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In vivo radiometric analysis of glucose uptake and distribution in mouse bone

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Bone Research 2016年第1期4卷 31-38页

作者： Meredith l Zoch Diane S Abou thomas l clemens Daniel lJ Thorek Ryan C Riddle Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Baltimore USA Division of Nuclear Medicine an Molecular Imaging Department of Radiology and Radiological Science Johns Hopkins University School of Medicine Baltimore USA Baltimore Veterans Administration Medical Center Baltimore USA Department of Oncology Cancer Molecular and Functional Imaging Program Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore USA

Bone formation and remodeling occurs throughout life and requires the sustained activity of osteoblasts and osteoclasts, particularly during periods of rapid bone growth. Despite increasing evidence linking bone cell activity to global energy homeostasis, little is known about the relative energy requirements or substrate utilization of bone cells. In these studies, we measured the uptake and distribution of glucose in the skeleton in vivo using positron-emitting 18F-fluorodeoxyglucose （[lSF]-FDG） and non-invasive, high-resolution positron emission tomography/computed tomography （PE~/CT） imaging and ex vivo autoradiography. Assessment of [~SF]-FDG uptake demonstrated that relative to other tissues bone accumulated a significant fraction of the total dose of the glucose analog..Skeletal accumulation was greatest in young mice undergoing the rapid bone formation that characterizes early development. PET/CT imaging revealed that [lSF]-FDG uptake was greatest in the epiphyseal and metaphyseal regions of long bones, which accords with the increased osteoblast numbers and activity at this skeletal site. Insulin administration significantly increased skeletal accumulation of [lSF]-FDG, while uptake was reduced in mice lacking the insulin receptor specifically in osteoblasts or fed a high-fat diet. Our results indicated that the skeleton is a site of significant glucose uptake and that its consumption by bone cells is subject to regulation by insulin and disturbances in whole-body metabolism.

关键词： bone FDG

Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma

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Bone Research 2022年第3期10卷 615-626页

作者： Qizhi Qin Mario Gomez-Salazar Masnsen Cherief Chase A.Pagani Seungyong lee Charles Hwang Robert J.Tower Sharon Onggo Yuxiao Sun Abhinav Piplani Zhao li Sowmya Ramesh thomas l.clemens Benjamin levi Aaron W.James Department of Pathology Johns Hopkins UniversityBaltimoreMD 21205USA Center for Organogenesis and Trauma Department of SurgeryUniversity of TexasSouthwesternTXUSA Department of Plastic Surgery HarvardCambridgeMA 02138USA Department of Orthopaedics Johns Hopkins UniversityBaltimoreMD 21205USA Baltimore Veterans Administration Medical Center BaltimoreMD 21201USA

The functional interdependence of nerves and blood vessels is a well-established concept during tissue morphogenesis, yet the role of neurovascular coupling in proper and aberrant tissue repair is an emerging field of interest. Here, we sought to define the regulatory relationship of peripheral nerves on vasculature in a severe extremity trauma model in mice, which results in aberrant cell fate and heterotopic ossification(HO). First, a high spatial degree of neurovascular congruency was observed to exist within extremity injury associated heterotopic ossification. Vascular and perivascular cells demonstrate characteristic responses to injury,as assessed by single cell RNA sequencing. This vascular response to injury was blunted in neurectomized mice, including a decrease in endothelial proliferation and type H vessel formation, and a downregulation of key transcriptional networks associated with angiogenesis. Independent mechanisms to chemically or genetically inhibit axonal ingrowth led to similar deficits in HO site angiogenesis, a reduction in type H vessels, and heterotopic bone formation. Finally, a combination of single cell transcriptomic approaches within the dorsal root ganglia identified key neural-derived angiogenic paracrine factors that may mediate neuron-to-vascular signaling in HO. These data provide further understanding of nerve-to-vessel crosstalk in traumatized soft tissues, which may reflect a key determinant of mesenchymal progenitor cell fate after injury.

关键词： aberrant trauma nerves

The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

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Bone Research 2016年第2期4卷 85-90页

作者： Qian Zhang Michele Doucet Ryan E Tomlinson Xiaobin Han l Darryl Quarles Michael T Collins thomas l clemens Department of Orthopaedic Surgery Johns Hopkins University Baltimore MD USA Department of Medicine University of Tennessee Health Science Center Memphis TN USA Skeletal Clinical Studies Unit craniofacial and Skeletal Diseases Branch National Institutes of HealthBethesda MD USA Baltimore Veterans Administration Medical Center Baltimore MD USA

Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.

