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A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

Bone Research 2020年第2期8卷 157-168页

作者： Tobias Schwerd Freia Krause Stephen R.F.Twigg Dominik Aschenbrenner Yin-Huai Chen Uwe Borgmeyer Miryam Müller Santiago Manrique Neele Schumacher Steven A.Wall Jonathan Jung Timo Damm Claus-Christian Glüer Jürgen Scheller Stefan Rose-John e.yvonne jones Arian Laurence Andrew O.M.Wilkie Dirk Schmidt-Arras Holm H.Uhlig Translational Gastroenterology Unit John Radcliffe HospitalUniversity of OxfordOxfordUK Department of Pediatrics Dr von Hauner Children’s HospitalLMU MunichMunichGermany Christian-Albrechts-University Kiel Institute of BiochemistryKielGermany Clinical Genetics Group MRC Weatherall Institute of Molecular MedicineUniversity of OxfordJohn Radcliffe HospitalOxfordUK Center for Molecular Neurobiology Hamburg(ZMNH) University Medical Center Hamburg-EppendorfHamburgGermany Division of Structural Biology Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK Craniofacial Unit Department of Plastic and Reconstructive SurgeryOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK Section Biomedical Imaging Department of Radiology and NeuroradiologyUniversity Medical Center Schleswig-HolsteinKielGermany Institute of Biochemistry and Molecular Biology Ⅱ Medical FacultyHeinrich-Heine-UniversityDüsseldorfGermany Department of Paediatrics University of OxfordOxfordUK NIHR Oxford Biomedical Research Centre OxfordUK The Beatson Institute for Cancer Research GlasgowUK School of Medicine University of GlasgowGlasgowUK

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

关键词： IL11 cytokine facial

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Lipid nanoparticles deliver mRNA to the blood-brain barrier

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Nano Research 2024年第10期17卷 9126-9134页

作者： Yanina Kuzminich Avraham Shakked Randi Calkins Sebastian Rudden Camille jones Jessie Doan Bora Jang elisa Schrader echeverri Ryan Zenhausern Liming Lian David Loughrey Hannah e.Peck Rachelle Wiese Dorothy Koveal Philip J.Santangelo James e.Dahlman George C.Woodruff School of Mechanical engineering Georgia Institute of TechnologyAtlantaGA 30332USA Parker H.Petit Institute for Bioengineering and Biosciences Georgia Institute of TechnologyAtlantaGA 30332USA Wallace H.Coulter Department of Biomedical engineering Emory University School of Medicine and Georgia Institute of TechnologyAtlantaGA 30332USA

Lipid nanoparticles(LNPs)have delivered RNA to hepatocytes in patients after intravenous *** clinical data support efforts to design LNPs that transfect cells in the central nervous system(CNS).However,delivery to the CNS has been difficult,in large part because quantifying on-target delivery alongside common off-target cell types in adult mice remains *** we report methods to isolate different cell types from the CNS,and subsequently present mRNA delivery readouts using a liver-detargeted *** data suggest that LNPs without targeting ligands can transfect cerebral endothelial cells in mice after intravenous *** the difficulty of crossing the blood-brain barrier,they also underscore the value of quantifying delivery in the CNS with cell-type resolution instead of whole-tissue resolution.

关键词： lipid nanoparticle mRNA nanomedicine central nervous system blood-brain barrier

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LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis

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Genes & Diseases 2024年第3期11卷 417-426页

作者： Zijian Xu elizabeth R.Davies Liudi Yao Yilu Zhou Juanjuan Li Aiman Alzetani Ben G.Marshall David Hancock Tim Wallis Julian Downward Rob M.ewing Donna e.Davies Mark G.jones Yihua Wang Biological Sciences Faculty of Environmental and Life SciencesUniversity of SouthamptonSouthampton SO171BJUK clinical and experimental Sciences Faculty of MedicineUniversity of SouthamptonSouthampton SO166YDUK Institute for Life Sciences University of SouthamptonSouthampton SO171BJUK NIHR Southampton Biomedical Research Centre University Hospital SouthamptonSouthampton SO166YDUK University Hospital Southampton Southampton SO166YDUK Oncogene Biology The Francis Crick InstituteLondon NW11ATUK

