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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

Bone Research 2018年第2期6卷 167-176页

作者： Babita Madan mitchell J.McDonald Gabrielle e.Foxa Cassandra R.Diegel Bart O.Williams David M.Virshup Program in Cancer and Stem Cell Biology Duke-NUS Medical School Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute Department of Pediatrics Duke University

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine（PORCN） that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and eTC-1922159（eTC-159） had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably,simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family,mitigated loss-of-bone mass seen upon eTC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN *** of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

关键词： Wnt eTC Bone loss Wnt inhibition mitigated concurrent alendronate therapy

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Progressive heterosis in genetically defined tetraploid maize

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Journal of Genetics and Genomics 2019年第8期46卷 389-396页

作者： Jacob D.Washburn mitchell J.Mcelfresh James A.Birchler Division of Biological Sciences University of Missouri

Progressive heterosis, i.e., the additional hybrid vigor in double-cross tetraploid hybrids not found in their single-cross tetraploid parents, has been documented in a number of species including alfalfa,potato, and maize. In this study, four artificially induced maize tetraploids, directly derived from standard inbred lines, were crossed in pairs to create two single-cross hybrids. These hybrids were then crossed to create double-cross hybrids containing genetic material from all four original lines. Replicated fieldbased phenotyping of the materials over four years indicated a strong progressive heterosis phenotype in tetraploids but not in their diploid counterparts. In particular, the above ground dry weight phenotype of double-cross tetraploid hybrids was on average 34% and 56% heavier than that of the single-cross tetraploid hybrids and the double-cross diploid counterparts, respectively. Additionally,whole-genome resequencing of the original inbred lines and further analysis of these data did not show the expected spectrum of alleles to explain tetraploid progressive heterosis under the complementation of complete recessive model. These results underscore the reality of the progressive heterosis phenotype,its potential utility for increasing crop biomass production, and the need for exploring alternative hypothesis to explain it at a molecular level.

关键词： Maize Tetraploid Heterosis Dominance complementation Progressive heterosis

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Climate change effects on rangelands and rangeland management:affirming the need for monitoring

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ecosystem Health and Sustainability 2017年第3期3卷 1-14页

作者： Daniel W.McCollum John A.Tanaka Jack A.Morgan John e.mitchell William e.Fox Kristie A.Maczko Lori Hidinger Clifford S.Duke Urs P.Kreuter Rocky Mountain Research Station USDAForest Service240 W.Prospect RoadFort CollinsColorado 80526 USA James C.Hageman Sustainable Agriculture Research and extension Center University of WyomingDept 33541000 E.University AvenueLaramieWyoming 82071 USA USDA ARS Rangelands Resources Research Unit8408 Hildreth RoadCheyenneWyoming 82009 USA Texas A&M AgriLife Research Ecosystem Science&Management720 E.Blackland RoadTempleTexas 76502 USA Consortium for Science Policyand OutcomesArizona State UniversityPO Box 875603TempeArizona 85287 USA ecological Society of America 1990 M StreetNWSuite 700WashingtonD.C.20036 USA ecosystem Science and Management Texas A&M University2138 TAMUCollege StationTexas 77843 USA

Uncertainty as to the extent and magnitude of changes in conditions that might occur due to climate change poses a problem for land and resource managers as they seek to adapt to changes and mitigate effects of climate *** illustrate using scenarios of projected future conditions on rangelands in the Northern Great Plains and Desert Southwest of the United *** two regions are different in the ways climate change is projected to affect the *** of a longer and warmer growing season in the Northern Great Plains could lead to increased forage production and land *** uncertain effects on summer monsoons that primarily control rangeland productivity in the Desert Southwest,combined with the possibility of more intense and/or frequent drought events,could present land managers with challenges stemming from decreased forage production and land *** projections,though uncertain,provide land managers with basic insight into future conditions they might *** need more.A focus on vulnerability and resilience,with explicit recognition of interactions between ecological and socio-economic factors,coupled with systematic monitoring and assessment of observable conditions on the land to supplement information based on climate projections,will more effectively provide critical and specific information managers need to adaptively manage rangelands under uncertain climate futures.

