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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 use.WLB-73502 is a dual,bispecific compound that binds sigma-1(S1R)and mu-opioid(MOR)receptors.WLB-73502 is an antagonist at the S1R.It 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 pathways.Despite 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 pain.WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect.Contrary to morphine and oxycodone,tolerance to its antinociceptive effect did not develop after repeated 4-week administration.Also,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 doses.WLB-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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The effect of slime accumulated in a long-term operating UASB using crude glycerol to treat S-rich wastewater

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Journal of Environmental Sciences 2024年第1期135卷 353-366页

作者： Xudong Zhou Eva Fernández-Palacios Antoni DDorado Javier Lafuente xavier Gamisans David Gabriel Key Laboratory of Urban Pollutant Conversion Institute of Urban EnvironmentChinese Academy of SciencesXiamen 361021China GENOCOV Research Group Department of ChemicalBiological and Environmental EngineeringEscola d’EnginyeriaUniversitat Autònoma de Barcelona08193 BellaterraSpain Department of Mining Industrial and ICT EngineeringUniversitat Politècnica de CatalunyaAvinguda de les Bases de Manresa 61-7308242 ManresaSpain

An up-flow anaerobic sludge blanket(UASB)reactor targeting sulfate reduction was operated under a constant TOC/S-SO2-4ratio of 1.5±0.3 g C/g S for 639 days using crude glycerol as carbon source.A filamentous and fluffy flocculant material,namely slime-like substances(SLS),was gradually accumulated in the bioreactor after the cease of methanogenic activity.The accumulation of SLS was followed by a decrease in the removal efficiencies and a deterioration in the performance.Selected characteristics of SLS were investigated to explore the causes of its formation and the effect of SLS on the UASB performance.Results showed that glycerol fermentation and sulfate reduction processes taking place in the reactor were mainly accomplished in the bottom part of the UASB reactor,as the sludge concentration in the bottom was higher.The accumulation of SLS in the UASB reactor caused sludge flotation that further led to biomass washout,which decreased the sulfate and glycerol removal efficiencies.Batch activity tests performed with granular sludge(GS),slime-covered granular sludge(SCGS)and SLS showed that there was no difference between GS and SLS in the mechanism of glycerol fermentation and sulfate reduction.However,the specific sulfate reduction rate of GS was higher than that of SLS,while SLS showed a higher glycerol fermentation rate than that of GS.The different rates in GS and SLS were attributed to the higher relative abundances of fermentative microorganisms found in SLS and higher relative abundances of sulfate reducing bacteria(SRB)found in GS.

关键词： Sludge flotation Granular sludge Slime-like substances Glycerol fermentation Sulfate reduction Removal efficiency

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Peri-articular elbow fracture fixations with magnesium implants and a review of current literature: A case series

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World Journal of Orthopedics 2024年第3期15卷 215-229页

作者： Christopher Fang Antony xavier Rex Premchand Derek Howard Park Dong Hao Toon Department of Orthopaedic Surgery Khoo Teck Puat HospitalNational Healthcare GroupSingapore 768828Singapore

BACKGROUND In recent years,the use of Magnesium alloy implants have gained renewed popularity,especially after the first commercially available ConformitéEuropéenne approved Magnesium implant became available(MAGNEZIX®CS,Syntellix)in 2013.AIM To document our clinical and radiographical outcomes using magnesium implants in treating peri-articular elbow fractures.METHODS Our paper was based on a retrospective case series design.Intra-operatively,a standardized surgical technique was utilized for insertion of the magnesium implants.Post–operatively,clinic visits were standardized and physical exam findings,functional scores,and radiographs were obtained at each visit.All complications were recorded.RESULTS Five patients with 6 fractures were recruited(2 coronoid,3 radial head and 1 capitellum).The mean patient age and length of follow up was 54.6 years and 11 months respectively.All fractures healed,and none exhibited loss of reduction or complications requiring revision surgery.No patient developed synovitis of the elbow joint or suffered electrolytic reactions when titanium implants were used concurrently.CONCLUSION Although there is still a paucity of literature available on the subject and further studies are required,magnesium implants appear to be a feasible tool for fixation of peri-articular elbow fractures with promising results in our series.INTRODUCTION In recent years,the use of Magnesium alloy implants in orthopaedic surgeries have gained renewed popularity.Apart from being bioabsorbable,negating the need for implant removal,magnesium also has good osteoconductive properties[1-4].Biomechanically,it exhibits greater biomechanical strength than any pre-existing polymers,and reduces the stress-shielding effect associated with titanium and steel implants as it has a Young’s modulus closer to bone[4].Currently,the main utility of magnesium implants in the orthopaedic community is within the foot and ankle community where satisfactory results have been reported with its utility in forefoot osteotomies[5-7].Ho

