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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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骨研究:英文版 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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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

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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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Investigation of HCAR2 antagonists as a potential strategy to modulate bovine leukocytes

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journal of Animal Science and Biotechnology 2024年第4期15卷 1567-1577页

作者： Laman K.Mamedova Kirby C.Krogstad Paiton O.mcdonald Laxman Pokhrel Duy H.Hua Evan C.Titgemeyer Barry j.Bradford Department of Animal Science Michigan State UniversityEast LansingMichigan 48824USA Department of Animal Sciences and Industry Kansas State UniversityManhattanKS 66506USA Comparative Medicine and Integrative Biology East LansingMI 48824USA Department of Chemistry Kansas State UniversityManhattanKS 66506USA

Background Dairy cows experiencing ketosis after calving suffer greater disease incidence and are at greater risk of leaving the herd. In vitro administration of beta-hydroxybutyric acid(BHBA;the primary blood ketone) has inhibitory effects on the function of bovine leukocytes. BHBA is a ligand of HCAR2 and the activation of these receptors promotes an anti-inflammatory response which may be related with immunosuppression observed in transition dairy cattle. The objective of this study was to identify and test antagonists for HCAR2 in bovine immune cells cultured with *** We observed expression of HCAR2 at the protein level within lymphocytes, monocytes, and granulocytes. The proportion of cells expressing HCAR2 tended to be greater in mid-lactation compared to early lactation cows;the increase was a result of increased proportion of T and B cells expressing HCAR2. Stimulation of HCAR2 with niacin or BHBA promoted Ca^(2+) mobilization in neutrophils and mononuclear cells. Mononuclear cells treated with BHBA had diminished intracellular Ca^(2+) responses when HCAR2 was knocked down by si RNA silencing, indicating Ca^(2+) mobilization was mediated by HCAR2 signaling. Two candidate antagonists for HCAR2, synthesized from niacin(NA-1 and NA-5), were tested;monocytes and neutrophils pre-treated with NA-1 and NA-5 had reduced Ca^(2+) mobilization after incubation with BHBA. Furthermore, NA-5 but not NA-1 prevented BHBA-associated reductions in cyclic *** We demonstrated that HCAR2 is present on bovine leukocytes and has greater expression later in lactation. We confirmed that BHBA and niacin derived HCAR2 antagonists alter bovine leukocyte activity. Our results demonstrate that both BHBA and niacin affect bovine leukocyte Ca^(2+) mobilization in a HCAR2-dependent manner.

关键词： Flow cytometry GPR109A HM74A Ketosis

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从机械机器人到智能机器人:人工智能的图像学

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外国文学研究 2024年第3期46卷 1-7页

作者： W.j.T.米切尔韦清琦(译) 美国芝加哥大学东南大学外国语学院

智能机器人将人类带入了自原子弹、电灯或是印刷术以来最伟大的科技革命之中,同时智能机器也能走火入魔这一构思也向来是科幻作品的核心想象。纵观媒体发明的历史长河,对人工智能的恐慌并不新鲜,人们曾认为书写的发明和照相术将扼杀记... 详细信息

智能机器人将人类带入了自原子弹、电灯或是印刷术以来最伟大的科技革命之中,同时智能机器也能走火入魔这一构思也向来是科幻作品的核心想象。纵观媒体发明的历史长河,对人工智能的恐慌并不新鲜,人们曾认为书写的发明和照相术将扼杀记忆和绘画,现在又照例指责数码正在毁灭模拟技术的独一性。人类应该冷静下来,采取对症下药的态度。有必要解构关于人与机器之差异的想象,而毋需躲避与智能机器人的交互谈话。人类物种虽然在作茧自缚,但同时又以进化与生态智能为基础,努力建设可持续全球体系。图像学研究的图像和文字同时包括了机器和人类的作品,因而相关的研究者应明确自己的任务:就文字与图像和智能机器人展开对话,在上述人类的生存努力中谋求与智能机器人携手合作。

关键词：智能机器人人工智能机器图像学传媒人文

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Preliminary Insights into the Habitat Preferences of the Centralian Bandy Bandy (Vermicella vermiformis)(Squamata: Elapidae) in Central Australia

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Asian Herpetological Research 2014年第1期5卷 49-53页

作者： Peter j.mcdonald Gary W.LUCK Flora and Fauna Division Department of Land Resource Management Northern Territory Government School of Environmental Sciences Charles Sturt University Institude for Land Water and Society Charles Sturt University

Bandy Bandy’s（Vermicella spp.）are a striking,black-and-white ringed genus of small elapid snakes endemic to *** taxa are burrowers and little is known of their biology and *** investigated the habitat preferences of the only arid-dwelling species,the centralian bandy bandy（Vermicella vermiformis）,in the MacDonnell Ranges west of Alice Springs in the Northern *** systematic road-cruising,we encountered *** over a 12 months period between 2009 and *** used logistic regression to model the occurrence of the species against a range of different habitat variables collected at multiple *** the small sample size,*** exhibited a clear preference for acacia shrubland habitats,with acacia variables present in all AICc ranked models in the 95%confidence *** factors driving this association,together with the preference for habitat not burnt in the most recent wildfires,may be related to the abundance of their only known prey,blind snakes（Ramphotyphlops spp.）.

