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Bone research 2023年第1期11卷 193-200页

作者： robert Brommage Jeff Liu david r.powell Department of Metabolism research Lexicon PharmaceuticalsThe WoodlandsTX77381USA

Mutations in SFrP4 cause Pyle’s bone disease with wide metaphyses and increased skeletal *** WNT signaling pathway plays important roles in determining skeletal architecture and SFrP4 is a secreted Frizzled decoy receptor that inhibits WNT *** cohorts of male and female Sfrp4 gene knockout mice,examined through 2 years of age,had a normal lifespan but showed cortical and trabecular bone *** human Erlenmeyer flask deformities,bone cross-sectional areas were elevated 2-fold in the distal femur and proximal tibia but only 30%in femur and tibia *** cortical bone thickness was observed in the vertebral body,midshaft femur and distal *** trabecular bone mass and numbers were observed in the vertebral body,distal femur metaphysis and proximal tibia *** femurs retained extensive trabecular bone through 2 years of *** bodies had increased compressive strength,but femur shafts had reduced bending ***,but not cortical,bone parameters in heterozygous Sfrp4mice were modestly *** resulted in similar declines in both cortical and trabecular bone mass in wild-type and Sfrp4 KO ***4 is critical for metaphyseal bone modeling involved in determining bone ***4 KO mice show similar skeletal architecture and bone fragility deficits observed in patients with Pyle’s disease with SFrP4 mutations.

关键词： SFrP4 skeletal elevated

High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

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Bone research 2014年第3期2卷 152-181页

作者： robert Brommage Jeff Liu Gwenn M Hansen Laura L Kirkpatrick david G Potter Arthur T Ss Brian Zambrowicz david r powell Peter Vogel Lexicon Pharmaceuticals The Woodlands TX USA

Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening （HTS） data for 3 762 distinct global gene knockout （KO） mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female mice at 14 weeks of age and by microCT analyses of bones from male mice at 16 weeks of age. Wild-type （WT） cagemates/littermates were examined for each gene KO. Lethality was observed in an additional 850 KO lines. Since primary HTS are susceptible to false positive findings, additional cohorts of mice from KO lines with intriguing HTS bone data were examined. Aging, ovariectomy, histomorphometry and bone strength studies were performed and possible non-skeletal phenotypes were explored. Together, these screens identified multiple genes affecting bone mass： 23 previously reported genes （Calcr, Cebpb, Crtap, Dcstamp, Dkkl, Duoxa2, Enppl, Fgf23, Kissl/Kisslr, Kl （Klotho）, Lrp5, Mstn, Neol, Npr2, Ostml, Postn, Sfrp4, S1c30a5, Sic39a13, Sost, Sumf1, Src, Wnt10b）, five novel genes extensively characterized （Cldn18, Fam20c, Lrrkl, Sgpll, Wnt16）, five novel genes with preliminary characterization （Agpat2, rassfS, Slc10a7, Stc26a7, Slc30a10） and three novel undisclosed genes coding for potential osteoporosis drug targets.

关键词： KO High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes BMD HTS DEXA gene

NOTUM inhibition increases endocortical bone formation and bone strength

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Bone research 2019年第1期7卷 54-65页

作者： robert Brommage Jeff Liu Peter Voge Faika Mseeh Andrea Y.Thompson david G.Potter Melanie K.Shadoan Gwenn M.Hansen Sabrina Jeter-Jones Jie Cui Dawn Bright Jennifer P.Bardenhagen Deon D.Doree Sofia Moverare-Skrtic Karin H.Nilsson Petra Henning Ulf H.Lerner Claes Ohlsson Arthur T.Sands James E.Tarver david r.powell Brian Zambrowicz Qingyun Liu Lexicon Pharmaceuticals The WoodlandsTXUSA Wntrix HoustonTXUSA PrA Health Sciences RaleighNCUSA University of Pennsylvania PhiladelphiaPAUSA regeneron Pharmaceuticals TarrytownNYUSA University of Texas HoustonTXUSA Centre for Bone and Arthritis research Institute of MedicineThe Sahlgrenska Academy at University of GothenburgGothenburgSweden Centre for Bone and Arthritis research University of GothenburgGothenburgSweden Biogen CambridgeMAUSA St.Jude Children’s research Hospital MemphisTNUSA MD Anderson Cancer Center HoustonTXUSA Bethyl Laboratories MontgomeryTXUSA Merck RahwayNJUSA Nurix San FranciscoCAUSA

The disability,mortality and costs caused by non-vertebral osteoporotic fractures are *** osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral *** bone is a major determinant of non-vertebral bone *** identify novel osteoporosis drug targets,we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable *** bone thickness was substantially elevated in Notum?/?*** is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not *** orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were *** increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone ***,inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.

