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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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Influence of Livestock Soil Eutrophication on Floral Composition in the Pyrenees Mountains

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Journal of Mountain Science 2008年第1期5卷 63-72页

作者： BADíA David MARTí Clara SáNCHEZ josé Ramón FILLAT Federico AGUIRRE javier GóMEZ Daniel High School of Agricultural Engineering E-22071 HuescaSpain Pyreneean Institut of Ecology CSICE-22700 JacaSpain

Livestock behaviour in the Pyrenees includes free grazing and a long resting period that provokes the accumulation of dung and urine in some places,so-called camping areas. The aims of this study were (i) to analyze any change in floral composition,and in nutritional and chemical contents of plants in a livestock camping area; and (ii) to relate the floral composition with soil chemical properties. In a linear transect,five sampling zones were established,from the centre of the camping area to the surrounding Nardus stricta-dominant pasture. The above ground plant biomass and the topsoil were sampled in each zone with 6 replicates per zone. Plant species were classified and weighed to calculate above ground biomass,nutritional and chemical contents,and Shannon diversity and evenness indices. Additionally,soils were sampled in two periods,at the beginning and at the end of grazing period. Soil available nutrients (nitrate,ammonium,phosphorus,potassium,calcium and magnesium),total nitrogen,organic carbon and pH were measured. Plant chemical contents (protein,lignin and others) were significantly related to the proportions of grasses,legumes and other plants; so,the protein content is positively correlated with legumes plant biomass while lignin content is negatively correlated with grasses. Both plant and soil nutrients increased linearly towards the centre of the camping area. However,the relationship among plant species richness,diversity and evenness relative to its position along the studied transect was bell-shaped. From the outskirts to the centre of the camping area,plants with low nutrient demand were progressively replaced by those with medium and high nutrients demand and by pioneers. Nardus stricta-dominant pasture has low plant diversity and plant nutrient content as well as a poor soil nutrient availability. The presence of the camping area introduced patches with more soil nutrients and new species in the large spatial scale. However at a small spatial s

关键词：超营养作用家禽土壤比利牛斯山脉

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Encephalitis with convulsive status in an immunocompetent pediatric patient caused by Bartonella henselae

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Asian Pacific Journal of Tropical Medicine 2016年第6期9卷 591-594页

作者： Rosario Cerpa Polar Gabriela Orellana Wilmer Silva Caso josé Sánchez Carbonel javier Santisteban Juana del Valle Mendoza javier Santisteban Infectogía Pediátrica Servicio de Pediatría Especializada Hospital Edgardo Rebagliati Martins Neurologia Pediátrica Hospital Edgardo Rebagliati Martins School of Medicne Faculty of Health Sciences Universidad Peruana de Ciencias Aplicadas Faculty of Health Sciences Research Center of the Faculty of Health Sciences Universidad Peruana de Ciencias Aplicadas Clínica Pediatrica Hospital Edgardo Rebagliati Martins

Cat scratch's disease caused by Bartonella henselae, is known to be a self-limited benign process in immunocompetent children. The association with neurologic manifestations is very uncommon especially in patient with no immunologic defects and in cases without specific treatment. A 7 years old male patient, without any immunocromised defect, presented an atypic presentation of the cat scratch disease. The patient came to the hospital in two opportunities in a status epilepticus, in both cases the diagnosis was encephalitis by Bartonella henselae and the evolution with treatment was monitored with PCR(polymerase chain reaction) in cerebrospinal fluid and blood, as well as IFI(IgM, IgG) serology(indirect immunofluorescence). The patient had a favorable clinical and laboratory evolution for 6 months showing no recurrence of the disease.

关键词： Bartonella henselae Encephalitis Immunocompetent Pediatric patient Convulsive status Cat scratch’s disease

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Sarcoma stratification by combined pH2AX and MAP17(PDZK1IP1)levels for a better outcome on doxorubicin plus olaparib treatment

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Signal Transduction and Targeted Therapy 2020年第1期5卷 697-709页

作者： Marco Perez joséManuel García-Heredia Blanca Felipe-Abrio Sandra Muñoz-Galván javier Martín-Broto Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS) Hospital Universitario Virgen del RocíoUniversidad de SevillaConsejo Superior de Investigaciones CientíficasSevillaSpain Ciber de Cancer IS Carlos IIIMadridSpain Departamento de Bioquímica Vegetal y Biología Molecular Universidad de SevillaSevillaSpain Departamento de Anatomía Patológica Hospital Universitario Virgen del RocíoSevillaSpain

Sarcomas constitute a rare heterogeneous group of tumors,including a wide variety of histological *** advances in our understanding of the pathophysiology of the disease,first-line sarcoma treatment options are still limited and new treatment approaches are *** H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug *** this study,we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein,an inducer of DNA damage through ROS increase,as prognostic biomarkers in sarcoma ***,we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both *** evaluate retrospectively the levels of pH2AX(Ser139)and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological *** found that the levels of pH2AX and MAP17 were related to clinical features and poor ***,we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in *** demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro,inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation,as a result of DNA *** synergism was corroborated in patient-derived xenografts(PDX)where the combination was effective in tumors with high levels of pH2AX and MAP17,suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.

