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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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Simulated rainfall in Brazil:An alternative for assesment of soil surface processes and an opportunity for technological development

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International Soil and Water Conservation Research 2024年第1期12卷 29-42页

作者： Camila Calazans da Silva luz Wilk Sampaio de Almeida Adilson Pacheco de Souza Nivaldo Schultz Jamil Alexandre Ayach Anache Daniel Fonseca de Carvalho Postgraduate Program in Agronomy-Soil Sciences Federal Rural University of Rio de JaneiroSeropédicaRJBrazil Agronomy Department Federal Institute of EducationScience and Technology of RondôniaAriquemesROBrazil Federal University of Mato Grosso SinopMTBrazil Federal Rural University of Rio de Janeiro SeropédicaRJBrazil Federal University of Mato Grosso do Sul Campo GrandeMSBrazil

Rainfall simulators(RS)have been used,above all,to evaluate hydrological processes related to soil water infiltration,surface runoff and soil erosion.They allow repeatability of rain application with different precipitation intensities in field and/or laboratory conditions and should produce events with physical characteristics similar to natural rain.In this manuscript,we carried out a bibliometric and scientometric analysis of studies with simulated rainfall in Brazil to assess the temporal evolution of publications,the main topics addressed and the degree of technological development of the equipment.We searched for the terms“rainfall simulator”OR“simulated rainfall”AND“Brazil”in the Scopus,Web of Science,SciELO and Google Scholar databases.We found 143 articles published in the last 37 years(1985-2022).Our findings indicate that the main research areas covered in papers are soil erosion(57.34%),soil water infiltration(24.47%),nutrient losses(9.8%)and RS development and calibration/assessment(8.39%).In recent years,the number of published papers in international high-impact factor journals has increased.Most of the papers(49.65%)refer to studies carried out by institutions located in the south and southeast regions of Brazil.Moreover,there is a large gap of studies on simulated rainfall in other regions of Brazil,where important biomes such as the Cerrado,Amazon,Caatinga,and their transitions are located.This study informs research priorities on soil erosion under simulated rainfall and provides a bibliographic database that can assist in more detailed future analyses.

关键词： Rainfall simulator Soil and water losses Soil water infiltration Bibliometrics Scientific review

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Interpolation of closed ideals of bilinear operators

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Acta Mathematica Sinica,English Series 2024年

作者： Fernando COBOS luz M.FERNáNDEZ-CABRERA Antón MARTíNEZ Departamento de Análisis Matemático y Matemática Aplicada Facultad de MatemáticasUniversidad Complutense de Madrid Sección Departamental del Departamento de Análisis Matemático y Matemática Aplicada Facultad de Estudios EstadísticosUniversidad Complutense de Madrid Departamento de Matemática Aplicada I Escuela de Ingeniería IndustrialUniversidad de Vigo

AbstractWe extend the （outer） measureγIassociated to an operator ideal I to a measureγJfor bounded bilinear operators.If I is surjective and closed,and J is the class of those bilinear operators such thatγJ（T）=0,we prove that J coincides with the composition bideal I o B.If I satisfies the ∑r-condition,we establish a simple necessary and sufficient condition for an interpolated operator by the real method to belong to J.Furthermore,if in addition I is symmetric,we prove a formula for the measureγJof an operator interpolated by the real method.In particular,results apply to weakly compact operators.

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A Tutorial on Federated Learning from Theory to Practice:Foundations,Software Frameworks,Exemplary Use Cases,and Selected Trends

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IEEE/CAA Journal of Automatica Sinica 2024年第4期11卷 824-850页

作者： M.Victoria luzón Nuria Rodríguez-Barroso Alberto Argente-Garrido Daniel Jiménez-López Jose M.Moyano Javier Del Ser Weiping Ding Francisco Herrera Department of Software Engineering Andalusian Research Institute in Data Science and Computational Intelligence(DaSCI)University of GranadaGranada 18071Spain Department of Computer Science and Artificial Intelligence Andalusian Research Institute in Data Science and Computational Intelligence(DaSCI)University of GranadaGranada 18071Spain Department of Communications Engineering University of the Basque Country(UPV/EHU)and also with TECNALIABasque Research&Technology Alliance(BRTA)Spain School of Information Science and Technology Nantong UniversityNantong 226019China

