267 articles,of which,after completion of the screening,49 studies were *** were 1425 animals in those 49 studies,being rats,mice,guinea pigs,rabbits,cats and dogs the different pre-clinical *** nerves used were classified into three groups:head and neck(11),forelimb(8)and hindlimb(30).The techniques used to perform the coaptation were:microsuture(46),glue(12),laser(8)and mechanical(2).The follow-up examinations were histology(43),electrophysiological analysis(24)and behavioral observation(22).Conclusion:The most widely used animal model in the study of peripheral nerve repair is the *** animal models are also used but the cost-benefit of the rat model provides several strengths over the ***

关键词： nerve microsurgery peripheral nerve regeneration repair reconstruction direct nerve repair animal model coaptation PRISMA systematic review

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Spectral analysis of new black hole candidate AT2019wey observed by NuSTAR

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Science China(Physics,Mechanics & Astronomy) 2022年第1期65卷 92-102页

作者： Ye Feng XueShan Zhao LiJun Gou YuFeng Li James FSteiner javier AGarc´ıa Yuan Wang Nan Jia ZhenXuan Liao HuiXian Li Key Laboratory for Computational Astrophysics National Astronomical ObservatoriesChinese Academy of SciencesBeijing 100012China School of Astronomy and Space Sciences University of Chinese Academy of SciencesBeijing 100049China Harvard-Smithsonian Center for Astrophysics Cambridge MA 02138USA Cahill Centre for Astronomy and Astrophysics California Institute of TechnologyPasadena CA 91125USA Dr.Karl Remeis-Observatory and Erlangen Centre for Astroparticle Physics Bamberg 96052Germany School of Science Jimei UniversityXiamen 361021China

AT2019 wey is a new galactic X-ray binary that was first discovered as an optical transient by the Asteroid Terrestrial-impact Last Alert System(ATLAS)on December 7,***2019 wey consists of a black hole candidate as well as a low-mass companion star(M_(star)≤1.0 M_(■))and is likely to have a short orbital period(P_(orb)≤16h).Although AT2019 wey began activation in the X-ray band on March 8,2020,it did not enter the soft state during almost the entire *** this study,we present a detailed spectral analysis of AT2019 wey in the low/hard state during its X-ray outburst on the basis of Nuclear Spectroscopic Telescope Array(Nu S T AR)*** obtain tight constraints on several of its important physical parameters by applying the state of the art relxill relativistic reflection model *** particular,we determine that the measured inner radius of the accretion disk is most likely to have extended to the innermost stable circular orbit(isco)radius,i.e.,R_(in)=1.38^(+0.23)_(-0.16)R_(isco).Hence,assuming R_(in)=R_(isco),we find the spin of AT2019 wey to be a*~0.97,which is close to the extreme and an inner disk inclination angle of i~22°.Additionally,according to our adopted models,AT2019 wey tends to have a relatively high iron abundance of AFe~5A_(Fe,■)and a high disk ionization state of logξ~3.4.

关键词： NuSTAR black hole physics X-rays binaries-stars individual AT2019wey

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燕雀亚科鸟类的贝叶斯系统发生:非洲鹂雀的分类地位及朱雀属的进化与异质起源(英文)

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动物学报 2007年第5期53卷 826-834页

作者： Antonio ARNAIZ-VILLENA Juan MOSCOSO Valentin RUIZ-DEL-VALLE javier GONZALEZ Raquel REGUERA Michael WINK Juan I.SERRANO-vela Department of Immunology Universidad ComplutenseThe Madrid Regional Blood Center Institut für Pharmazie und Molekulare Biotechnologie-Abteilung Biologie Universitt Heidelberg

鹂雀(Linurgus olivaceus)是非洲热带森林中一种独特的鸣禽,为鹂雀属(Linurgus)的惟一物种。在已有的研究中,通过对鹂雀和雀形目现存鸟类中每个科及亚科至少一个物种的线粒体DNA序列测定,分析了鹂雀与其它现存雀形目鸟类的系统发生关系... 详细信息