关键词： H2AX doxorubicin treatment

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Minimizing sperm oxidative stress using nanotechnology for breeding programs in rams

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Journal of Animal Science and Biotechnology 2023年第6期14卷 2395-2410页

作者： Alejandro Jurado‑Campos Pedro javier Soria‑Meneses Maria Arenas‑Moreira Carlos Alonso‑Moreno Virginia Rodriguez‑Robledo Ana josefa Soler jose Julian Garde Maria del Rocio Fernandez‑Santos SaBio IREC(CSIC-UCLM-JCCM) Campus UniversitarioS/N02071 AlbaceteSpain. Departamento de Quimica Inorganica Organica Y Bioquimica‑Centro de Innovacion en Quimica Avanzada(ORFEO‑CINQA)Facultad de FarmaciaUniversidad de Castilla-La Mancha02008 AlbaceteSpain. Centro Regional de Investigacion Biomedicas Unidad nanoDrugUniversidad de Castilla-La Mancha02008 AlbaceteSpain. Facultad de Farmacia Universidad de Castilla La Mancha02071 AlbaceteSpain.

Background Artificial insemination(AI)is a routine breeding technology in animal ***,the temperature-sensitive nature and short fertile lifespan of ram sperm samples hamper its use in *** this sense,nanotechnology is an interesting tool to improve sperm protection due to the development of nanomaterials for AI,which could be used as delivery *** this work,we explored the feasibility of vitamin E nanoemulsion(NE)for improving sperm quality during *** With the aim of evaluating this proposal,ejaculates of 7 mature rams of Manchega breed were collected by artificial vagina and extended to 60×10^(6)spz/mL in *** containing control and NE(12 mmol/L)with and without exogenous oxidative stress(100μmol/L Fe2+/ascorbate)were stored at 22 and 15℃and motility(CASA),viability(YO-PRO/PI),acrosomal integrity(PNA-FITC/PI),mitochondrial membrane potential(Mitotracker Deep Red 633),lipoperoxidation(C11 BODIPY 581/591),intracellular reactive oxygen species(ROS)production and DNA status(SCSAR)monitored during 96 *** results show that NE could be used to maintain ram spermatozoa during transport at 15 and 22℃for up to 96 h,with no appreciable loss of kinematic and physiological characteristics of freshly collected *** The storage of ram spermatozoa in liquid form for 2-5 d with vitamin E nanoemulsions may lead more flexibility to breeders in AI *** view of the potential and high versatility of these nanodevices,further studies are being carried out to assess the proposed sperm preservation medium on fertility after artificial insemination.

关键词： Breeding technology Nanoemulsions Nanotechnology Sperm oxidative stress Vitamin E

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Role of artificial intelligence in multidisciplinary imaging diagnosis of gastrointestinal diseases

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World Journal of Gastroenterology 2021年第27期27卷 4395-4412页

作者： M Alvaro Berbís josé Aneiros-Fernández F javier Mendoza Olivares Enrique Nava Antonio Luna Department of R&D HT MédicaMadrid 28046MadridSpain Department of Pathology Hospital Universitario Clínico San CecilioGranada 18012Spain Department of Gastroenterology Fatima ClinicSevilla 41012Spain Department of Communications Engineering University of MálagaMalaga 29016Spain MRI Unit Department of RadiologyHT MédicaJaén 23007Spain

The use of artificial intelligence-based tools is regarded as a promising approach to increase clinical efficiency in diagnostic imaging,improve the interpretability of results,and support decision-making for the detection and prevention of ***,endoscopy and pathology images are suitable for deep-learning analysis,potentially changing the way care is delivered in *** aim of this review is to examine the key aspects of different neural network architectures used for the evaluation of gastrointestinal conditions,by discussing how different models behave in critical tasks,such as lesion detection or characterization(*** distinction between benign and malignant lesions of the esophagus,the stomach and the colon).To this end,we provide an overview on recent achievements and future prospects in deep learning methods applied to the analysis of radiology,endoscopy and histologic whole-slide images of the gastrointestinal tract.

关键词： Artificial intelligence Machine learning Radiology Endoscopy Pathology Gastroenterology

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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： Francisco javier Vela Guadalupe Martínez-Chacón Alberto Ballestín joséLuis Campos Francisco 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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Water-soluble hollow nanocrystals from self-assembly of AIEEactive Pt(II)metallomesogens

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Nano Research 2021年第1期14卷 245-254页

作者： Cristian Cuerva javier Fernandez-Lodeiro Mercedes Cano jose Luis Capelo-Martinez Carlos Lodeiro BIOSCOPE Research Group LAQV@REQUIMTE Chemistry DepartmentNOVA School of Science and TechnologyNOVA University Lisbon2829-516 CaparicaPortugal PROTEOMASS Scientific Society Rua dos InventoresMadam ParqueCaparica Campus2829-516 CaparicaPortugal Department of Inorganic Chemistry Complutense University of MadridCiudad Universitaria28040 MadridSpain