关键词： adaptive management climate change indicators monitoring rangelands resilience uncertainty vulnerability

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A Comparison of Various Normalization Methods for LC/MS Metabolomics Data

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Advances in Bioscience and Biotechnology 2018年第8期9卷 339-351页

作者： Jacob e. Wulff Matthew W. mitchell Metabolon Inc. Research Triangle Park NC USA

In metabolomics data, like other -omics data, normalization is an important part of the data processing. The goal of normalization is to reduce the variation from non-biological sources (such as instrument batch effects), while maintaining the biological variation. Many normalization techniques make adjustments to each sample. One common method is to adjust each sample by its Total Ion Current (TIC), i.e. for each feature in the sample, divide its intensity value by the total for the sample. Because many of the assumptions of these methods are dubious in metabolomics data sets, we compare these methods to two methods that make adjustments separately for each metabolite, rather than for each sample. These two methods are the following: 1) for each metabolite, divide its value by the median level in bridge samples (BRDG);2) for each metabolite divide its value by the median across the experimental samples (MeD). These methods were assessed by comparing the correlation of the normalized values to the values from targeted assays for a subset of metabolites in a large human plasma data set. The BRDG and MeD normalization techniques greatly outperformed the other methods, which often performed worse than performing no normalization at all.

关键词： Metabolomics Normalization Liquid Chromatography Mass Spectrometry TIC

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Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis

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Neural Regeneration Research 2017年第8期12卷 1262-1267页

作者： Rebecca M.Heidker mitchell R.emerson Steven M.Le Vine Department of Molecular and Integrative Physiology University of Kansas Medical Center Department of Pharmaceutical Sciences College of Pharmacy-Glendale Midwestern University

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth： insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

关键词： acetyl-coenzyme A carboxylase biotin estrogen iron Kynurenine pathway mitochondria thyroidhormone remyelination stem cells vitamin D

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p63基因在肺癌组织中的表达

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中华病理学杂志 2004年第4期33卷 324-327页

作者：余永伟 mitchell e Garber KarstenSchlüns ManuelaPacyna-Gengelbach IverPetersen Institute of Pathology Humboldt University Charite Medical School Berlin Germany Department of Genetics University of Stanford CA U.S.A

目的研究肺鳞状细胞癌、腺癌、大细胞肺癌、小细胞肺癌以及淋巴结或肺内转移性肿瘤标本组织中p63基因的mRNA转录因子和蛋白表达水平,探讨p63基因表达与其定位在3q 27-q29区域改变的关系。方法采用cDNA微阵列技术同时检测72例不同病理... 详细信息

目的研究肺鳞状细胞癌、腺癌、大细胞肺癌、小细胞肺癌以及淋巴结或肺内转移性肿瘤标本组织中p63基因的mRNA转录因子和蛋白表达水平,探讨p63基因表达与其定位在3q 27-q29区域改变的关系。方法采用cDNA微阵列技术同时检测72例不同病理组织学类型的原发性肺癌(包括鳞状细胞癌、腺癌、大细胞癌、小细胞癌)和肺癌肺内转移及淋巴结转移灶内的p63基因mRNA水平。另外,利用组织芯片技术构建150例原发性肺癌石蜡包埋标本组织芯片,采用免疫组织化学LSAB法检测p63基因蛋白表达情况。同时应用比较基因组杂交(CGH)技术对70例原发性肺癌标本进行了3号染色体长臂改变的分析。结果 p63mRNA转录因子在肺鳞状细胞癌标本表达明显增强,与腺癌、大细胞癌、小细胞癌相比增多10倍以上。肺癌转移灶内p63基因mRNA表达水平明显高于其相对应的原发性灶,差异有统计学意义(P<0.001)。免疫组织化学染色结果显示:肺鳞状细胞癌阳性表达率为94.64％;腺癌是1.79％;4例大细胞肺癌中2例为阳性染色;但所有小细胞肺癌标本免疫组织化学染色均为阴性。pT1分期肺癌的p63基因蛋白表达阳性率与pT2分期肺癌相比有统计学差异(P<0.05)。比较基因组杂交结果发现:肺鳞状细胞癌3号染色体长臂27-29区域有显著的扩增,腺癌表现为缺失。鳞状细胞癌p63基因的?