When data privacy is imposed as a necessity,Federated learning(FL)emerges as a relevant artificial intelligence field for developing machine learning(ML)models in a distributed and decentralized environment.FL allows ML models to be trained on local devices without any need for centralized data transfer,thereby reducing both the exposure of sensitive data and the possibility of data interception by malicious third parties.This paradigm has gained momentum in the last few years,spurred by the plethora of real-world applications that have leveraged its ability to improve the efficiency of distributed learning and to accommodate numerous participants with their data sources.By virtue of FL,models can be learned from all such distributed data sources while preserving data privacy.The aim of this paper is to provide a practical tutorial on FL,including a short methodology and a systematic analysis of existing software frameworks.Furthermore,our tutorial provides exemplary cases of study from three complementary perspectives:i)Foundations of FL,describing the main components of FL,from key elements to FL categories;ii)Implementation guidelines and exemplary cases of study,by systematically examining the functionalities provided by existing software frameworks for FL deployment,devising a methodology to design a FL scenario,and providing exemplary cases of study with source code for different ML approaches;and iii)Trends,shortly reviewing a non-exhaustive list of research directions that are under active investigation in the current FL landscape.The ultimate purpose of this work is to establish itself as a referential work for researchers,developers,and data scientists willing to explore the capabilities of FL in practical applications.

关键词： Data privacy distributed machine learning federated learning software frameworks

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New avenues for the treatment of immunotherapy-resistant pancreatic cancer

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1134-1153页

作者： Luis Guilherme de Oliveira Silva Fabian Fellipe Bueno Lemos Marcel Silva luz Samuel Luca Rocha Pinheiro Mariana dos Santos Calmon Gabriel Lima Correa Santos Gabriel Reis Rocha Fabrício Freire de Melo Instituto Multidisciplinar em Saúde Universidade Federal da BahiaVitória da Conquista 45029-094BahiaBrazil

Pancreatic cancer(PC)is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide.However,due to its complexity,it ranks 7th in the list of the most lethal cancers worldwide.The pathogenesis of PC involves several complex processes,including familial genetic factors associated with risk factors such as obesity,diabetes mellitus,chronic pancreatitis,and smoking.Mutations in genes such as KRAS,TP53,and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and,consequently,cancer.In this context,some therapies are used for PC,one of which is immunotherapy,which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency.It is therefore clear that the tumor microenvironment(TME)has a huge impact on the resistance process,since cellular and non-cellular elements create an immunosuppressive environment,characterized by a dense desmoplastic stroma with cancerassociated fibroblasts,pancreatic stellate cells,extracellular matrix,and immunosuppressive cells.Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells,resulting in a shortage of CD8+T cells and limited expression of activation markers such as interferon-gamma.In this way,finding new strategies that make it possible to manipulate resistance mechanisms is necessary.Thus,techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance,the use of genetic manipulation in specific regions,such as microRNAs,the modulation of extrinsic and intrinsic factors associated with T cells,and,above all,therapeutic models that combine these modulation techniques constitute the promising future of PC therapy.Thus,this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process,resulting in a more efficient therapy

关键词： Pancreatic cancer Immunotherapy Resistance Tumor microenvironment manipulation Combined immunotherapy

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Immune pathway through endometriosis to ovarian cancer

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World Journal of Clinical Oncology 2024年第4期15卷 496-522页

作者： Mariana Santos Calmon Fabian Fellipe Bueno Lemos Marcel Silva luz Samuel Luca Rocha Pinheiro Luis Guilherme de Oliveira Silva Gabriel Lima Correa Santos Gabriel Reis Rocha Fabrício Freire de Melo Instituto Multidisciplinar em Saúde Universidade Federal da BahiaVitória da Conquista 45029-094BahiaBrazil

Endometriosis is an estrogen-dependent inflammatory disease,defined by the presence of functional endometrial tissue outside of the uterine cavity.This disease is one of the main gynecological diseases,affecting around 10%-15%women and girls of reproductive age,being a common gynecologic disorder.Although endometriosis is a benign disease,it shares several characteristics with invasive cancer.Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer,representing an earlier stage of neoplastic processes.This is particularly true for women with clear cell carcinoma,low-grade serous carcinoma and endometrioid.However,the carcinogenic pathways between both pathologies remain poorly understood.Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers(EAOCs)via pathways associated with oxidative stress,inflammation,and hyperestrogenism.This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis,specifically focusing on the complex relationship between the immune response to endometriosis and cancer,including the molecular mechanisms and their ramifications.Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.

