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The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair

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Bone Research 2024年第2期12卷 289-301页

作者： Heeseog Kang Amy L.Strong Yuxiao Sun Lei Guo Conan Juan Alec C.Bancroft Ji Hae Choi Chase A.Pagani Aysel A.Fernandes Michael woodard Juhoon Lee Sowmya Ramesh aaron w.james David Hudson Kevin N.Dalby Lin Xu Robert J.Tower benjamin levi Center for Organogenesis Regeneration and TraumaDepartment of SurgeryUniversity of Texas SouthwesternDallasTX 75390USA Section of Plastic Surgery Department of SurgeryUniversity of MichiganAnn ArborMI 48109USA Quantitative Biomedical Research Center Peter O’Donnell Jr.School of Public HealthUniversity of Texas SouthwesternDallasTX 75390USA Department of Orthopedics and Sports Medicine University of WashingtonSeattleWA 98195USA Division of Chemical Biology and Medicinal Chemistry College of PharmacyUniversity of Texas at AustinAustinTX 78712USA Department of Pathology Johns Hopkins UniversityBaltimoreMD 21218USA

while hypoxic signaling has been shown to play a role in many cellular processes,its role in metabolism-linked extracellular matrix(ECM)organization and downstream processes of cell fate after musculoskeletal injury remains to be ***(HO)is a debilitating condition where abnormal bone formation occurs within extra-skeletal *** andhypoxia-inducible factor 1α(HIF-1α)activation have been shown to promote ***,the underlying molecular mechanisms bywhich the HIF-1αpathway in mesenchymal progenitor cells(MPCs)contributes to pathologic bone formation remain to ***,we used a proven mouse injury-induced HO model to investigate the role of HIF-1αon aberrant cell ***-cell RNA sequencing(scRNA-seq)and spatial transcriptomics analyses of the HO site,we found that collagen ECM organizationis the most highly up-regulated biological process in *** mesenchymal cell-specific deletion of Hif1α(Hoxa11-CreER^(T2);Hif1a^(fl/fl))significantly mitigated HO in ***-seq analysis of these Hoxa11-CreER^(T2);Hif1a^(fl/fl)mice identified the PLOD2/LOXpathway for collagen cross-linking as downstream of the HIF-1αregulation of ***,our scRNA-seq data and mechanisticstudies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1α*** a translational aspect,a pan-LOX inhibitor significantly decreased HO.A newly screened compound revealed that the inhibition of PLOD2 activity in MPCssignificantly decreased osteogenic differentiation and glycolytic *** suggests that the HIF-1α/PLOD2/LOX axis linked tometabolism regulates HO-forming MPC *** results suggest that the HIF-1α/PLOD2/LOX pathway represents a promisingstrategy to mitigate HO formation.

关键词： metabolism skeletal aberrant

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Cerebral venous sinus thrombosis:changing trends in the incidence,age and gender(findings from the CMC Vellore CVT registry)

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Stroke & Vascular Neurology 2024年第3期9卷 252-257页

作者： Angel Miraclin T John Davis Prasad George Abraham Ninan Mahasampath Gowri Deepti Bal Atif Iqbal Ahmed Shaikh Rohit N benjamin Appaswamy Thirumal Prabhakar Ajith Sivadasan Vivek Mathew Sanjith aaron Department of Neurological Sciences Christian Medical CollegeVelloreTamil NaduIndia Department of Biostatistics Christian Medical CollegeVelloreTamil NaduIndia