The factors that determine fibrosis progression or normal tissue repair are largely *** previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(eMT)in human alveolar epithelial type Il(ATIl)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine ***,we report that liver kinase B1(LKB1)inactivation in ATIl cells inhibits autophagy and induces eMT as a *** IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATIl cells and MRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATIl cells and fibroblasts augmented myofibroblast ***,these data suggest that reduced autophagy caused by LKB1 inhibition can induce eMT in ATIl cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

关键词： CAB39L Crosstalk eMT LKB1 Pulmonary fibrosis

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Dysregulated bidirectional epithelial-mesenchymal crosstalk:A core determinant of lung fibrosis progression

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2024年第1期2卷 27-33页

作者： Liudi Yao Zijian Xu Donna e.Davies Mark G.jones Yihua Wang Biological Sciences Faculty of Environmental and Life SciencesUniversity of SouthamptonSouthampton SO171BJUK Clinical and experimental Sciences Faculty of MedicineUniversity of SouthamptonSouthampton SO166YDUK Institute for Life Sciences University of SouthamptonSouthampton SO171BJUK NIHR Southampton Biomedical Research Centre University Hospital SouthamptonSouthampton SO166YDUK

Progressive lung fibrosis is characterized by dysregulated extracellular matrix(eCM)***-ing of disease pathogenesis remains limited and has prevented the development of effective *** an abnormal wound-healing response is strongly implicated in lung fibrosis initiation,factors that determine why fi-brosis progresses rather than regular tissue repair occur are not fully *** human lung fibrosis,there is evidence of altered epithelial and mesenchymal populations as well as cells undergoing epithelial-mesenchymal transition(eMT),a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell-cell adhesion to gain migratory *** review will focus on the role of eMT and dysregulated epithelial-mesenchymal crosstalk in progressive lung fibrosis.

关键词： Lung fibrosis epithelial-mesenchymal transition(eMT) Crosstalk

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Manipulation of photosensory and circadian signaling restricts phenotypic plasticity in response to changing environmental conditions in Arabidopsis

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Molecular Plant 2024年第9期17卷 1458-1471页

作者： Martin William Battle Scott Fraser ewing Cathryn Dickson Joseph Obaje Kristen N.edgeworth Rebecca Bindbeutel Rea LAntoniou-Kourounioti Dmitri A.Nusinow Matthew Alan jones Plant Science Group School of Molecular BiosciencesUniversity of GlasgowGlasgow G128QQUK Danforth Plant Science Center St.LouisMO 63132USA Department of Biological and Biomedical Sciences Washington University in St.LouisSt.LouisMO 63130USA Present address:School of Biological and environmental Sciences Liverpool John Moores UniversityLiverpool L22QPUK

Plants exploit phenotypic plasticity to adapt their growth and development to prevailing environmental *** of light and temperature signals is aided by the circadian system,which provides a temporal *** plasticity provides a selective and competitive advantage in nature but is obstructive during large-scale,intensive agricultural practices since economically important traits(including vegetative growth and flowering time)can vary widely depending on local environmental *** prevents accurate prediction of harvesting times and produces a variable *** this study,we sought to restrict phenotypic plasticity and circadian regulation by manipulating signaling systems that govern plants'responses to environmental *** modeling of plant growth and develop-ment predicted reduced plant responses to changing environments when circadian and light signaling pathways were *** tested this prediction by utilizing a constitutively active allele of the plant photoreceptor phytochrome B,along with disruption of the circadian systemvia mutation of *** found that these manipulations produced plants that are less responsive to light and temper-ature cues and thus fail to anticipate *** engineered plants have uniform vegetative growth and flowering time,demonstrating how phenotypic plasticity can be limited while maintaining plant *** has significant implications for future agriculture in both open fields and controlled environments.