Luminescent hollow micro-and nanocrystals have been successfully obtained taking advantage of the self-assembly behavior and the aggregation-induced emission enhancement properties of several bispyrazolate Pt(II)metallomesogens decorated with four terminal alkyl ***-in-water droplets have been used to confine the Pt(II)compounds and drive them to be self-assembled via intermolecular Pt…Pt interactions into spherical aggregates of about 200 or 50 *** of the oil phase generates highly-stable aqueous dispersions of nanocrystals that emit a bright orange light as a result of the existence of^(3)MMLCT excited *** methods and conditions have been tested for studying the effect of several parameters such as the temperature and the stirring speed in the final particle size and in the polydispersity ***,the micro-and nanocrystals are able to entrap hydrophobic drugs between the alkyl chains of the compounds,forming stable dispersions of drug-loaded capsules in *** droplet method is applied in the area of metallomesogens for the first time to synthesize self-assembled Pt(II)nanocapsules,which opens a new field of study that could allow the use of these liquid crystal materials in biomedical applications.

关键词： R(II)metallomesogens self-assembly luminescent nanomaterials droplets nanocapsules

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Morphoagronomic characterization and wholegenome resequencing of eight highly diverse wild and weedy *** and *** *** accessions used for the first interspecific tomato MAGIC population

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Horticulture Research 2020年第1期7卷 477-492页

作者： Pietro Gramazio Leandro Pereira-Dias Santiago Vilanova Jaime Prohens Salvador Soler javier Esteras Alfonso Garmendia María joséDíez Faculty of Life and Environmental Sciences University of Tsukuba1-1-1 Tennodai305-8572 TsukubaJapan Instituto de Conservación y Mejora de la Agrodiversidad Valenciana Universitat Politècnica de ValènciaCamino de Vera 1446022 ValenciaSpain Departamento de Ecosistemas Agroforestales Universitat Politècnica de ValènciaCamino de Vera 1446022 ValenciaSpain Instituto Agroforestal Mediterráneo Universitat Politècnica de ValènciaCamino de Vera 1446022 ValenciaSpain

The wild Solanum pimpinellifolium(SP)and the weedy *** ***(SLC)are largely unexploited genetic reservoirs easily accessible to breeders,as they are fully cross-compatible with cultivated tomato(*** ***).We performed a comprehensive morphological and genomic characterization of four wild SP and four weedy SLC accessions,selected to maximize the range of variation of both *** eight accessions are the founders of the first tomato interspecific multi-parent advanced generation inter-cross(MAGIC)*** morphoagronomic characterization was carried out with 39 descriptors to assess plant,inflorescence,fruit and agronomic traits,revealing the broad range of diversity *** of the morphological variation observed in SP was likely associated to the adaptation of the accessions to different environments,while in the case of SLC to both human activity and adaptation to the ***-genome resequencing of the eight accessions revealed over 12 million variants,ranging from 1.2 to 1.9 million variants in SLC and from 3.1 to 4.8 million in SP,being 46.3%of them(4,897,803)private *** genetic principal component analysis also confirmed the high diversity of SP and the complex evolutionary history of *** was also reflected in the analysis of the potential footprint of common ancestors or old introgressions identified within and between the two *** functional characterization of the variants revealed a significative enrichment of GO terms related to changes in cell walls that would have been negatively selected during domestication and *** comprehensive morphoagronomic and genetic characterization of these accessions will be of great relevance for the genetic analysis of the first interspecific MAGIC population of tomato and provides valuable knowledge and tools to the tomato community for genetic and genomic studies and for breeding purposes.

关键词： agronomic breeding MAGIC

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5Ws of Green and Sustainable Software

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Tsinghua Science and Technology 2020年第3期25卷 401-414页

作者： Coral Calero javier Mancebo Felix Garcia Maria Angeles Moraga jose Alberto Garcia Berna jose Luis Fernandez-Aleman Ambrosio Toval the Institute of Technology and Information Systems University of Castilla-La ManchaCiudad Real 13071Spain. the Department of Informatics and Systems University of MurciaMurcia 30003Spain

Green and Sustainable Software has emerged as a new and highly active area in the software *** several years of research and work,we believe that it is now necessary to obtain a general snapshot of how the research in this area is *** do so,we have applied the 5 Ws(why,when,who,where,and what),a formula for getting the complete story on a *** have therefore carried out a study,using 542 publications related to Green and Sustainable Software research;these were recovered using *** results obtained allow us to conclude that it is important to identify key elements of the research to allow researchers be fully aware of the state of the research on Green and Sustainable Software(why);the study uses papers published between 2000 and the beginning of November 2018(when);the most prolific authors are mainly from Europe,although the USA is the most active country,Green and Sustainable Software being a very interactive area with a good number of multinational publications(who);the top five keywords related to sustainable aspects are Green Software,Green IT,Software Sustainability,Energy Consumption,and Energy Efficiency(what);finally,as regards the places authors prefer to publish in,there is almost a complete balance between conferences and journals,with a trend towards an increase in the number of publications(where).

关键词： Green Software Sustainable Software Software Engineering Software Sustainability Energy Efficiency Energy Utilization

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