关键词： Magnesium screw Fracture Peri-articular Elbow

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Reproductive ecology of the black rat (Rattus rattus) in Madagascar: the influence of density-dependent and -independent effects

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Integrative Zoology 2024年第1期19卷 66-86页

作者： Kathryn SCOBIE Soanandrasana RAHELINIRINA Voahangy SOARIMALALA Fehivola Mandanirina ANDRIAMIARIMANANA Corinne RAHAINGOSOAMAMITIANA Toky RANDRIAMORIA Soloandry RAHAJANDRAIBE xavier LAMBIN Minoarisoa RAJERISON Sandra TELFER School of Biological Sciences University of AberdeenAberdeenUK Plague Unit Institut Pasteur de MadagascarAntananarivoMadagascar Association Vahatra AntananarivoMadagascar

The black rat(Rattus rattus)poses a severe threat to food security and public health in Madagascar,where it is a major cause of pre-and post-harvest crop losses and an important reservoir for many zoonotic diseases,including plague.Elsewhere,ecologically based rodent management(EBRM)strategies have been developed using ecologi-cal information to inform decisions on where and when to target control.EBRM could deliver improved health and well-being outcomes in Madagascar if adapted to the local ecological context.Using data collected from removal studies,we explored spatio-temporal patterns in the breeding activity of the black rat(R.rattus)in domestic and agricultural habitats across Madagascar and investigated to what extent these trends are influenced by rainfall and rat density.We identified clear spatio-temporal variation in the seasonality of R.rattus reproduction.Reproduction was highly seasonal both inside and outside of houses,but seasonal trends varied between these two habitats.Sea-sonal trends were explained,in part,by variation in rainfall;however,the effect of rainfall on reproductive rates did itself vary by season and habitat type.A decline in breeding intensity with increasing rat density was recorded outside of houses.This has important implications for control,as populations may compensate for removal through increased reproduction.We recommend that sustained control initiated before the main breeding season,combined with improved hygiene and adequate rodent-proofing in homes and grain stores,could curtail population growth and reduce pre-and post-harvest losses provided that these measures overcome the compensatory response of rodent populations.

关键词： Madagascar Rattus rattus reproductive ecology rodent control

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Massive abdominal muscle atrophy during prolonged mechanical ventilation: Implications for tracheostomy removal

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Journal of Intensive Medicine 2024年第1期4卷 133-135页

作者： Pascal Beuret Florian Michelin Audrey Tientcheu Laurane Chalvet Benedicte Philippon-Jouve Jean-Charles Chakarian xavier Fabre Service de Réanimation et Soins continus Centre Hospitalier de RoanneRoanneFrance

Introduction Maintaining the functional integrity of respiratory muscles is crucial for critically ill patients to be weaned from mechanical ventilation and decannulated if tracheotomized.Dysfunction of the diaphragm is frequent in patients under mechanical ventilation and has been associated with a longer duration of weaning.[1,2]Studies on expiratory muscles are scarce.Two recent studies demonstrated the feasibility and reproducibility of ultrasound in measuring the thickness of abdominal muscles,[3,4]with one study showing abdominal muscle atrophy in 22%of mechanically ventilated critically ill patients during the first week of mechanical ventilation.[4]

关键词： critically mechanical abdominal

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The Barrier of the Child and Parent Expected Models for Entering the School System-A Secondary Publication

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Journal of Contemporary Educational Research 2024年第2期8卷 243-255页

作者： xavier Conus Department of Education and Training Sciences University of Fribourg1700 FribourgSwitzerland

The recognition of the positive value of student diversity and their right to full participation are key aspects of inclusion as a means of managing heterogeneity of the school population from an equality perspective.As the school cannot welcome the diversity of children without including their families,the same logic needs to apply to the relationship between the school and parents,particularly in the current environment where the school-family partnership appears as a privileged institutional leverage in the fight against inequalities at school.Based on an ethnographical study exploring how the relationship between the school and the families builds up in a Swiss school located in a context of strong cultural diversity,this paper interrogates how the school norm can be the main limitation to the inclusion of students and parents who are unfamiliar with the school.Derived from field observations and interviews,our results show how the teachers tend to approach their relationship with new students and their parents from the standpoint of narrowly defined expected models,leading them to engage in a vain attempt to conform the students and parents when they deviate from these models.The possibility of entering the school system for students and parents unfamiliar with school is hindered by the exclusive and excluding normativity on which the models of the child and the parent expected by the teachers are grounded.Based on these observations,we discuss how an inclusive approach seems to us to require in the first place a necessary process of decentering from the school and teachers,as a condition for recognition of the actual child and parent.