关键词： circadian developmental plasticity phenotypic plasticity external coincidence light temperature

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An alfalfa MYB-like transcriptional factor MsMYBH positively regulates alfalfa seedling drought resistance and undergoes MsWAV3-mediated degradation

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Journal of Integrative Plant Biology 2024年第4期66卷 683-699页

作者： Kun Shi Jia Liu Huan Liang Hongbin Dong Jinli Zhang Yuanhong Wei Le Zhou Shaopeng Wang Jiahao Zhu Mingshu Cao Chris S.jones Dongmei Ma Zan Wang College of Grassland Science and Technology China Agricultural UniversityBeijing 100193China Institute of Animal Sciences Chinese Academy of Agricultural SciencesBeijing 100193China AgResearch Grasslands Research Centre Palmerston North 4442New Zealand International Livestock Research Institute Nairobi 00100Kenya School of ecology and environment Ningxia UniversityYinchuan 750021China

Drought is a major threat to alfalfa(Medicago sativa L.)*** discovery of important alfalfa genes regulating drought response will facilitate breeding for drought-resistant alfalfa ***,we report a genome-wide association study of drought resistance in *** identified and functionally characterized an MYB-like transcription factor gene(MsMYBH),which increases the drought resistance in *** with the wild-types,the biomass and forage quality were enhanced in MsMYBH overexpressed *** RNA-seq,proteomics and chromatin immunoprecipitation analysis showed that MsMYBH can directly bind to the promoters of MsMCP1,MsMCP2,MsPRX1A and MsCARCAB to improve their *** outcomes of such interactions include better water balance,high photosynthetic efficiency and scavenge excess H_(2)O_(2)in response to ***,an e3 ubiquitin ligase(MsWAV3)was found to induce MsMYBH degradation under long-term drought,via the 26S proteasome ***,variable-number tandem repeats in MsMYBH promoter were characterized among a collection of germplasms,and the variation is associated with promoter ***,our findings shed light on the functions of MsMYBH and provide a pivotal gene that could be leveraged for breeding drought-resistant *** discovery also offers new insights into the mechanisms of drought resistance in alfalfa.

关键词： alfalfa drought resistance e3 ubiquitin ligase MsMYBH MsWAV3 MYB-like transcriptional factor

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There is more to the knee joint than just the quadriceps:A systematic review with meta-analysis and evidence gap map of hamstring strength,flexibility,and morphology in individuals with gradual-onset knee disorders

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Journal of Sport and Health Science 2024年第4期13卷 521-536页

作者： Helder S.Lopes Marina C.Waiteman Liliam B.Priore Neal R.Glaviano David M.Bazett-jones Ronaldo V.Briani Fabio M.Azevedo School of Science and Technology Physical Therapy DepartmentSao Paulo State University(UNESP)Presidente Prudente 19060-900Brazil Department of Kinesiology College of AgricultureHealth and Natural ResourcesUniversity of ConnecticutStorrsCT 06269USA School of exercise and Rehabilitation Sciences College of Health and Human ServicesUniversity of ToledoToledoOH 43606USA

Background:Impairments in hamstring strength,flexibility,and morphology have been associated with altered knee biomechanics,pain,and *** the presence of these impairments in individuals with gradual-onset knee disorders is important and may indicate targets for assessment and *** systematic review aimed to synthesize the literature to determine the presence of impairments in hamstring strength,flexibility,and morphology in individuals with gradual-onset knee ***:Five databases(MeDLINe,embase,CINAHL,SPORTDiscus,and Web of Science)were searched from inception to September *** studies comparing hamstring outcomes(e.g.,strength,flexibility,and/or morphology)between individuals with gradual-onset knee disorders and their unaffected limbs or pain-free controls were ***-analyses for each knee disorder were ***-level certainty was assessed using the Grading of Recommendations Assessment,Development,and evaluation,and evidence gap maps were ***:Seventy-nine studies across 4 different gradual-onset knee disorders(i.e.,knee osteoarthritis(OA),patellofemoral pain(PFP),chondromalacia patellae,and patellar tendinopathy)were *** with knee OA presented with reduced hamstring strength compared to pain-free controls during isometric(standard mean difference(SMD)=-0.76,95%confidence interval(95%CI):-1.32 to-0.21)and concentric contractions(SMD=-0.97,95%CI:-1.49 to-0.45).Individuals with PFP presented with reduced hamstring strength compared to painfree controls during isometric(SMD=-0.48,95%CI:-0.82 to-0.14),concentric(SMD=-1.07,95%CI:-2.08 to-0.06),and eccentric contractions(SMD=-0.59,95%CI:-0.97 to-0.21).No differences were observed in individuals with patellar *** with PFP presented with reduced hamstring flexibility when compared to pain-free controls(SMD=-0.76,95%CI:-1.15 to-0.36).evidence gap maps identified insufficient evidence for chondromalacia patel

