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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKm supports antitumor immunity

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Cellular & molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda mackenzie m.Lieberman Caitlin m.James Shivana m.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew m.Intlekofer Richard m.Higashi Teresa W.m.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber Cancer Institute BostonMA 02215USA Present address:massachusetts Institute of Technology BostonMA 02139USA Present address:melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the m1 isoform of pyruvate kinase in favor of PKm2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKm alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKm2

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In search of a pan-coronavirus vaccine:next-generation vaccine design and immune mechanisms

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Cellular & molecular Immunology 2024年第2期21卷 103-118页

作者： S.Cankat m.U.Demael L.Swadling Division of Infection and Immunity Institute of Immunity and TransplantationUniversity College LondonPears BuildingLondon NW32PPUK

members of the coronaviridae family are endemic to human populations and have caused several epidemics and pandemics in recent history.In this review,we will discuss the feasibility of and progress toward the ultimate goal of creating a pan-coronavirus vaccine that can protect against infection and disease by all members of the coronavirus family.We will detail the unmet clinical need associated with the continued transmission of SARS-CoV-2,mERS-CoV and the four seasonal coronaviruses(HCoV-OC43,NL63,HKU1 and 229E)in humans and the potential for future zoonotic coronaviruses.We will highlight how first-generation SARS-CoV-2 vaccines and natural history studies have greatly increased our understanding of effective antiviral immunity to coronaviruses and have informed next-generation vaccine design.We will then consider the ideal properties of a pan-coronavirus vaccine and propose a blueprint for the type of immunity that may offer cross-protection.Finally,we will describe a subset of the diverse technologies and novel approaches being pursued with the goal of developing broadly or universally protective vaccines for coronaviruses.

关键词： Vaccine Coronavirus Cross-reactive immunity Cross-protection Universal

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Role of Air Staging in a Batch-Type Fixed Bed Biomass Combustor under Constant Primary Air

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Journal of Thermal Science 2024年第1期33卷 284-299页

作者： Awais JUNEJO Yasir m.AL-ABDELI Jacobo PORTEIRO School of Engineering Edith Cowan UniversityJoondalupWA 6027Australia CINTECX Universidade de Vigo Grupo de Tecnoloxia Enerxetica(GTE)36310 VigoEspana

Staged combustion of biomass is the most suitable thermo-chemical conversion for achieving lower gaseous emissions and higher fuel conversion rates.In a staged fixed bed combustion of biomass,combustion air is supplied in two stages.In the first stage,primary air is provided below the fuel,whereas in the later stage,secondary air is supplied in the freeboard region.The available literature on the effects of air staging(secondary air location) at a constant primary air flow rate on combustion characteristics in a batch-type fixed bed combustor is limited and hence warrants further investigations.This study resolves the effect of air staging,by varying the location of secondary air in the freeboard at five secondary to total air ratios in a batch-type fixed bed combustor.Results are reported for the effects of these controlled parameters on fuel conversion rate,overall gaseous emissions(CO_(2),CO and NO_x) and temperature distributions.The fuel used throughout was densified hardwood pellets.Results show that a primary freeboard length(distance between fuel bed top and secondary air injection) of200 mm has higher fuel conversion rates and temperatures as well as lower CO emissions,at a secondary to total air ratio of 0.75 as compared to primary freeboard length of 300 mm.However,NO_x emissions were found to be lower for a primary freeboard length of 300 mm as compared to 200 mm.An increase in secondary to total air ratio from 0.33 to 0.75 resulted in higher freeboard temperatures and lower CO as well as NO_x emissions.The outcomes of this study will be helpful in the effective design of commercial scale biomass combustors for more efficient and environmentally friendly combustion.

关键词： fixed bed combustor biomass combustion air staging freeboard temperature burning rate gaseous emissions

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millimetric devices for nerve stimulation:a promising path towards miniaturization

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Neural Regeneration Research 2024年第8期19卷 1702-1706页

作者： Ryan m.Dorrian Anna V.Leonard Antonio Lauto Spinal Cord Injury Research Group School of BiomedicineThe University of AdelaideAdelaideSAAustralia School of Science Western Sydney UniversityPenrithNSWAustralia

Nerve stimulation is a rapidly developing field,demonstrating positive outcomes across several conditions.Despite potential benefits,current nerve stimulation devices are large,complicated,and are powered via implanted pulse generators.These facto rs necessitate invasive surgical implantation and limit potential applications.Reducing nerve stimulation devices to millimetric sizes would make these interventions less invasive and facilitate broader therapeutic applications.However,device miniaturization presents a serious engineering challenge.This review presents significant advancements from several groups that have overcome this challenge and developed millimetricsized nerve stimulation devices.These are based on antennas,mini-coils,magneto-electric and optoelectronic materials,or receive ultrasound power.We highlight key design elements,findings from pilot studies,and present several considerations for future applications of these devices.