关键词： Educational inclusion and exclusion Family and education Norms and regulations Primary and elementary education Switzerland

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Seasonal variation and host sex affect bat–bat fly interaction networks in the Amazonian savannahs

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Integrative Zoology 2024年第3期19卷 400-416页

作者： Paulo MEJIA Gustavo Lima URBIETA Bruna da Silva xavier IsaíJorge de CASTRO JoséJúlio DE TOLEDO Gustavo GRACIOLLI Lucio AndréVIANA DIAS William Douglas CARVALHO Programa de Pós-Graduação em Biodiversidade Tropical Universidade Federal do Amapá(UNIFAP)MacapáAPBrazil Programa de Pós-Graduação em Ecologia Instituto de BiologiaCentro de Ciências da SaúdeUniversidade Federal do Rio de Janeiro(UFRJ)Rio de JaneiroRJBrazil Laboratório de Mamíferos Instituto de Pesquisas Científicas e Tecnológicas do Estado do Amapá(IEPA)MacapáAPBrazil Programa de Pós-Graduação em Biologia Animal Laboratório de SistemáticaEcologia e Evolução(LSEE)Instituto de BiociênciasUniversidade Federal de Mato Grosso do Sul(UFMS)Campo GrandeMTBrazil Terrestrial Ecology Group(TEG-UAM) Departamento de EcologíaFacultad de CienciasUniversidad Autónoma de MadridMadridSpain Centro de Investigación en Biodiversidad y Cambio Global(CIBC-UAM) Universidad Autónoma de MadridMadridSpain

Bats are the second-most diverse group of mammals in the world,and bat flies are their main parasites.However,significant knowledge gaps remain regarding these antagonistic interactions,especially since diverse factors such as seasonality and host sex can affect their network structures.Here,we explore the influence of such factors by comparing species richness and composition of bat flies on host bats,as well as specialization and modularity of bat–bat fly interaction networks between seasons and adult host sexes.We captured bats and collected their ectoparasitic flies at 10 sampling sites in the savannahs of AmapáState,northeastern region of the Brazilian Amazon.Despite female bats being more parasitized and recording greater bat fly species richness in the wet season,neither relationship was statistically significant.The pooled network could be divided into 15 compartments with 54 links,and all subnetworks comprised>12 compartments.The total number of links ranged from 27 to 48(for the dry and wet seasons,respectively),and female and male subnetworks had 44 and 41 links,respectively.Connectance values were very low for the pooled network and for all subnetworks.Our results revealed higher bat fly species richness and abundance in the wet season,whereas specialization and modularity were higher in the dry season.Moreover,the subnetwork for female bats displayed higher specialization and modularity than the male subnetwork.Therefore,both seasonality and host sex contribute in different ways to bat–bat fly network structure.Future studies should consider these factors when evaluating bat–bat fly interaction networks.

关键词： Amapá Amazon biome bat flies bats interaction networks

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众脑之力:通过开放神经影像数据和大规模协作催化神经精神疾病的创新发现

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Science Bulletin 2024年第10期69卷 1536-1555页

作者：鲁彬陈骁 Francisco xavier Castellanos Paul M.Thompson 左西年臧玉峰严超赣 CAS Key Laboratory of Behavioral Science Institute of PsychologyBeijing 100101China Department of Psychology University of Chinese Academy of SciencesBeijing 100101China Department of Child and Adolescent Psychiatry NYU Grossman School of MedicineNew York 10016USA d Nathan Kline Institute for Psychiatric Research Orangeburg 10962USA Imaging Genetics Center Mark&Mary Stevens Institute for Neuroimaging&InformaticsKeck School of MedicineUniversity of Southern CaliforniaLos Angeles 90033USA Developmental Population Neuroscience Research Center IDG/McGovern Institute for Brain ResearchBeijing Normal UniversityBeijing 100875China National Basic Science Data Center Beijing 100190China Centre for Cognition and Brain Disorders The Affiliated Hospital of Hangzhou Normal UniversityHangzhou 310004China Institute of Psychological Science Hangzhou Normal UniversityHangzhou 310030China Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairment Hangzhou 311121China International Big-Data Center for Depression Research Institute of PsychologyChinese Academy of SciencesBeijing 100101China Magnetic Resonance Imaging Research Center Institute of PsychologyChinese Academy of SciencesBeijing 100101China