关键词： The hypoxia-inducible factor-1 activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia HIF

Adeno-associated virus as a delivery vector for gene therapy of human diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1808-1840页

作者： Jiang-Hui Wang Dominic J.Gessler Wei Zhan thomas l.Gallagher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia Department of Neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Neurosurgery University of MinnesotaMinneapolisMN55455USA Department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA li Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

Effects of the urban landscape on heatwave-mortality associations in Hong Kong: comparison of different heatwave definitions

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Frontiers of Environmental Science & Engineering 2024年第1期18卷 145-156页

作者： Jinglu Song Yi lu thomas Fischer Kejia Hu Department of Urban Planning and Design Xi’an Jiaotong-Liverpool UniversitySuzhou 215123China Department of Architecture and Civil Engineering City University of Hong KongKowloon TongHong Kong 999077China Environmental Assessment and Management Research Centre School of Environmental SciencesUniversity of LiverpoolLiverpool L35TRUK Research Unit for Environmental Sciences and Management Faculty of Natural and Agricultural SciencesNorth West UniversityPotchefstroom 31750South Africa Institute of Big Data in Health Science School of Public HealthZhejiang UniversityZijingang CampusHangzhou 310058China

Despite increased attention given to potential modifiers of temperature-mortality associations, evidence for variations between different urban landscape characteristics remains limited. It is in this context that in this paper effect modifications of multiple urban landscape characteristics are explored under different heatwave definitions for different age groups and gender in Hong Kong, China. Daily meteorological data and heatwave-related mortality counts from 2008 to 2017 were collected from the Hong Kong Census and Statistics Department, China. A case-only design was adopted, combined with logistic regression models to examine the modification effects of five urban landscape characteristics under six heatwave definitions. Stratified analyses were conducted to investigate age- and gender-specific effect modifications. It is found that individuals living in greener areas experienced lower levels of mortality during or immediately after heatwaves. In contrast, a higher building density and nighttime land surface temperature (lST) were associated with a higher heatwave-related mortality risk. Pronounced effect modifications of these urban landscape characteristics were observed under hotter and longer heatwaves, and in older adults (age ≥ 65 years) and males. The findings provide a scientific basis for policymakers and practitioners when considering measures for coping with hotter, longer, and more frequent heatwaves in the context of global climate change.

关键词： Urban landscape Heatwave Mortality Effect modification Intra-urban differences Health risk reduction

Population genomic analysis reveals key genetic variations and the driving force for embryonic callus induction capability in maize

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Journal of Integrative Agriculture 2024年第7期23卷 2178-2195页

作者： Peng liu langlang Ma Siyi Jian Yao He Guangsheng Yuan Fei Ge Zhong Chen Chaoying Zou Guangtang Pan thomas lübberstedt Yaou Shen State Key laboratory of Crop Gene Exploration and Utilization in Southwest China/Maize Research Institute Sichuan Agricultural UniversityChengdu 611130China Department of Agronomy Iowa State UniversityAmesIA 50011USA

Genetic transformation has been an effective technology for improving the agronomic traits of ***,it is highly reliant on the use of embryonic callus(EC)and shows a serious genotype *** this study,we performed genomic sequencing for 80 core maize germplasms and constructed a high-density genomic variation map using our newly developed pipeline(MQ2Gpipe).Based on the induction rate of EC(REC),these inbred lines were categorized into three *** low-REC germplasms displayed more abundant genetic diversity than the high-REC *** integrating a genome-wide selective signature screen and region-based association analysis,we revealed 95.23 Mb of selective regions and 43 REC-associated *** variants had phenotypic variance explained values ranging between 21.46 and 49.46%.In total,103 candidate genes were identified within the linkage disequilibrium regions of these REC-associated *** genes mainly participate in regulation of the cell cycle,regulation of cytokinesis,and other functions,among which MYB15 and EMB2745 were located within the previously reported QTl for EC *** leaf area-associated variants with large effects were closely linked to several REC-related loci,implying a potential synergistic selection of REC and leaf size during modern maize breeding.