Background Multiple cerebral venous sinus thrombosis(CVT)registries from various geographical regions indicate that female gender,the use of contraceptive pills,pregnancy and puerperium are important risk *** this study,we report the changes in the epidemiology of patients with CVT managed over the past 26 *** The CMC Vellore CVT registry is a prospectively maintained database at the Christian Medical College,Vellore since January *** software was used to analyse the data and assess the changes in the incidence,age and gender distribution over the previous 26 *** Among 1701 patients treated during the study period,908(53%)were women and 793(47%)were *** mean incidence of CVT was 49 per 100000 admissions before 2010,which increased to 96 per 100000 after *** gender had a higher odds of developing CVT OR–2.07(CI 1.68 to 2.55,pwith the decade before 2010(50%vs 20%).The mean age at presentation had increased from 24.5 to 33.2 years in the last *** There was a clear change in the gender pattern from being a condition with female preponderance,to one where equal or more men are being *** incidence of postpartum CVT cases could be the driving *** increase in the overall incidence of CVT cases was noted,probably due to a higher index of clinical suspicion and better diagnostic imaging modalities.

关键词： CVT driving maintained

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Tppp3~+synovial/tendon sheath progenitor cells contribute to heterotopic bone after trauma

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骨研究:英文版 2023年第3期11卷 548-559页

作者： Ji-Hye Yea Mario Gomez-Salazar Sharon Onggo Zhao Li Neelima Thottappillil Masnsen Cherief Stefano Negri Xin Xing Qizhi Qin Robert Joel Tower Chen-Ming Fan benjamin levi.aaron w.james Department of Pathology Johns Hopkins UniversityBaltimoreMD 21205USA Orthopaedic and Trauma Surgery Unit Department of SurgeryDentistryPaediatrics and Gynaecology of the University of VeronaVeronaItaly Center for Organogenesis and Trauma Department of SurgeryUniversity of Texas SouthwesternDallasTXUSA Carnegie Institution for Science BaltimoreMDUSA

Heterotopic ossification(HO)is a pathological process resulting in aberrant bone formation and often involves synovial lined *** this process,mesenchymal progenitor cells undergo endochondral ***,the specific cell phenotypes and mechanisms driving this process are not well understood,in part due to the high degree of heterogeneity of the progenitor cells ***,using a combination of lineage tracing and single-cell RNA sequencing(sc RNA-seq),we investigated the extent to which synovial/tendon sheath progenitor cells contribute to heterotopic bone *** this purpose,Tppp3(tubulin polymerization-promoting protein family member 3)-inducible reporter mice were used in combination with either Scx(Scleraxis)or Pdgfra(platelet derived growth factor receptor alpha)reporter *** tendon injury-and arthroplasty-induced mouse experimental HO models were *** RNA-seq of tendon-associated traumatic HO suggested that Tppp3 is an early progenitor cell marker for either tendon or osteochondral *** HO induction,Tppp3 reporter^(+)cells expanded in number and partially contributed to cartilage and bone formation in either tendon-or joint-associated *** double reporter animals,both Pdgfra^(+)Tppp3^(+)and Pdgfra^(+)Tppp3^(-) progenitor cells gave rise to HO-associated ***,analysis of human samples showed a substantial population of TPPP3^(-) expressing cells overlapping with osteogenic markers in areas of heterotopic ***,these data demonstrate that synovial/tendon sheath progenitor cells undergo aberrant osteochondral differentiation and contribute to HO after trauma.

关键词： progenitor tendon reporter

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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

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Understanding electricity prices beyond the merit order principle using explainable AI

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Energy and AI 2023年第3期13卷 149-159页

作者： Julius Trebbien Leonardo Rydin Gorjao aaron Praktiknjo benjamin Schafer Dirk witthaut Forschungszentrum Julich Institute for Energy and Climate Research–Systems Analysis and Technology Evaluation(IEK-STE)52428 JülichGermany University of Cologne Institute for Theoretical PhysicsZülpicher Str.7750937 CologneGermany Faculty of Science and Technology Norwegian University of Life Sciences1432 AsNorway Chair for Energy System Economics Institute for Future Energy Consumer Needs and Behavior(FCN)E.ON Energy Research CenterRWTH Aachen UniversityMathieustr.1052074 AachenGermany Institute for Automation and Applied Informatics Karlsruhe Institute of Technology76344 Eggenstein-LeopoldshafenGermany JARA-ENERGY 52074 AachenGermany