关键词： Chondromalacia patellae Knee flexors Knee osteoarthritis Patellar tendinopathy Patellofemoral pain

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Dual ecological and socio-cultural fragmentation induced by hydropower dams: Case studies from the Greater Himalayan region of India

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Zoological Research(Diversity and Conservation) 2024年第2期1卷 117-120页

作者： Garima Gupta Rahul Kotiyal Isabel L.jones Biological and environmental Sciences University of StirlingScotland FK94LAUK Baramasa.in Narrating Himalaya 248001India

Climate change and biodiversity loss are pressing global challenges(Pörtner et al.,2021).However,as global energy demand continues to increase(IeA,2021),nations face significant challenges to decarbonization and reaching“net zero”due to trade-offs between the often-competing needs of renewable energy generation and biodiversity *** example,hydropower generates renewable energy(Gibson et al.,2017),yet there are well-documented and severe consequences of dam development for biodiversity(e.g.,Zarfl et al.,2019)and people(e.g.,Bisht,2009)due to reservoir creation and disruption of river *** such potentially damaging ecological and social trade-offs,hydropower currently contributes 70%of global renewable energy and there are at least 3700 large dams planned or under construction globally(Zhang&Gu,2023).

关键词： reservoir consequences globally

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Urban heat mitigation by green and blue infrastructure:Drivers,effectiveness,and future needs

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The Innovation 2024年第2期5卷 145-166页

作者： Prashant Kumar Sisay e.Debele Soheila Khalili Christos H.Halios Jeetendra Sahani Nasrin Aghamohammadi Maria de Fatima Andrade Maria Athanassiadou Kamaldeep Bhui Nerea Calvillo Shi-Jie Cao Frederic Coulon Jill L.edmondson David Fletcher edmilson Dias de Freitas Hai Guo Matthew C.Hort Madhusudan Katti Thomas Rodding Kjeldsen Steffen Lehmann Giuliano Maselli Locosselli Shelagh K.Malham Lidia Morawska Rajan Parajuli Christopher D.F.Rogers Runming Yao Fang Wang Jannis Wenk Laurence jones Global Centre for Clean Air Research(GCARe) School of SustainabilityCivil and Environmental EngineeringFaculty of Engineering and Physical SciencesUniversity of SurreyGuildford GU27XHUK Institute for Sustainability University of SurreyGuildford GU27XHSurreyUK School of Built environment University of ReadingWhiteknightsReading RG66BUUK School Design and the Built environment Curtin University Sustainability Policy InstituteKent StBentley 6102Western Australia Harry Butler Institute Murdoch UniversityMurdoch 6150Western Australia Atmospheric Sciences Department Institute of AstronomyGeophysics and Atmospheric SciencesUniversity of Sao PauloSao Paulo 05508-090Brazil Met Office FitzRoy RoadExeter EX13PBUK Department of Psychiatry and Nuffield Department of Primary Care Health Sciences Wadham CollegeUniversity of OxfordOxfordUK Centre for Interdisciplinary Methodologies University of WarwickWarwickUK School of Architecture Southeast University2 SipailouNanjing 210096China Cranfield University School of WaterEnvironment and EnergyCranfield MK430ALUK Plants PhotosynthesisSoil ClusterSchool of BiosciencesUniversity of SheffieldSheffield S102TNUK UK Centre for ecology&Hydrology Environment Centre WalesDeiniol RoadBangor LL572UWUK Air Quality Studies Department of Civil and Environmental EngineeringThe Hong Kong Polytechnic UniversityHong KongChina Department of Forestry and environmental Resources Faculty Excellence Program for Leadership in Public ScienceNorth Carolina State UniversityChancellorRaleighNC 27695USA Departments of Architecture&Civil engineering and Chemical EngineeringUniversity of BathBath BA27AYUK School of Architecture University of NevadaLas VegasNV 89154USA Department of Tropical ecosystems Functioning Center of Nuclear Energy in AgricultureUniversity of São PauloPiracicaba 13416-000Sao PauloBrazil School of Ocean Sciences Bangor UniversityMenai BridgeAnglesey LL595 ABUK International Laboratory for Air Quality and Health Science and Engine