关键词： biomedical engineering deep brain stimulation electrical engineering electrical stimulation neuromodulation peripheral nerve stimulation

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Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance

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Genes & Diseases 2024年第1期11卷 189-204页

作者： Ebrahim H.maleki Ahmad Reza Bahrami maryam m.matin Department of Biology Faculty of ScienceFerdowsi University of Mashhad*** MashhadIran Jagiellonian Centre for Experimental Therapeutics(JCET) Jagiellonian University31-007 KrakowPoland Doctoral School of Exact and Natural Sciences Jagiellonian University30-348 KrakowPoland Industrial Biotechnology Research Group Institute of BiotechnologyFerdowsi University of Mashhad*** MashhadIran Novel Diagnostics and Therapeutics Research Group Institute of BiotechnologyFerdowsi University of Mashhad***MashhadIran Stem Cell and Regenerative medicine Research Group Iranian Academic Center for EducationCulture and Research(ACECR)Khorasan Razavi Branch917751376 MashhadIran

Intra-tumor heterogeneity is now arguably one of the most-studied topics in tumor biology,as it represents a major obstacle to effective cancer treatment.Since tumor cells are highly diverse at genetic,epigenetic,and phenotypic levels,intra-tumor heterogeneity can be assumed as an important contributing factor to the nullification of chemotherapeutic effects,and recurrence of the tumor.Based on the role of heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics and behavior during cancer progression and treatment;herein,we aim to establish a comprehensive definition for adaptation of neoplastic cells against therapy.We discuss two parallel and yet distinct subpopulations of tumor cells that play pivotal roles in reducing the effects of chemotherapy:"resistant"and"tolerant"popula-tions.Furthermore,this review also highlights the impact of the quiescent phase of the cell cycle as a survival mechanism for cancer cells.Beyond understanding the mechanisms under-lying the quiescence,it provides an insightful perspective on cancer stem cells(CsCs)and their dual and intertwined functions based on their cell cycle state in response to treatment.more-over,CSCs,epithelial-mesenchymal transformed cells,circulating tumor cells(CTCs),and disseminated tumor cells(DTCs),which are mostly in a quiescent state of the cell cycle are proved to have multiple biological links and can be implicated in our viewpoint of cell cycle heterogeneity in tumors.Overall,increasing our knowledge of cell cycle heterogeneity is a key to identifying new therapeutic solutions,and this emerging concept may provide us with new opportunities to prevent the dreadful cancer recurrence.

关键词： Cancer stem cells(CSCs) Carcinoma Cell cycle heterogeneity Quiescence Therapy resistance Therapy tolerance Tumor dormancy

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Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity

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Bone Research 2024年第1期12卷 180-198页

作者： morten S.Hansen Kaja madsen maria Price Kent Søe Yasunori Omata mario m.Zaiss Caroline m.Gorvin morten Frost Alexander Rauch molecular Endocrinology Laboratory(KmEB) Department of EndocrinologyOdense University HospitalDK-5000 Odense CDenmark Department of Clinical Research Faculty of Health SciencesUniversity of Southern DenmarkDK-5000 Odense CDenmark Clinical Cell Biology Pathology Research UnitDepartment of Clinical ResearchUniversity of Southern DenmarkDK-5000 Odense CDenmark Institute of metabolism and Systems Research(ImSR)and Centre for Diabetes Endocrinology and Metabolism(CEDAM)University of BirminghamBirmingham B152TTUK Centre for membrane Proteins and Receptors(COmPARE) Universities of Birmingham and NottinghamBirmingham B152TTUK Department of molecular medicine University of Southern DenmarkDK-5000 Odense CDenmark Department of Orthopedic Surgery Faculty of MedicineThe University of TokyoTokyo 113-8655Japan Department of Internal medicine 3 Rheumatology and ImmunologyFriedrich-Alexander-University Erlangen-Nürnberg(FAU)and Universitätsklinikum ErlangenD-91054 ErlangenGermany Deutsches Zentrum Immuntherapie(DZI) Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum ErlangenD-91054 ErlangenGermany Steno Diabetes Center Odense Odense University HospitalDK-5000 Odense CDenmark

