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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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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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PDGFRαreporter activity identifies periosteal progenitor cells critical for bone formation and fracture repair

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Bone Research 2022年第1期10卷 122-136页

作者： jiajia Xu Yiyun Wang Zhu Li Ye Tian Zhao Li Amy Lu Ching-Yun Hsu Stefano Negri Cammy Tang robert j.tower Carol Morris Aaron W.james Departments of Pathology Johns Hopkins UniversityBaltimoreMD 21205USA Departments of Orthopedics Johns Hopkins UniversityBaltimoreMD 21205USA Department of Oral and Maxillofacial Surgery School of StomatologyChina Medical UniversityShenyangLiaoningPR China

The outer coverings of the skeleton,which is also known as the periosteum,are arranged in concentric layers and act as a reservoir for tissue-specific bone *** cellular heterogeneity within this tissue depot is being increasingly ***,inducible PDGFRαreporter animals were found to mark a population of cells within the periosteum that act as a stem cell reservoir for periosteal appositional bone formation and fracture *** these processes,PDGFRαreporter^(+)progenitors give rise to Nestin+periosteal cells before becoming osteoblasts and *** diphtheria toxin-mediated ablation of PDGFRαreporter^(+)cells led to deficits in cortical bone formation during homeostasis and a diminutive hard callus during fracture *** ossicle transplantation,both mouse PDGFRαreporter^(+)periosteal cells and human Pdgfrα+periosteal progenitors expand,ossify,and recruit marrow to a greater extent than their counterpart periosteal cells,whereas PDGFRαreporter^(−)periosteal cells exhibit a predisposition to chondrogenesis in *** RNA sequencing identified enrichment of the secreted factors Fermt3 and Ptpn6 within PDGFRαreporter^(+)periosteal cells,which partly underlie the osteoblastogenic features of this cell population.

关键词： progenitor fracture reservoir

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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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Comparison of skeletal and soft tissue pericytes identifies CXCR4+ bone forming mural cells in human tissues

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Bone Research 2020年第3期8卷 286-299页

作者： jiajia Xu Dongqing Li Ching-Yun Hsu Ye Tian Leititia Zhang Yiyun Wang robert j.tower Leslie Chang Carolyn A.Meyers Yongxing Gao Kristen Broderick Carol Morris jody E.Hooper Sridhar Nimmagadda Bruno Peault Aaron W.james Departments of Pathology Johns Hopkins UniversityBaltimore 21205 MDUSA Department of Microbiology Wuhan University School of Basic Medical of ScienceWuhanHubeiP.R.China Department of Oral and Maxillofacial Surgery School of StomatologyChina Medical UniversityShenyangLiaoningP.R.China Departments of Orthopaedics Johns Hopkins UniversityBaltimore 21205 MDUSA Departments of Plastic Surgery Johns Hopkins UniversityBaltimore 21205 MDUSA Departments of Autopsy Service Johns Hopkins UniversityBaltimoreMD 21205USA Departments of Radiology and Radiological Science bonBaltimore 21205 MDUSA UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center Los AngelesCA 90095USA Center for Cardiovascular Science and MRC Center for Regenerative Medicine University of EdinburghEdinburghUK

Human osteogenic progenitors are not precisely defined,being primarily studied as heterogeneous multipotent cell populations and termed mesenchymal stem cells(MSCs).Notably,select human pericytes can develop into bone-forming ***,we sought to define the differentiation potential of CD146 f human pericytes from skeletal and soft tissue sources,with the underlying goal of defining cell surface markers that typify an osteoblastogenic ***146+CD31~CD45_pericytes were derived by fluorescence-activated cell sorting from human periosteum,adipose,or dermal *** CD146+CD31—CD45 cells retained canonical features of pericytes/*** pericytes demonstrated a striking tendency to undergo osteoblastogenesis in vitro and skeletogenesis in vivo,while soft tissue pericytes did not *** analysis revealed higher CXCR4 signaling among periosteal pericytes in comparison to their soft tissue counterparts,and CXCR4 chemical inhibition abrogated ectopic ossification by periosteal ***,enrichment of CXCR4+pericytes or stromal cells identified an osteoblastic/non-adipocytic precursor *** sum,human skeletal and soft tissue pericytes differ in their basal abilities to form *** exists in soft tissue pericytes,however,and CXCR4+pericytes represent an osteoblastogenic,non-adipocytic cell ***,enrichment for CXCR4-expressing stromal cells is a potential new tactic for skeletal tissue engineering.

关键词： CD146 CXCR4 pericyte

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Necrotic enteritis and antibiotic-free production of broiler chickens:Challenges in testing and using alternative products

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Animal Nutrition 2024年第1期16卷 288-298页

作者： robert j.Moore School of Science RMIT University

The global trend towards raising broiler chickens without the use of in-feed antibiotics(IFAs) means that there is an ongoing need to develop alternative treatments capable of delivering the benefits that IFAs previously provided. IFAs supported the productivity performance of chickens and played a key role in maintaining their health. Necrotic enteritis(NE) is an important disease of broilers that affects health,productivity, and welfare, and was previously well controlled by IFAs. However, with the reduction in IFA use, NE is resurgent in some countries. Vaccines and various feed additives, including pre-, pro-, and postbiotics, phytobiotics, fatty acids, and phage therapies have been introduced as alternative methods of NE control. While some of these feed additives have specific activity against the NE pathogen, Clostridium perfringens, most have the more general goal of reinforcing gut health. Extensive reviews of the effects of many of these feed additives on gut health have been published recently. Hence, rather than cover previously well reviewed areas of research this review focuses on the challenges and pitfalls in undertaking experimental assessment of alternative NE treatments and translating laboratory research to real world commercial production settings. The review is based on the author's particular experience,reading, thoughts, and analysis of the available information and inevitably presents a particular understanding that is likely to be at odds with others thinking on these issues. It is put forward to stimulate thinking and discussion on the issues covered.