关键词： maize genetic transformation embryonic callus selective signal association analysis

Utilization of RNA sequencing to investigate olfactory dysfunction in chronic rhinosinusitis without nasal polyps:A pilot study

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2024年第1期10卷 29-36页

作者： Jorge A.Gutierrez III Jeremy l.Barth Rodney J.Schlosser thomas S.Edwards Timothy l.Smith Zachary M.Soler Department of Otolaryngology-Head and Neck Surgery Medical University of South CarolinaCharlestonSouth CarolinaUSA Department of Regenerative Medicine&Cell Biology Medical University of South CarolinaCharlestonSouth CarolinaUSA Department of Otolaryngology-Head and Neck Surgery Oregon Health&Science UniversityPortlandOregonUSA

Objectives:Prior research on olfactory dysfunction in chronic rhinosinusitis(CRS)has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory *** purpose of this study was to evaluate gene expression in superior turbinate mucosal specimens,comparing normosmic and dysosmic CRS patients without polyps(CRSsNP).Methods:Tissue samples were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus *** subsequently underwent RNA sequencing and functional analysis to investigate biological pathways associated with differentially expressed genes between dysosmic(n=7)and normosmic(n=4)***:Differential gene expression analysis comparing dysosmic and normosmic CRSsNP patients showed upregulation of 563 genes and downregulation of 327 *** stringent criteria for multiple comparisons,one upregulated gene(Immediate Early Response 3[IER3])had an false discovery rate(FDR)correction adjustedP value considered statistically significant(Pld change 2.69).Reactome functional analysis revealed eight biological pathways significantly different between dysosmic and normosmic patients(Pluding Il-4 and Il-13 signaling,Il-10 signaling,and rhodopsin-like ***:RNA sequencing of the superior turbinates in patients with CRSsNP can provide valuable information regarding biological pathways and genes involved in olfactory *** study supports literature suggesting that Type 2 inflammation may play a role in olfactory dysfunction in at least some patients with *** study also prompts questions regarding the role of Il-10,rhodopsin-like receptors,andIER3 in the pathogenesis of olfactory dysfunction.

关键词： chronic rhinosinusitis without nasal polyps olfactory dysfunction RNA sequencing

Structural effects of reedbed grazing and its cessation on reed-nesting songbird densities

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Avian Research 2024年第2期15卷 238-248页

作者： thomas Pagnon Clemence Pechinot lea Sgro Jeremie Demay Remi Jullian Regis Gallais Brigitte Poulin Cyril Marmoex Theria Ecologie 6 avenue des martyrs05400VeynesFrance UMR 6249 Chrono-Environnement CNRSUniversite de Franche-Comte16 route de Gray25000BesanconFrance Conservatoire d’Espaces Naturels d’Occitanie 26 alle de Mycenes34000MontpellierFrance Office Français de la Biodiversite 12 cours Lumiere94300VincennesFrance Tour du Valat Research Institute for the Conservation of Mediterranean Wetlands Le Sambuc13200ArlesFrance

Reedbeds are crucial breeding habitats for vulnerable songbird *** of their protection status,these habitats may be threatened by organic matter accumulation,progressively leading to structural homoge-nization and habitat succession towards *** prevent excessive litter build-up with various in-terventions opening-up the reedbeds,such as grazing,which may be detrimental or suitable for some reed bird *** assessed the effects of extensive grazing by horses and its cessation in the medium and long terms on reedbed structure,and the consequences on reed-nesting songbird densities in Estagnol Nature Reserve,a pro-tected wetland near the French Mediterranean *** compared reedbed structural features between grazed,newly ungrazed and old-ungrazed *** nine years,we censused four songbird species in spring and collected water level data in the same survey *** reduced reedbed extent,rejuvenated the vegetation with more short green stems on a thinner litter,and produced higher structural heterogeneity and discontinuity compared to long-lasting non *** ungrazed plot showed intermediate *** surveyed songbird total densities were similar among plots while species numbers and densities *** reedbed was more attractive to Moustached Warblers(Acrocephalus melanopogon)and Great Reed Warblers(Acrocephalus arundi-naceus),likely due to the large edges and the high vegetation structural ***,Moustached Warblers were more negatively affected by higher water level in grazed reedbed,presumably because flooding prevents litter *** newly ungrazed reedbed was not preferred by any *** warbler species were found under low density in the old-ungrazed reedbed,where Reed Buntings(Emberiza schoeniclus)were exclu-sively *** availability related to thick litter layer may explain this *** Reed Warblers(Acrocephalus scirpaceus)were found everywhere in similar

关键词： Bird conservation Edge complexity Fragmentation Habitat management Horse grazing Phragmites australis Reed passerine

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

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Cellular & Molecular Immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong lamao Meichao Gu Xuanxuan Jin Ying liu Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao thomas S.Fulford Adam P.Uldrich Catherine C.l Wong Wensheng Wei Biomedical Pioneering Innovation Center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina Center for Precision Medicine Multi-Omics Research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity The University of MelbourneParkvilleVIC3010Australia Cancer Immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key laboratory for Complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate *** our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer *** found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T *** coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX ***,an enzyme called QPCTl was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer *** our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T ***,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell Cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite Immunotherapy