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutics are needed,understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets.This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation.Osteoclasts were differentiated from CD14+monocytes from eight female donors.RNA sequencing during differentiation revealed 8980 differentially expressed genes grouped into eight temporal patterns conserved across donors.These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs.Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks.The donor-specific expression patterns revealed genes at the monocyte stage,such as filamin B(FLNB)and oxidized low-density lipoprotein receptor 1(OLR1,encoding LOX-1),that are predictive of the resorptive activity of mature osteoclasts.The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation,and these receptors are associated with bone mineral density SNPs,suggesting that they play a pivotal role in osteoclast differentiation and activity.The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1(C5AR1),somatostatin receptor 2(SSTR2),and free fatty acid receptor 4(FFAR4/GPR120).Activating C5AR1 enhanced osteoclast formation,while activating SSTR2 decreased the resorptive activity of mature osteoclasts,and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts.In conclusion,we report the occurrence of transcriptional

关键词： osteoclast programming identif

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Leveraging User-Generated Comments and Fused BiLSTm models to Detect and Predict Issues with mobile Apps

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Computers, materials & Continua 2024年第4期79卷 735-759页

作者： Wael m.S.Yafooz Abdullah Alsaeedi Department of Computer Science College of Computer Science and EngineeringTaibah UniversityMedina42353Saudi Arabia

In the last decade, technical advancements and faster Internet speeds have also led to an increasing number ofmobile devices and users. Thus, all contributors to society, whether young or old members, can use these mobileapps. The use of these apps eases our daily lives, and all customers who need any type of service can accessit easily, comfortably, and efficiently through mobile apps. Particularly, Saudi Arabia greatly depends on digitalservices to assist people and visitors. Such mobile devices are used in organizing daily work schedules and services,particularly during two large occasions, Umrah and Hajj. However, pilgrims encounter mobile app issues such asslowness, conflict, unreliability, or user-unfriendliness. Pilgrims comment on these issues on mobile app platformsthrough reviews of their experiences with these digital services. Scholars have made several attempts to solve suchmobile issues by reporting bugs or non-functional requirements by utilizing user comments.However, solving suchissues is a great challenge, and the issues still exist. Therefore, this study aims to propose a hybrid deep learningmodel to classify and predict mobile app software issues encountered by millions of pilgrims during the Hajj andUmrah periods from the user perspective. Firstly, a dataset was constructed using user-generated comments fromrelevant mobile apps using natural language processing methods, including information extraction, the annotationprocess, and pre-processing steps, considering a multi-class classification problem. Then, several experimentswere conducted using common machine learning classifiers, Artificial Neural Networks (ANN), Long Short-Termmemory (LSTm), and Convolutional Neural Network Long Short-Term memory (CNN-LSTm) architectures, toexamine the performance of the proposed model. Results show 96% in F1-score and accuracy, and the proposedmodel outperformed the mentioned models.

关键词： mobile apps issues play store user comments deep learning LSTm bidirectional LSTm

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Bringing gut microbiota into the spotlight of clinical research and medical practice

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World Journal of Clinical Cases 2024年第14期12卷 2293-2300页

作者： Efstathia Davoutis Zoi Gkiafi Panagis m Lykoudis School of medicine National and Kapodistrian University of AthensAthens 11527Greece Division of Surgery and Interventional Science University College LondonLondon WC1E 6BTUnited Kingdom

Despite the increasing scientific interest and expanding role of gut microbiota(Gm)in human health,it is rarely reported in case reports and deployed in cli-nical practice.Proteins and metabolites produced by microbiota contribute to im-mune system development,energy homeostasis and digestion.Exo-and endoge-nous factors can alter its composition.Disturbance of microbiota,also known as dysbiosis,is associated with various pathological conditions.Specific bacterial taxa and related metabolites are involved in disease pathogenesis and therefore can serve as a diagnostic tool.Gm could also be a useful prognostic factor by predicting future disease onset and preventing hospital-associated infections.Ad-ditionally,it can influence response to treatments,including those for cancers,by altering drug bioavailability.A thorough understanding of its function has per-mitted significant development in therapeutics,such as probiotics and fecal trans-plantation.Hence,Gm should be considered as a ground-breaking biological parameter,and it is advisable to be investigated and reported in literature in a more consistent and systematic way.