关键词： p63基因肺癌基因表达癌组织 cDNA微阵列技术

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Correction:Deep Learning-enhanced Brain Tumor Prediction via entropy-Coded BPSO in CIeLAB Color Space

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Computers, Materials & Continua 2025年第1期82卷 1461-1461页

作者： Mudassir Khalil Muhammad Imran Sharif Ahmed Naeem Muhammad Umar Chaudhry Hafiz Tayyab Rauf Adham e.Ragab Department of Computer engineering Bahauddin Zakariya UniversityMultan60000Pakistan Department of Computer Science Kansas State UniversityManhattanKS 66506USA Department of Computer Science University of Management and TechnologyLahore54000Pakistan Independent Researcher BradfordBD80HSUK Industrial engineering Department Collage of EngineeringKing Saud UniversityP.O.Box 800Riyadh11421Saudi Arabia

In the article“Deep Learning-enhanced Brain Tumor Prediction via entropy-Coded BPSO in CIeLAB Color Space”by Mudassir Khalil,Muhammad Imran Sharif,Ahmed Naeem,Muhammad Umar Chaudhry,Hafiz Tayyab Rauf,Adham *** Computers,Materials&Continua,2023,Vol.77,No.2,pp.2031–***:10.32604/cmc.2023.043687,URL:https://***/cmc/v77n2/54831,there was an error regarding the affiliation for the author Hafiz Tayyab *** of“Centre for Smart Systems,AI and Cybersecurity,Staffordshire University,Stoke-on-Trent,ST42De,UK”,the affiliation should be“Independent Researcher,Bradford,BD80HS,UK”.

关键词： Deep Code CIeLAB

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31p ( p,α) 28Si ReACTION FROM ep=l.00-4.01 MeV

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Chinese Physics Letters 1988年第11期5卷 501-504页

作者： FANG Dufei YANG Fujia e.G.Bilpuch G.e.mitchell Fudan University Shanghaiand Triangle Universities Nuclear LaboratoryDurhamNCUSA Center of Atom Nuclear and SurfaceCCASTWorld Lab and Fudan UniversityShanghai Triangle Universities Nuclear Laboratory DurhamNCUSA

By using the principle of detailed balance, the thermonuclear reaction rates for the 28Si (α , p ) 31p reaction were evaluated from the 31p ( p ,α ) 28Si resonance parameters. The reaction rates vary from 1.75x10-1 ... 详细信息

关键词： parameters rates resonance

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Inhibiting WNT secretion reduces high bone mass caused by Sost loss-of-function or gain-of-function mutations in Lrp5

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Bone Research 2023年第3期11卷 595-606页

作者： Cassandra R.Diegel Ina Kramer Charles Moes Gabrielle e.Foxa mitchell J.McDonald Zachary B.Madaj Sabine Guth Jun Liu Jennifer L.Harris Michaela Kneissel Bart O.Williams Department of Cell Biology Van Andel Institute333 Bostwick Ave.NEGrand RapidsMI 49503USA Diseases of Aging and Regenerative Medicine Novartis Institutes for Biomedical ResearchCH-4002 BaselSwitzerland Bioinformatics and Biostatistics Core Van Andel Institute333 Bostwick Ave.NEGrand RapidsMI 49503USA Oncology Novartis Institutes for Biomedical ResearchSan DiegoCA 92121USA