Recent advances in open neuroimaging data are enhancing our comprehension of neuropsychiatric disorders.By pooling images from various cohorts,statistical power has increased,enabling the detection of subtle abnormalities and robust associations,and fostering new research methods.Global collaborations in imaging have furthered our knowledge of the neurobiological foundations of brain disorders and aided in imaging-based prediction for more targeted treatment.Large-scale magnetic resonance imaging initiatives are driving innovation in analytics and supporting generalizable psychiatric studies.We also emphasize the significant role of big data in understanding neural mechanisms and in the early identification and precise treatment of neuropsychiatric disorders.However,challenges such as data harmonization across different sites,privacy protection,and effective data sharing must be addressed.With proper governance and open science practices,we conclude with a projection of how large-scale imaging resources and collaborations could revolutionize diagnosis,treatment selection,and outcome prediction,contributing to optimal brain health.

关键词： Magnetic resonance imaging Neuropsychiatric disorders Big data Open science Artificial intelligence

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Analysis of the Energy and Environmental Sustainability of a Built Space System: The Case of Patte d’Oie University Campus in Ouagadougou

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Energy and Power Engineering 2024年第5期16卷 197-215页

作者： Daouda Sawadogo Ousmane Coulibaly xavier Chesneau Belkacem Zeghmati Laboratoire de Physique et de Chimie de l’ Environnement (LPCE) Department of Physics Universit&#233 Joseph KI-ZERBO Ouagadougou Burkina Faso Multidisciplinary Modeling and Simulation Laboratory (LAMPS) Mechanics and Energetics Group (GME) Universit&#233 Perpignan Via Domitia Perpignan France

The aim of this study was to carry out a dynamic simulation of the energy and environmental performance of a built space system, with a view to assessing its energy and environmental class. The use of a simulation and modeling tool, supported by various methodological references, formed the basis of our approach. Adopting a systemic perspective, we described the structural and functional aspects of the systems making up built spaces, as well as the associated energy flows. Our approach was also based on a typology, taking into account typical days, structural and functional configurations at different scales and angles of observation. The analysis tool we developed in Java was applied to the built space system of the Patte d’Oie university campus in Ouagadougou. Annual electricity consumption was measured at 124387.34 kWh, closely aligned with the average annual electricity bill (125224.31 kWh), with a maximum relative deviation of 1%, followed by a carbon emission balance of 58337.66 kg eq CO2 per year. This validation confirmed the effectiveness of our tool. In addition, following the analysis of electricity consumption using our tool, the university campus was classified in energy class B and environmental class C. These results will be based on the emission factors of the energy mix of the West African Economic and Monetary Union (WAEMU) territory, with particular emphasis on Burkina Faso.

关键词： Energy Function Energy Class Carbon Footprint Built Space Consumption Item Systemic Approach Typological Approach

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Inclusive Education in the Context of Ethnocultural Diversity: Understanding the Process of Exclusion to Act in the School - A Secondary Publication

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Journal of Contemporary Educational Research 2024年第3期8卷 124-135页

作者： Marie-Odile Magnan Justine Gosselin-Gagné Geneviève Audet xavier Conus Faculty of Educational Sciences Department of Administration and Foundations of EducationUniversity of MontrealCanada Department of Special Education and Training University of Quebec at MontrealCanada Department of Educational Sciences and Training University of FriborgSwitzerland

This paper reveals that the implementation of inclusive education is an unfinished challenge,both within the system and for individual self-improvement.This process of changing practices,by continually questioning the school’s responsibility for the(re)production of inequalities,exclusion,and unequal social relations,is riddled with obstacles,unpredictable situations,and strong emotions.In particular,the researchers point out that many systemic mechanisms of school culture contribute to replicating and reifying hierarchical school experiences and exacerbating processes of institutional discrimination against immigrant backgrounds and/or racialized students.The empirical research presented also highlights the school staff’s deficit thinking toward immigrant students and their parents.The results show that staff tend to use linguistic and cultural gaps between students and the school system to explain academic failure.Be that as it may,the researchers as well as the school actors and students interviewed in this paper suggest multiple ways to improve inclusion in the school context,stressing the importance of giving voice to the various actors in order to move toward institutional transformation.

关键词： Educational inclusion and exclusion Canada Switzerland

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