关键词： Necrotic enteritis Clostridium perfringens Vaccines Feed additive Farm management

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Glycolysis and glucose metabolism as a target for bioenergetic and neuronal protection in glaucoma

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Neural Regeneration Research 2024年第8期19卷 1637-1638页

作者： Pete A.Williams robert j.Casson Department of Clinical Neuroscience Division of Eye and VisionSt.Erik Eye HospitalKarolinska InstitutetStockholmSweden Ophthalmic Research Laboratories Discipline of Ophthalmology and Visual SciencesUniversity of AdelaideAdelaideAustralia

Vision is arguably our most valued sense,yet approximately 340 million people globally suffer blindness or moderate visual impairment,highlighting the need to further develop and advance treatments for ophthalmic *** refers to a group of ocular disorders united by a clinically characteristic optic neuropathy with associated retinal ganglion cell loss.

关键词： metabolism glaucoma globally

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Does MgSO_(4) protect the preterm brain?Dissecting its role in the pathophysiology of hypoxic ischemic encephalopathy

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Neural Regeneration Research 2024年第9期19卷 1861-1862页

作者： robert Galinsky Laura Bennet Alistair j.Gunn The Ritchie Centre Hudson Institute of Medical ResearchMelbourneVICAustralia Department of Obstetrics and Gynaecology Monash UniversityMelbourneVICAustralia Department of Physiology The University of AucklandAucklandNew Zealand

Mitigating preterm encephalopathy continues to be one of the greatest challenges in perinatal *** encephalopathy is associated with high mortality,serious morbidity,and significant socio-economic impacts on the individuals,their families,and public health sectors and welfare systems that last a *** cost of disability associated with preterm brain injury continues to *** of this injury,and disability,would significantly reduce this socioeconomic burden.

关键词： encephalopathy mortality hypoxic

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Extracellular vesicles and angiotensin-converting enzyme 2 in COVID-19 disease

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BIOCELL 2024年第1期48卷 1-8页

作者： YU LIU robert j.KASPER NATALIE j.S.CHOI Department of Family and Community Medicine Northwestern University Feinberg School of MedicineChicagoIllinois

Extracellular vesicles(EVs)are membranous vesicular structures released from almost all eukaryotic cell types under different physiological or pathological *** evidence demonstrates that EVs can serve as mediators of intercellular communication between donor and recipient cells or microorganism-infected and noninfected *** disease 2019(COVID-19)disease is caused by infection of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)of host cells in the respiratory system and various extra-pulmonary tissue/organs,resulting in complications of multiple organ *** the cell surface receptor,angiotensin-converting enzyme 2(ACE2)mediates cellular entry of SARS-CoV-2 into the host cells in patients with *** studies have found that ACE2 can be released with EVs,which have been shown to interfere with the entry of the virus into host cells and thus may be involved in COVID-19 *** addition,ACE2,neprilysin(NEP),and thimet oligopeptidase(TOP)are the key enzymes that regulate angiotensin metabolism by converting angiotensin II or angiotensin I to angiotensin 1-7,the latter of which has protective effects in counterbalancing the harmful effects of angiotensin II in COVID-19 *** review summarizes the recent research progress regarding EV-associated ACE2,NEP,and TOP and the perspectives of their potential involvement in the pathophysiology of COVID-19 disease.

关键词： Extracellular vesicles COVID-19 Angiotensin converting enzyme 2 Thimet oligopeptidase

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Bioactive compounds in Hericium erinaceus and their biological properties:a review

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Food Science and Human Wellness 2024年第4期13卷 1825-1844页

作者： Yue Qiu Genglan Lin Weiming Liu Fuming Zhang robert j.Linhardt Xingli Wang Anqiang Zhang College of Food Science and Engineering Zhejiang University of TechnologyHangzhou 310014China Zhejiang Biosan Biotech Co. Ltd.Hangzhou 310052China Department of Chemical and Biological Engineering Center for Biotechnology and Interdisciplinary StudiesRensselaer Polytechnic InstituteTroyNY 12180USA Departments of Chemistry and Chemical Biology and Biomedical Engineering Biological ScienceCenter for Biotechnology and Interdisciplinary StudiesRensselaer Polytechnic InstituteTroyNY 12180USA

Hericium erinaceus is a nutritious edible and medicinal fungi,rich in a variety of functional active ingredients,with various physiological functions such as antioxidation,anticancer,and enhancing *** is also effective in protecting the digestive system and preventing neurodegenerative *** this review paper,we summarize the sources,structures and efficacies of the main active components in *** fruiting body,mycelium,and culture media,and update the latest research progress on their biological activities and the related molecular *** on this information,we provide detailed challenges in current research,industrialization and information on the active ingredients of *** for future studies and new applications of *** are proposed.

关键词： Hericium erinaceus Bioactive compounds Biological activities Antioxidation Neuroprotection Immunoregulation

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