鹂雀(Linurgus olivaceus)是非洲热带森林中一种独特的鸣禽,为鹂雀属(Linurgus)的惟一物种。在已有的研究中,通过对鹂雀和雀形目现存鸟类中每个科及亚科至少一个物种的线粒体DNA序列测定,分析了鹂雀与其它现存雀形目鸟类的系统发生关系;在遗传上,对鹂雀与金丝雀、金翅雀及燕雀亚科其它鸟类亦有比较研究。本研究共使用了燕雀亚科83种鸟类,重点对该亚科的系统发生进行了修订。使用贝叶斯法构建了系统发生树,结果表明:鹂雀属于燕雀亚科,系统发生树中聚在金翅雀族(Carduelini),与金丝雀属(Serinus)、金翅雀属(Carduelis)及交嘴雀属(Loxia)的种类形成一组;在系统发生中,鹂雀可能是一个基部物种,它同金丝雀属和金翅雀属鸟类一同进化并分歧出来。在本研究中未能涉及的一些已灭绝种类,可能与鹂雀有着较近的遗传学关系。另一方面,研究也表明锡嘴雀(Coccotharustes coccothraustes)肯定包括在欧亚蜡嘴雀(蜡嘴雀属Eophona和拟蜡嘴雀属Mycerobas)中,美洲的朱雀(Carpodacus)可能是从亚洲种类分歧出来并经过进化辐射形成。

关键词：朱雀锡嘴雀蜡嘴雀家朱雀鹂雀雀形目鸣禽

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Topical Applications of Thiosulfinate-Enriched Allium sativum Extract Accelerates Acute Cutaneous Wound Healing in Murine Model

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Chinese Journal of Integrative Medicine 2020年第11期26卷 812-818页

作者： Juan Luis Santiago Eva Maria Galan-Moya Jose Ramon Munoz-Rodriguez Miguel Angel de la Cruz-Morcillo fran.isco javier Redondo-Calvo Ignacio Gracia-Fernandez Peter M.Elias Jose Manuel Perez-Ortiz Mao-Qiang Man Dermatology Service Hospital General Universitario de Ciudad RealCiudad Real(13004)Spain Translational Research Unit Hospital General Universitario de Ciudad RealCiudad Real(13004)Spain Translational Oncology Laboratory Centro Regional de Investigaciones BiomedicasUniversidad de Castilla-La ManchaAlbacete(02008)Spain Instituto de Tecnologia Quimica y Medioambiental Universidad de Castilla-La ManchaCiudad Real(13004)Spain Dermatology Service Vetera ns Affairs Medical Centerand Department of DermatologyUniversity of CaliforniaSan FranciscoCA(94121)USA Dermatology Hospital Southern Medical UniversityGuangzhou(510091)China

Objective To determine whether topical applications of thiosulfinate-enriched Allium sativum extract(TASE)can accelerate acute cutaneous wound healing(WH)in a murine *** Keratinocyte viability and in vitro wound closure were assessed in keratinocyte *** of topical TASE(0.5μg/mL of allicin in 97%ethanol)on acute cutaneous WH were determined in a murine model of acute cutaneous *** mice were alternately assigned to the vehicle-and TASE-treated groups(n=6 per group).Expression levels of mRNA for keratinocyte differentiation marker-related proteins(filaggrin,loricrin and involucrin)and lipid synthetic enzymes(elongation of very long chain fatty acids protein 4(ELOVL4),fatty acid synthase(FA2H),3-hydroxy-3-methyl-glutaryl-coenzyme A reductase(HMGCoA),and serine palmitoyltransferase(SPT))were assessed using real-time quantitative polymerase chain reaction on day 3 and 8 after wounding,while transepidermal water loss(TEWL)rates were measured in wounded *** TASE accelerated WH both in vivo(40%vs.22%reduction in wound area,P<0.01)and in vitro(90%vs.65%reduction in wound area,P<0.01).Moreover,topical applications of TASE upregulated the expression levels of epidermal mRNA for ELOVL4,HMGCoA,SPT,filaggrin,loricrin and involucrin(P<0.05 ***-treated controls)on day 3 after ***,TASE significantly lowered TEWL rates in comparison with vehicle alone on day 8(33.06±2.09 g/(m^2·h)vs.24.60±2.04 g/(m^2·h),P<0.01).Conclusions Topical applications of TASE stimulated keratinocyte proliferation and formation of epidermal permeability barrier function,leading to acceleration of acute cutaneous *** products containing TASE could be used to manage acute cutaneous WH.

关键词： Allium sativum thiosulfinate wound healing permeability barrier keratinocytes proliferation

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