Electricity prices in liberalized markets are determined by the supply and demand for electric power,which are in turn driven by various external influences that vary strongly in *** perfect competition,the merit order principle describes that dispatchable power plants enter the market in the order of their marginal costs to meet the residual load,*** difference of load and renewable *** market models are based on this principle when attempting to predict electricity prices,yet the principle is fraught with assumptions and simplifications and thus is limited in accurately predicting *** this article,we present an explainable machine learning model for the electricity prices on the German day-ahead market which foregoes of the aforementioned assumptions of the merit order *** model is designed for an ex-post analysis of prices and builds on various external *** SHapley Additive exPlanation(SHAP)values we disentangle the role of the different features and quantify their importance from empiric data,and therein circumvent the limitations inherent to the merit order *** show that load,wind and solar generation are the central external features driving prices,as expected,wherein wind generation affects prices more than solar ***,fuel prices also highly affect prices,and do so in a nontrivial ***,large generation ramps are correlated with high prices due to the limited flexibility of nuclear and lignite ***,we offer a model that describes the influence of the main drivers of electricity prices in Germany,taking us a step beyond the limited merit order principle in explaining the drivers of electricity prices and their relation to each other.

关键词： Electricity prices Merit order principle Explainable artificial intelligence Machine learning Fuel prices Energy market

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The outcomes and safety of patients undergoing endoscopic retrograde cholangiopancreatography combining a single-use cholangioscope and a single-use duodenoscope:A multicenter retrospective international study

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Hepatobiliary & Pancreatic Diseases International 2024年第1期23卷 71-76页

作者： Alessandro Fugazza Matteo Colombo Michel Kahaleh V.Raman Muthusamy Bick benjamin wim Laleman Carmelo Barbera Carlo Fabbri Jose Nieto Abed Al-Lehibi Mohan Ramchandani Amy Tyberg Haroon Shahid Avik Sarkar Dean Ehrlich Stuart Shermand Cecilia Binda Marco Spadaccini Andrea Iannone Kareem Khalaf Nageshwar Reddy Andrea Anderloni Alessandro Repici Division of Gastroenterology and Digestive Endoscopy Humanitas Research Hospital-IRCCSVia Manzoni 5620089RozzanoMilanoItaly Gastroenterology Rutgers Robert Wood JohnsonNew BrunswickNew JerseyUSA Vatche and Tamar Manoukian Division of Digestive Diseases University of CaliforniaLos Angeles School of Medicine at UCLALos AngelesCaliforniaUSA Division of Digestive and Liver Disorders Indiana University School of MedicineIndianapolisINUSA Department of Gastroenterology and Hepatology University Hospitals LeuvenKU Leuven3000 LeuvenBelgium U.O.C.di Gastroenterologia ed Endoscopia Digestiva Ospedale Giuseppe MazziniASL TeramoItaly Gastroenterology and Digestive Endoscopy Unit Forlì-Cesena HospitalsAUSL RomagnaForlì-CesenaItaly Borland Groover Clinic JacksonvilleFloridaUSA Department of Gastroenterology and Hepatology King Fahad Medical CityRiyadhSaudi Arabia Asian Institute of Gastroenterology HyderabadIndia Section of Gastroenterology Department of Emergency and Organ TransplantationUniversity of BariBari 70124Italy Department of Biomedical Sciences Humanitas UniversityVia Rita Levi Montalcini 420090Pieve EmanueleMilanItaly