Proper regulation of Wnt signaling is critical for normal bone development and *** in several Wnt signaling components,which increase the activity of the pathway in the skeleton,cause high bone mass in human subjects and mouse *** bone mass is often accompanied by severe headaches from increased intracranial pressure,which can lead to fatality and loss of vision or hearing due to the entrapment of cranial *** addition,progressive forehead bossing and mandibular overgrowth occur in almost all *** that would provide symptomatic relief in these subjects are ***-mediated palmitoylation is necessary for Wnt secretion and binding to the frizzled *** inhibition of porcupine is a highly selective method of Wnt signaling *** treated three different mouse models of high bone mass caused by aberrant Wnt signaling,including homozygosity for loss-of-function in Sost,which models sclerosteosis,and two strains of mice carrying different point mutations in Lrp5(equivalent to human G171V and A214V),at 3 months of age with porcupine inhibitors for 5–6 *** significantly reduced both trabecular and cortical bone mass in all three *** demonstrates that porcupine inhibition is potentially therapeutic for symptomatic relief in subjects who suffer from these disorders and further establishes that the continued production of Wnts is necessary for sustaining high bone mass in these models.

关键词： homeostasis function mass

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The Global Boundary Stratotype Section and Point （GSSP） for the base of the Hirnantian Stage （the uppermost of the Ordovician System）

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episodes 2006年第3期29卷 183-196页

作者： Xu Chen Jiayu Rong Junxuan Fan Renbin Zhan Charles e. mitchell David A. T. Harper Michael J. Melchin Ping＇an Peng Stan C. Finney Xiaofeng Wang State Key Laboratory of Palaeobiology and Stratigraphy Nanjing Institute of Geology and Palaeontology Chinese Academy of Sciences 39 East Beijing Road Nanjing 210008 China Department of Geology the State University of New York at Buffalo NY 14260-3050 USA. Geological Museum University of Copenhagen Фster Voldgade 5-7 DK-1350 Copenhagen Denmark Department of earth Sciences St. Francis Xavier University Antigonish N.S. B2G 2W5 Canada State Key Laboratory of Organic Geochemistry Guangzhou Institute of Geochemistry Chinese Academy of Sciences Guangzhou 510640 China Department of Geological Sciences California State University at Long Beach Long Beach CA 90840 USA. Yichang Institute of Geology and Mineral Resources 21 Gangyao Road Yichang 443003 China.

The Global boundary Stratotype Section and Point （GSSP） for the base of the Hirnantian Stage （the uppermost of the Ordovician System） is defined at a point 0.39m below the base of the Kuanyinchiao Bed in the Wangjiawan North section. The section is located near Wangjiawan village, 42 km north of Yichang city （western Hubei, China）, at 30° 58′56″N and 111° 25′10″e. The GSSP level coincides with the first appearance of the graptolite species Normalograptus extraordinarius （Sobolevskaya）. Secondary markers include the onset of a positive carbon-isotope excursion, and a slightly earlier first appearance of Normalograptus ojsuensis （ Koren and Mikhailova ）. The Wangjiawan North section possesses continuity of sedimentation and biozonation with completeness of exposures, abundant and well-preserved graptolites and shelly fossils, i. e. the Hirnantia- Dalmanitina shelly fauna which is a key element for recognition of the Hirnantian Stage. The Wangjiawan North, South and Riverside sections possess favorable facies and widespread correlation potential, are free from structure complication, metamorphism and other alteration, and have good accessibility. The Riverside section in particular possesses amenability to isotopic age determination. The beginning of the Hirnantian was followed by a global episode of a major extinction event, which happened in the Diceratograptus mirus Subzone. The proposal was voted by the International Subcommission on Ordovician Stratigraphy in October, 2004, approved by the International Commission on Stratigraphy in February, 2006, and ratified by the International Union of Geological Sciences in May, 2006.

关键词：全球界线层型剖面和节点奥陶纪 GSSP 地层学

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