The combination of urbanization and global warming leads to urban overheating and compounds the frequency and intensity of extreme heat events due to climate ***,the risk of urban overheating can be mitigated by urban green-blue-grey infrastructure(GBGI),such as parks,wetlands,and engineered greening,which have the potential to effectively reduce summer air *** many reviews,the evidence bases on quantified GBGI cooling benefits remains partial and the practical recommendations for implementation are *** systematic literature review synthesizes the evidence base for heat mitigation and related co-benefits,identifies knowledge gaps,and proposes recommendations for their implementation to maximize their *** screening 27,486 papers,202 were reviewed,based on 51 GBGI types categorized under 10 main *** GBGI(green walls,parks,street trees)have been well researched for their urban cooling ***,several other GBGI have received negligible(zoological garden,golf course,estuary)or minimal(private garden,allotment)*** most efficient air cooling was observed in botanical gardens(5.0±3.5℃),wetlands(4.9±3.2℃),green walls(4.1±4.2℃),street trees(3.8±3.1℃),and vegetated balconies(3.8±2.7℃).Under changing climate conditions(2070–2100)with consideration of RCP8.5,there is a shift in climate subtypes,either within the same climate zone(e.g.,Dfa to Dfb and Cfb to Cfa)or across other climate zones(e.g.,Dfb[continental warm-summer humid]to BSk[dry,cold semi-arid]and Cwa[temperate]to Am[tropical]).These shifts may result in lower efficiency for the current GBGI in the *** the importance of multiple services,it is crucial to balance their functionality,cooling performance,and other related co-benefits when planning for the future *** global GBGI heat mitigation inventory can assist policymakers and urban planners in prioritizing effective interventions to reduce the risk of urban overheating,fi

关键词： estuary walls extreme

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Hexavalent Chrome: Threshold Concept for Carcinogenicity

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Biomedical and environmental Sciences 1990年第1期3卷 20-34页

作者： ROSS e.jones Texas Instruments MS 8308 P.O. Box 655303 Dallas Texas 75265

Certain hexavalent chromium (Cr^(6+)) compounds when administered via inhalation at high doses have the potential to induce lung tumors in humans and experimental animals. Trivalent chromium (Cr^(3+)) is an essential human and animal nutrient at levels of 50 to 200 μg/day. Recent data have shown that the human body is able to reduce Cr^(6+) to Cr^(3+). This reduction occurs in bodily fluids such as gastric juice, epithelial lining fluid *** respiratory tract, blood, and other fluids. Secondary reduction occurs at the cellular level by the cytosol, mitochondria, and microsomes. Thus, at low levels of exposure hexavalent chromium ions are reduced befor the 6+ ions can interact with DNA unless the dose is sufficient to overwhelm the body's reduction capacity. This paper summarizes the available data concerning the reducing ability of the body and formulates the steps in the mechanism of cancer induction. These steps include: (1) only certain Cr^(6+) compounds have the capacity to interact with cellular components; (2) Cr^(6+) is reduced by body fluids and excess Cr^(6+) enters the cell (Cr^(3+) is poorly absorbed across membranes); (3) cellular organelles and the cytoplasm reduce Cr^(6+) to Cr^(3+); (4) excess Cr^(6+) can enter the nucleus; (5) Cr^(6+) reduction through 5+ and 4+ to 3+ has a potential to interact with the DNA molecule; and (6) if unrepaired, this DNA damage can lead to cancer induction. On the basis of current evidence Cr^(6+) has a threshold for carcinogenic potential in humans that is greater than the current TLV. 1990 Academic Press. Inc.

关键词： DNA Threshold Concept for Carcinogenicity Hexavalent Chrome

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