Background: Duodenoscope-related multidrug-resistant organism(MDRO) infections raise concerns. Disposable duodenoscopes have been recently introduced in the market and approved by regulatory agencies with the aim to reduce the risk of endoscopic retrograde cholangiopancreatography(ERCP) associated infections. The aim of this study was to evaluate the outcome of procedures performed with single-use duodenoscopes in patients with clinical indications to single-operator cholangiopancreatoscopy. Methods: This is a multicenter international, retrospective study combining all patients who underwent complex biliopancreatic interventions using the combination of a single-use duodenoscope and a single-use cholangioscope. The primary outcome was technical success defined as ERCP completion for the intended clinical indication. Secondary outcomes were procedural duration, rate of cross-over to reusable duodenoscope, operator-reported satisfaction score(1 to 10) on performance rating of the single-use duodenoscope, and adverse event(AE) rate. Results: A total of 66 patients(26, 39.4% female) were included in the study. ERCP was categorized according to ASGE ERCP grading system as 47(71.2%) grade 3 and 19(28.8%) grade 4. The technical success rate was 98.5%(65/66). Procedural duration was 64(interquartile range 15-189) min, cross-over rate to reusable duodenoscope was 1/66(1.5%). The satisfaction score of the single-use duodenoscope classified by the operators was 8.6 ± 1.3 points. Four patients(6.1%) experienced AEs not directly related to the single-use duodenoscope, namely 2 post-ERCP pancreatitis(PEP), 1 cholangitis and 1 ***: Single-use duodenoscope is effective, reliable and safe even in technically challenging procedures with a non-inferiority to reusable duodenoscope, making these devices a viable alternative to standard reusable equipment.

关键词： Single-operator cholangioscopy Single-use duodenoscope Endoscopic retrograde cholangiopancreatography Indeterminate biliary stricture Difficult biliary stones

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Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification

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Bone Research 2019年第4期7卷 371-387页

作者： Charles Hwang Simone Marini Amanda KHuber David MStepien Michael Sorkin Shawn Loder Chase APagani John Li Noelle DVisser Kaetlin Vasquez Mohamed AGarada Shuli Li Jiajia Xu Ching-Yun Hsu Paul BYu aaron wjames Yuji Mishina Shailesh Agarwal Jun Li benjamin levi Department of Surgery University of MichiganAnn ArborMI 48109USA Department of Computational Medicine and Bioinformatics University of MichiganAnn ArborMI 48109USA Department of Pathology Johns Hopkins UniversityBaltimoreMD 21218USA Division of Cardiovascular Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolBostonMA 02115USA Department of Biologic and Materials Sciences&Prosthodontics School of DentistryUniversity of MichiganAnn ArborMI 48109USA

Heterotopic ossification(HO)is a debilitating condition characterized by the pathologic formation of ectopic *** occurs commonly following orthopedic surgeries,burns,and neurologic *** surgical excision may provide palliation,the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native *** on these clinical observations,we set out to examine the role of vascular signaling in *** endothelial growth factor A(VEGFA)has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and *** findings,using a validated mouse model of HO,demonstrate that HO lesions are highly vascular,and that VEGFA is critical to ectopic bone formation,despite lacking a contribution of endothelial cells within the developing anlagen.

关键词： VEGFA injuries ossification

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Keratoconus in a patient with Alport syndrome: A case report

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world Journal of Clinical Cases 2019年第19期7卷 3012-3017页

作者： Majid Moshirfar David F Skanchy aaron T Gomez Yasmyne C Ronquillo benjamin Buckner Phillip C Hoopes John A.Moran Eye Center Department of Ophthalmology and Visual SciencesUniversity of Utah School of MedicineSalt Lake CityUT 84101United States Utah Lions Eye Bank Salt Lake CityUT 84101United States Hoopes Durrie Rivera Research Center Hoopes VisionDraperUT 84020United States Kellogg Eye Center Department of OphthalmologyUniversity of Michigan Medical SchoolAnn ArborMI 48103United States The University of Texas Rio Grande Valley School of Medicine EdinburgTX 78542United States

BACKGROUND Known ocular manifestations of Alport syndrome include features such as anterior lenticonus and fleck retinopathy. Reports of keratoconus in such patients are limited. we report tomographic findings consistent with keratoconus in a patient with Alport *** SUMMARY A 52-year-old female was referred to our ophthalmology clinic with decreased vision and increased tearing. She was diagnosed with stage Ⅲ Alport syndrome two years prior. Upon examination she was found to have average keratometries of 48D bilaterally with tomographic evidence of *** Although a rare presentation, concurrent Alport syndrome and keratoconus should be considered when reviewing the ocular health of Alport syndrome patients and appropriate management steps should be taken upon the diagnosis.