关键词： Snake Arid Acacia Fire Ramphotyphlops

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Decreased bioavailability of aminomethylphosphonic acid(AMPA)in genetically modified corn with activated carbon or calcium montmorillonite clay inclusion in soil

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journal of Environmental Sciences 2021年第2期33卷 131-143页

作者： Sara E.Hearon Meichen Wang Thomas j.mcdonald Timothy D.Phillips Veterinary Integrative Biosciences Department College of Veterinary Medicine and Biomedical Sciences Texas A&M Uniuersity College StationTx 77845USA Department of Environmental and Occupational Health School of Public Health Texas A&M UniversityCollege Station400 Bizzell St College StationTX 77843USA

The widespread use of pesticides has resulted in detectable residues throughout the environment,sometimes at concentrations well above regulatory ***,the development of safe,effective,field-practical,and economically feasible strategies to mitigate the effects of pesticides is *** is an organophosphorus herbicide that is degraded to aminomethylphosphonic acid(AMPA),a toxic and persistent metabolite that can accumulate in soil and sediment and translocate to *** this study,we investigated the binding efficacy of activated carbon(AC)and calcium montmorillonite(CM)clay to decrease AMPA bioavailability from soil and AMPA translocation to *** isotherms and thermodynamic studies on AC and CM were conducted and showed tight binding(enthalpy values>-20 k j/mol)for AMPA with high capacities(0.25 mol/kg and 0.38 mol/kg,respectively),based on derivations from the Langmuir model.A hydra assay was utilized to indicate toxicity of AMPA and the inclusion of 1%AC and CM both resulted in 90%protection of the hydra(**p≤0.01).Further studies in glyphosate-contaminated soil showed that AC and CM significantly reduced AMPA bioavailability by 53%and 44%,*** in genetically modified(GM)corn showed a conversion of glyphosate to AMPA in roots and sprouts over a 10-day exposure *** of AC and CM reduced AMPA residues in roots and sprouts by 47%-61%.These studies collectively indicate that AC and CM are effective sorbents for AMPA and could be used to reduce AMPA bioavailability from soil and AMPA residues in GM corn plants.

关键词： Glyphosate AMPA Activated carbon Calcium montmorillonite Sorbent

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Elimination of antibiotic resistance genes and control of horizontal transfer risk by UV-based treatment of drinking water: A mini review

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Frontiers of Environmental Science & Engineering 2019年第3期13卷 3-11页

作者： Virender K.Sharma Xin Yu Thomas j.mcdonald Chetan jinadatha Dionysios D.Dionysiou Mingbao Feng Department of Environmental and Occupational Health School of Public Health Texas A&M University College Station TX 77843 USA Institute of Urban Environment Chinese Academy of Sciences Xiamen 361021 China Central Texas Veterans Health Care System Temple TX 76504 USA College of Medicine Texas A&M Health Science Center Bryan TX 77807 USA Environmental Engineering and Science Program Department of Chemical and Environmental Engineering (DChEE) 705 Engineering Research Center University of Cincinnati Cincinnati OH 45221 USA

Antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) have been recognized as one of the biggest public health issues of the 21 st century. Both ARB and ARGs have been determined in water after treatment with conventional disinfectants. Ultraviolet (UV) technology has been seen growth in application to disinfect the water. However, UV method alone is not adequate to degrade ARGs in water. Researchers are investigating the combination of UV with other oxidants (chlorine, hydrogen peroxide (H2O2), peroxymonosulfate (PMS), and photocatalysts) to harness the high reactivity of produced reactive species (C1-, C1O -, Cl2-,-OH, and SO4-_) in such processes with constituents of cell (e.g., deoxyribonucleic acid (DNA) and its components) in order to increase the degradation efficiency of ARGs. This paper briefly reviews the current status of different UV-based treatments (UV/chlorination, UV/H2O2, UV/PMS, and UV-photocatalysis) to degrade ARGs and to control horizontal gene transfer (HGT) in water. The review also provides discussion on the mechanism of degradation of ARGs and application of q-PCR and gel electrophoresis to obtain insights of the fate of ARGs during UV-based treatment processes.