关键词： Ovarian neoplasms Endometriosis Endometriosis-associated ovarian cancers Immune response Immunotherapy

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Urea breath test for Helicobacter pylori infection in adult dyspeptic patients: A meta-analysis of diagnostic test accuracy

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World Journal of Gastroenterology 2024年第6期30卷 579-598页

作者： Fabian Fellipe Bueno Lemos Caroline Tianeze de Castro Marcel Silva luz Gabriel Reis Rocha Gabriel Lima Correa Santos Luís Guilherme de Oliveira Silva Mariana Santos Calmon Cláudio Lima Souza Ana Carla Zarpelon-Schutz Kádima Nayara Teixeira Dulciene Maria de Magalhães Queiroz Fabrício Freire de Melo Instituto Multidisciplinar em Saúde Universidade Federal da BahiaVitória da Conquista 45029-094BahiaBrazil Instituto de Saúde Coletiva Universidade Federal da BahiaSalvador 40110040BahiaBrazil Campus Toledo Universidade Federal do ParanáToledo 85919-899ParanáBrazil Laboratory of Research in Bacteriology UFMGBelo Horizonte 30130-100Minas GeraisBrazil

BACKGROUND Helicobacter pylori(H.pylori)infection has been well-established as a significant risk factor for several gastrointestinal disorders.The urea breath test(UBT)has emerged as a leading non-invasive method for detecting H.pylori.Despite numerous studies confirming its substantial accuracy,the reliability of UBT results is often compromised by inherent limitations.These findings underscore the need for a rigorous statistical synthesis to clarify and reconcile the diagnostic accuracy of the UBT for the diagnosis of H.pylori infection.AIM To determine and compare the diagnostic accuracy of 13C-UBT and 14C-UBT for H.pylori infection in adult patients with dyspepsia.METHODS We conducted an independent search of the PubMed/MEDLINE,EMBASE,and Cochrane Central databases until April 2022.Our search included diagnostic accuracy studies that evaluated at least one of the index tests(^(13)C-UBT or ^(14)C-UBT)against a reference standard.We used the QUADAS-2 tool to assess the methodo-logical quality of the studies.We utilized the bivariate random-effects model to calculate sensitivity,specificity,positive and negative test likelihood ratios(LR+and LR-),as well as the diagnostic odds ratio(DOR),and their 95%confidence intervals.We conducted subgroup analyses based on urea dosing,time after urea administration,and assessment technique.To investigate a possible threshold effect,we conducted Spearman correlation analysis,and we generated summary receiver operating characteristic(SROC)curves to assess heterogeneity.Finally,we visually inspected a funnel plot and used Egger’s test to evaluate publication bias.endorsing both as reliable diagnostic tools in clinical practice.CONCLUSION In summary,our study has demonstrated that ^(13)C-UBT has been found to outperform the ^(14)C-UBT,making it the preferred diagnostic approach.Additionally,our results emphasize the significance of carefully considering urea dosage,assessment timing,and measurement techniques for both tests to enhance diagnostic precision.Nevertheless,it is cru

关键词： Helicobacter pylori Urea breath test Diagnosis Diagnostic test accuracy Meta-analysis

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Camalote Grass (Paspalum fasciculatum Willd) as a Sustainable Raw Material for the Production of Lignocellulosic Ethanol

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Journal of Sustainable Bioenergy Systems 2024年第2期14卷 23-33页

作者： María luz May-Reyes Cintya Valerio-Cárdenas Gloria Ivette Bolio-López Manuel Mateo Hernández-Villegas Miguel Ángel Velázquez-Carmona Patricia De la Cruz-Burelo Research and Postgraduate Coordination Universidad Popular de la Chontalpa Crdenas Tabasco Mexico

The current trend of replacing a percentage of gasoline with ethanol has promoted the development of new processes for its production from lignocellulosic biomass. This work reports the production of ethanol from the Camalote grass (Paspalum fasciculatum Willd). The lignocellulosic biomass was subjected to acid hydrolysis at 125C and 15 psi with H2SO4 concentrations at 5%, 10%, and 20%, obtaining an average of reducing sugars (pentoses and hexoses) from the hydrolyzed juice with 12.3%, 10%, and 17% Brix, respectively. The sugars were fermented using yeast of the Saccharomyces cerevisiae at 30C for 48 hours. Finally, the ethanol was distilled at 78C, and the average yields were obtained through analysis of variance with a 95% confidence level. The values indicate that there is a significant difference (p > 0.05), the Tukey study shows that all the % v/v averages are different from each other. For H2SO4 concentration at 5% (10.33 ± 2), H2SO4 at 10% (9.33 ± 1.8), and H2SO4 at 20% (6.33 ± 2). The acidity analysis for the ethanol obtained from each treatment gave a value of 1.8 mg/L of acetic acid in all cases.