关键词： disability osteoporosis fractures

Calcium channels caught in peripheral glia’s tug-of-war on axon regeneration in Drosophila

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Neural regeneration research 2025年第2期20卷 475-476页

作者： Jackson powell Tobias Steinschaden rose Horowitz Yuanquan Song raymond G.Perelman Center for Cellular and Molecular Therapeutics The Children’s Hospital of PhiladelphiaPhiladelphiaPAUSA The Neuroscience Graduate Group University of PennsylvaniaPhiladelphiaPAUSA Department of Pathology and Laboratory Medicine University of PennsylvaniaPhiladelphiaPAUSA Medical University of Vienna Center for Brain ResearchDepartment of NeuroimmunologyViennaAustria

Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural *** intrinsic and extrinsic factors dictate a neuron’s ability to regenerate,and the combination of these factors results in the great regenerative capacity of the peripheral nervous system(PNS)and the poor regenerative capacity of the central nervous system(CNS)following *** the core of a neuron’s function is its ability to relay electrochemical signals,and a neuron’s excitability is a key factor in its ability to *** works have focused on the changes in neuronal electrophysiological properties,firing patterns,and ion flux after injury,which differentially activate signaling pathways at the core of *** role of glia in neuron regeneration has long been studied.

关键词： degeneration firing system

role of hospitalization for inflammatory bowel disease in the postbiologic era

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World Journal of Clinical Cases 2021年第26期9卷 7632-7642页

作者： Celine r Soriano Charleston r powell Michael V Chiorean Vlad V Simianu Department of Surgery Virginia Mason Franciscan HealthSeattleWA 98101United States Department of Internal Medicine Madigan Army Medical CenterTacomaWA 98431United States Department of Gastroenterology Swedish Medical CenterSeattleWA 98109United States

Treatment for inflammatory bowel disease (IBD) often requires specialized *** much of IBD care has shifted to the outpatient setting, hospitalizationsremain a major site of healthcare utilization and a sizable proportion of patientswith inflammatory bowel disease require hospitalization or surgery during theirlifetime. In this review, we approach IBD care from the population-level with aspecific focus on hospitalization for IBD, including the shifts from inpatient tooutpatient care, the balance of emergency and elective hospitalizations, regionalizationof specialty IBD care, and contribution of surgery and endoscopy tohospitalized care.

关键词： Inflammatory bowel disease Hospitalization Elective Emergent surgery Endoscopy

Post-COVID recovery and renewal through whole-of-society resilience in cities

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Journal of Safety Science and resilience 2022年第3期3卷 222-228页

作者： Andrew G.McClelland roisin Jordan Szymon Parzniewski Duncan Shaw Nat O’Grady david powell Alliance Manchester Business School University of ManchesterManchester M139PLUK Alliance Manchester Business School Humanitarian&Conflict Response InstituteUniversity of ManchesterManchester M139PLUK Humanitarian&Conflict response Institute University of ManchesterManchester M139PLUK

This paper explores and extends understanding of the role and significance of whole-of-society resilience pro-grammes that support cities when dealing with complex crises,like the COVID-19 *** the complexity of whole-of-society resilience as different actors locally shape it,we ask the question:How can collab-oration between formal and informal resilience practices help to enhance resilience across the‘whole-of-society’?We answer this question by reviewing the importance of whole-of-society resilience and its complexity in a city’s governance of the COVID-19 *** argue that the necessity of renewing approaches to building lo-cal resilience capabilities across the whole-of-society requires synchronisation across and between formal and informal approaches-that is,“bottom-up”and governmental initiatives-to meet the diverse needs of ***,we detail two recent practice-orientated initiatives that have taken a renewal approach to building resilience through the involvement of whole-of-society in planning recovery from COVID-19 using in-ternational standard ISO/TS 22393;and a new initiative called the National Consortium for Societal resilience[UK+].Finally,we signpost a set of critical questions for whole-of-society resilience practice.