关键词： Gut microbiota Biomarker Fecal microbiota transplantation Dysbiosis Prebiotics

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On self-affine tiles that are homeomorphic to a ball

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Science China mathematics 2024年第1期67卷 45-76页

作者： Jorg m.Thuswaldner Shu-Qin Zhang mathematics and Statistics University of LeobenLeoben 8700Austria School of mathematics and Statistics Zhengzhou UniversityZhengzhou 450001China

Let m be a 3×3 integer matrix which is expanding in the sense that each of its eigenvalues is greater than 1 in modulus and let D?Z^(3)be a digit set containing|det m|elements.Then the unique nonempty compact set T=T(m,D)defined by the set equation mT=T+D is called an integral self-affine tile if its interior is nonempty.If D is of the form D={0,v,...,(|det m|-1)v},we say that T has a collinear digit set.The present paper is devoted to the topology of integral self-affine tiles with collinear digit sets.In particular,we prove that a large class of these tiles is homeomorphic to a closed 3-dimensional ball.moreover,we show that in this case,T carries a natural CW complex structure that is defined in terms of the intersections of T with its neighbors in the lattice tiling{T+z:z∈Z^(3)}induced by T.This CW complex structure is isomorphic to the CW complex defined by the truncated octahedron.

关键词： self-afine sets tiles and tilings low-dimensional topology truncated octahedron

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Prevalence and intensity of urinary schistosomiasis and soil-transmitted helminths among women of reproductive age in mwaluphamba,Kwale

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Asian Pacific Journal of Tropical medicine 2024年第2期17卷 71-83页

作者： Samuel m.Ngui Joseph m.mwangangi Joachim Richter Josephine W.Ngunjiri Department of Biological Sciences University of EmbuKenya medical Entomology Kenya Medical Research Institute(KEMRI)Center for Geographic Medicine Research Coast KilifiKenya Institute of International Health Global Health CenterCharitéUniversity MedicineBerlinCorporate Member of Free University and Humboldt University and Berlin Institute of HealthBerlinGermany Swiss Tropical and Public Health Institute BaselSwitzerland Tropical and Infectious Diseases Department of Biological sciencesUniversity of EmbuKenya

Objective:To assess the epidemiology of urinary schistosomiasis and soil-transmitted helminthiasis among women of reproductive age in mwaluphamba,Kwale County,Kenya.methods:A community-based cross-sectional study design was employed to randomly sample 422 women of reproductive age(15-m four villages in mwaluphamba location.Stool specimens were collected and examined using the Kato-Katz method,while filtration technique was used to analyze urine specimens.Participants’sociodemographic details were obtained using a standardized questionnaire.Results:Urinary schistosomiasis prevalence was at 4.7%(20/422,95%CI 2.8%-6.9%)while the prevalence of soil-transmitted helminthiasis infection was 4.5%(19/422,95%CI 2.6%-6.7%).The infection intensities of urinary schistosomiasis among the study participants ranged from 1 to 120 eggs/10 mL of urine with median egg count of 18.45 eggs/10 mL.The patients were diagnosed with light infection,of 56.16 egg/gram and 48.48 egg/gram for Trichuris trichiura and hookworms,respectively.Women without latrines had 15.7 times higher risk of having urinary schistosomiasis compared to those with a latrine.Similarly,use of surface water(aOR=1.0,95%CI 0.2-1.4,P=0.010)and crossing the river to go to a place(aOR=1.1,95%CI 0.3-1.6,P=0.009)were statistically significant risk factors for getting urinary schistosomiasis.In bivariable regression analysis,defecating around the water source(OR=4.3,95%CI 1.5-12.9)had a statistically significant association with the prevalence of soil-transmitted helminthiasis(P=0.008).Conclusions:This study has given an insight on the prevalence and intensity of urinary schistosomiasis and soil-transmitted helminthiasis in mwaluphamba location that form a basis for strengthening the control and elimination programmes for these neglected tropical diseases.

关键词： Urinary schistosomiasis Prevalence Soiltransmitted helminths mwaluphamba

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