关键词： Lignocellulosic Ethanol Lignocellulosic Biomass Camalote Grass Acid Hydrolysis Energy Crops

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Celiac disease screening in patients with cryptogenic cirrhosis

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World Journal of Gastroenterology 2023年第2期29卷 410-412页

作者： Janaina luz Narciso-Schiavon Leonardo Lucca Schiavon Gastroenterology Division Internal Medicine DepartmentFederal University of Santa CatarinaFlorianopolis 88040-900SCBrazil

We write a letter to the editor commenting the article“Who to screen and how to screen for celiac disease”.We discuss the present literature on cirrhosis and celiac disease(CD)and recommend screening and treating CD... 详细信息

关键词： Celiac disease Liver cirrhosis Liver failure Aspartate aminotransferase Alanine aminotransferase

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Impact of payment source, referral site, and place of residence on outcomes after allogeneic transplantation in Mexico

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World Journal of Transplantation 2024年第2期14卷 76-87页

作者： Andrés Gómez-De León Yesica A López-Mora Valeria García-Zárate Ana Varela-Constantino Sergio U Villegas-De Leon Xitlaly J González-Leal Raúl del Toro-Mijares Anna C Rodríguez-Zúñiga Juan F Barrios-Ruiz Victor Mingura-Ledezma Perla R Colunga-Pedraza Olga G Cantú-Rodríguez César H Gutiérrez-Aguirre luz Tarín-Arzaga Elías E González-López David Gómez-Almaguer Hematology Service Universidad Autónoma de Nuevo LeónFacultad de Medicina y Hospital Universitario Dr.JoséEleuterio GonzálezMonterrey 64460Nuevo LeónMexico Hemato-logy Service Clínica Gómez AlmaguerMonterrey 64710Nuevo LeónMexico Hematology Service Instituto Tecnológico de Estudios Superiores de MonterreyTec SaludEscuela de Medicina Ignacio SantosMonterrey 64710Nuevo LeónMexico

BACKGROUND The impact of social determinants of health in allogeneic transplant recipients in low-and middle-income countries is poorly described.This observational study analyzes the impact of place of residence,referring institution,and transplant cost coverage(out-of-pocket vs government-funded vs private insurance)on outcomes after allogeneic hematopoietic stem cell transplantation(alloHSCT)in two of Mexico's largest public and private institutions.AIM To evaluate the impact of social determinants of health and their relationship with outcomes among allogeneic transplant recipients in Mexico.METHODS In this retrospective cohort study,we included adolescents and adults≥16 years who received a matched sibling or haploidentical transplant from 2015-2022.Participants were selected without regard to their diagnosis and were sourced from both a private clinic and a public University Hospital in Mexico.Three payment groups were compared:Out-of-pocket(OOP),private insurance,and a federal Universal healthcare program“Seguro Popular”.Outcomes were compared between referred and institution-diagnosed patients,and between residents of Nuevo Leon and out-of-state.Primary outcomes included overall survival(OS),categorized by residence,referral,and payment source.Secondary outcomes encompassed early mortality,event-free-survival,graft-versus-host-relapse-free survival,and non-relapse-mortality(NRM).Statistical analyses employed appropriate tests,Kaplan-Meier method,and Cox proportional hazard regression modeling.Statistical software included SPSS and R with tidycmprsk library.RESULTS Our primary outcome was overall survival.We included 287 patients,n=164 who lived out of state(57.1%),and n=129 referred from another institution(44.9%).The most frequent payment source was OOP(n=139,48.4%),followed by private insurance(n=75,26.1%)and universal coverage(n=73,25.4%).No differences in OS,event-free-survival,NRM,or graft-versus-host-relapse-free survival were observed for patients diagnosed locally vs in another institution,nor pat

关键词： Hematopoietic cell transplant Social determinants of health Geography Haploidentical Out-of-pocket Financial toxicity Survival Health services and outcomes Hematopoietic malignancy Aplastic anemia

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