关键词： Whole-of-society resilience Crisis recovery renewal Cities,COVID-19

Advanced casting technologies for lightweight automotive applications

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China Foundry 2010年第4期7卷 463-469页

作者： Alan A.Luo Anil K.Sachdev Bob r.powell General Motors Global research and Development Center

This paper provides an overview of alloy and process developments in aluminum and magnesium castings for lightweight automotive applications. Wear-resistant aluminum alloys, creep-resistant and high strength/ductility magnesium alloys have been developed for automotive applications. On the process front, vacuumassisted die casting and high vacuum die casting technologies have been developed for high-integrity body and chassis applications. Thin-wall and hollow casting components are being produced by low-pressure die casting processes for structural applications. Overcasting technology is gaining traction and has enabled mixed material designs for automotive sub-systems such as engine cradles and instrument panel beams. Simulation tools developed to predict the interfacial interactions of the dissimilar components and the structural integrity of the overcast systems are being validated in the casting trials.

关键词： lightweight aluminum alloy magnesium alloy die casting

A review of stochastic algorithms with continuous value function approximation and some new approximate policy iteration algorithms for multidimensional continuous applications

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控制理论与应用（英文版） 2011年第3期9卷 336-352页

作者： Warren B.powell Department of Operations research and Financial Engineering Princeton University

We review the literature on approximate dynamic programming,with the goal of better understanding the theory behind practical algorithms for solving dynamic programs with continuous and vector-valued states and actions and complex information *** build on the literature that has addressed the well-known problem of multidimensional(and possibly continuous) states,and the extensive literature on model-free dynamic programming,which also assumes that the expectation in Bellman’s equation cannot be ***,we point out complications that arise when the actions/controls are vector-valued and possibly *** then describe some recent research by the authors on approximate policy iteration algorithms that offer convergence guarantees(with technical assumptions) for both parametric and nonparametric architectures for the value function.

关键词： Approximate dynamic programming reinforcement learning Optimal control Approximation algorithms

The law as it relates to subsidence as a consequence of mining activity in Britain

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中国有色金属学会会刊：英文版 2005年第S1期15卷 258-261页

作者： G. T. powell K. Leighfield University of Glamorgan Wales United KingdomUniversity of Glamorgan Wales United Kingdom

Subsidence as a consequence of mining activity has been an onerous problem associated with mineral extraction in Britain. Mining law as it relates to subsidence has developed over several centuries. This paper will outline the legal implications for mineral subsidence and compensation, considering both common law and statute. Particular reference is made to the extraction of coal, salt in brine, protection of public utilities, working facilities orders, ironstone and ancient mining rights.

关键词： subsidence compensation coal working facilities orders

Computational prediction and validation of specific Embr binding site on PknH

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Synthetic and Systems Biotechnology 2021年第4期6卷 429-436页

作者： Insung Na Huanqin Dai Hantian Li Anvita Gupta david Kreda powell Zhang Xiangyin Chen Lixin Zhang Gil Alterovitz Computational Health Informatics Program Boston Children’s Hospital/Harvard Medical SchoolBostonMA 02115USA Department of Medicine Brigham and Women’s Hospital/Harvard Medical SchoolBostonMA 02115USA State Key Laboratory of Mycology Institute of MicrobiologyBeijing100101 China Department of Computer Sciences Stanford UniversityStanford CA 94305USA Center for Biomedical Informatics Harvard Medical SchoolBostonMA 02115USA State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghaiChina Department of Biology The Johns Hopkins UniversityBaltimoreMD 21218USA Lexington High School BostonMA 02115USA

Tuberculosis drug resistance continues to threaten global health but the underline molecular mechanisms are not ***(EMB),one of the well-known first-line drugs in tuberculosis treatment is,unfortunately,not free from drug resistance *** studies have shown that some genetic mutations in Mycobacterium tuberculosis(Mtb)Embr,and EmbC/A/B genes cause EMB ***-PknH pair controls embC/A/B operon,which encodes EmbC/A/B genes,and EMB interacts with EmbA/B ***,the Embr binding site on PknH was *** conducted molecular simulation on the Embr-peptides binding structures and discovered phosphorylated PknH 273-280(N′-HEALS^(P)DPD-C′)makesβstrand with the Embr FHA domain,asβ-MorF(MorF;molecular recognition feature)does at its binding *** bond number analysis also supported the peptides’β-MorF forming activity at the Embr FHA ***,we discovered that previously known phosphorylation residues might have their chronological order according to the phosphorylation *** discovery validated that Mtb PknH 273-280(N′-HEALSDPD-C′)has reliable Embr binding *** approach is revolutionary in the computer-aided drug discovery field,because it is the first trial to discover the protein-protein interaction site,and find binding partner in nature from this site.

关键词： Disorder-to-order transition Protein intrinsic disorder Binding site prediction Drug resistance Molecular simulation