关键词： Alport syndrome,Keratoconus Type Ⅳ collagen COL4A genes Corneal ectasia Case report

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Spatial transcriptomic interrogation of the murine bone marrow signaling landscape

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Bone Research 2023年第4期11卷 847-859页

作者： Xue Xiao Conan Juan Tingsheng Drennon Cedric R.Uytingco Neda Vishlaghi Dimitri Sokolowskei Lin Xu benjamin levi Mimi C.Sammarco Robert J.Tower Quantitative Biomedical Research Center Peter O’Donnell Jr.School of Public HealthUniversity of Texas Southwestern Medical CenterDallasTXUSA Department of Surgery University of Texas Southwestern Medical CenterDallasTXUSA Department of Cell Biology&Applications 10x GenomicsPleasantonCAUSA Department of Surgery Tulane School of MedicineNew OrleansLAUSA

Self-renewal and differentiation of skeletal stem and progenitor cells(SSPCs)are tightly regulated processes,with SSPC dysregulation leading to progressive bone *** the application of single-cell RNA sequencing(scRNAseq)to the bone field has led to major advancements in our understanding of SSPC heterogeneity,stem cells are tightly regulated by their neighboring cells which comprise the bone marrow ***,unbiased interrogation of these cells at the transcriptional level within their native niche environment has been ***,we combined spatial transcriptomics and scRNAseq using a predictive modeling pipeline derived from multiple deconvolution packages in adult mouse femurs to provide an endogenous,in vivo context of SSPCs within the *** combined approach localized SSPC subtypes to specific regions of the bone and identified cellular components and signaling networks utilized within the ***,the use of spatial transcriptomics allowed us to identify spatially restricted activation of metabolic and major morphogenetic signaling gradients derived from the vasculature and bone surfaces that establish microdomains within the marrow ***,we demonstrate,for the first time,the feasibility of applying spatial transcriptomics to fully mineralized tissue and present a combined spatial and single-cell transcriptomic approach to define the cellular components of the stem cell niche,identify cell-cell communication,and ultimately gain a comprehensive understanding of local and global SSPC regulatory networks within calcified tissue.

关键词： landscape utilized Spatial

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Hypoxia-inducible factor 2α is a negative regulator of osteoblastogenesis and bone mass accrual

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Bone Research 2019年第1期7卷 91-104页

作者： Christophe Merceron Kavitha Ranganathan Elizabeth wang Zachary Tata Shreya Makkapati Mohd Parvez Khan Laura Mangiavini Angela Qing Yao Laura Castellini benjamin levi Amato J.Giaccia Ernestina Schipani Department of Orthopaedic Surgery School of MedicineUniversity of MichiganAnn ArborMIUSA Division of Plastic and Reconstructive Surgery Department of SurgeryUniversity of MichiganAnn ArborMIUSA Department of Radiation Oncology Stanford University Medical SchoolStanfordCAUSA

Osteoblasts,which are the bone-forming cells,operate in a hypoxic *** transcription factors hypoxia-inducible factor-1α(HIF1)and HIF2 are key mediators of the cellular response to *** are expressed in ***1 is known to be a positive regulator of bone ***,the role of HIF2 in the control osteoblast biology is still poorly *** this study,we used mouse genetics to demonstrate that HIF2 is an inhibitor of osteoblastogenesis and bone mass ***,we provided evidence that HIF2 impairs osteoblast differentiation at least in part,by upregulating the transcription factor *** findings constitute a paradigm shift,as activation of the hypoxia-signaling pathway has traditionally been associated with increased bone formation through *** HIF2 could thus represent a therapeutic approach for the treatment of the low bone mass observed in chronic diseases,osteoporosis,or aging.

关键词： is cells has

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