关键词： Antibiotic resistance bacteria Advanced oxidation processes Disinfection Reactive chlorine species Sulfate radicals Reactive oxygen species

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The complexity of sediment recycling as revealed by common Pb isotopes in K-feldspar

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Geoscience Frontiers 2018年第5期9卷 1515-1527页

作者： Simon P.johnson Christopher L.Kirkland Noreen j.Evans Brad j.mcdonald Huntly N.Cutten Geological Survey of Western Australia Mineral House100 Plain StreetEast PerthWestern Australia6004Australia Centre for Exploration Targeting-Curtin Node The Institute for Geoscience ResearchDepartment of Applied GeologyWestern Australian School of MinesCurtin UniversityPerthWestern Australia6102Australia john de Laeter Centre The Institute for Geoscience ResearchDepartment of Applied Geology and Applied PhysicsCurtin UniversityPerthWestern Australia6102Australia

Detrital zircon U-Pb geochronology has become the gold standard in evaluating source to sink relationships in sedimentary basins. However, the physical and chemical robustness of zircon, which make it such a useful mineral for provenance studies, is also a hindrance as zircon can be recycled through numerous sedimentary basins, thus obscuring the first cycle source to sink relationship. An elegant approach to addressing this potential issue is to compare the Pb isotope composition of detrital K-feldspar, a mineral which is unlikely to survive more than one erosion-transport-deposition cycle, with that of magmatic K-feldspar from potential basement source terranes. Here we present new in situ Pb isotope data on detrital K-feldspar from two Proterozoic arkosic sandstones from Western Australia, and magmatic K-feldspar grains from potential igneous source rocks, as inferred by the age and Hf isotope composition of detrital zircon grains. The data indicate that the detrital zircon and K-feldspar grains could not have been liberated from the same source rocks, and that the zircon has most likely been recycled through older sedimentary basins. These results provide a more complete understanding of apparently simple source to sink relationships in this part of Proterozoic Western Australia.

关键词： Detrital zircon K-feldspar Pb isotopes Sediment provenance Sediment recycling

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Neurological heterotopic ossification:novel mechanisms,prognostic biomarkers and prophylactic therapies

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Bone Research 2020年第4期8卷 379-392页

作者： Ker Rui Wong Richelle Mychasiuk Terence j.O’Brien Sandy R.Shultz Stuart j.mcdonald Rhys D.Brady Department of Neuroscience Central Clinical SchoolMonash UniversityMelbourneVICAustralia Department of Medicine Royal Melbourne HospitalThe University of MelbourneParkvilleVICAustralia Department of Physiology Anatomy and MicrobiologySchool of Life SciencesLa Trobe UniversityBundooraVICAustralia

Neurological heterotopic ossification(NHO)is a debilitating condition where bone forms in soft tissue,such as muscle surrounding the hip and knee,following an injury to the brain or spinal *** abnormal formation of bone can result in nerve impingement,pain,contractures and impaired *** are often diagnosed with NHO after the bone tissue has completely mineralised,leaving invasive surgical resection the only remaining treatment *** resection of NHO creates potential for added complications,particularly in patients with concomitant injury to the central nervous system(CNS).Although recent work has begun to shed light on the physiological mechanisms involved in NHO,there remains a significant knowledge gap related to the prognostic biomarkers and prophylactic treatments which are necessary to prevent NHO and optimise patient *** article reviews the current understanding pertaining to NHO epidemiology,pathobiology,biomarkers and treatment *** particular,we focus on how concomitant CNS injury may drive ectopic bone formation and discuss considerations for treating polytrauma patients with *** conclude that understanding of the pathogenesis of NHO is rapidly advancing,and as such,there is the strong potential for future research to unearth methods capable of identifying patients likely to develop NHO,and targeted treatments to prevent its manifestation.

关键词： such has likely

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Adding Value to Crop Production Systems by Integrating Forage Cover Crop Grazing

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American journal of Plant Sciences 2024年第3期15卷 180-192页

作者： Robert B. mitchell Daren D. Redfearn Kenneth P. Vogel Terry j. Klopfenstein Galen Erickson P. Stephen Baenziger Bruce E. Anderson Mary E. Drewnoski jay Parsons Steven D. Masterson Marty R. Schmer Virginia L. jin USDA-ARS Wheat Sorghum and Forage Research Unit University of Nebraska-Lincoln Lincoln NE USA Department of Agronomy and Horticulture University of Nebraska-Lincoln Lincoln NE USA Department of Animal Science University of Nebraska-Lincoln Lincoln NE USA Department of Agricultural Economics University of Nebraska-Lincoln Lincoln NE USA USDA-ARS Agroecosystem Management Research Unit University of Nebraska-Lincoln Lincoln NE USA

In addition to their value as cereal grains, wheat (Triticum aestivum L.) and triticale (× Triticosecale Wittmack) are important cool-season annual forages and cover crops. Yearling steer (Bos taurus) performance was compared in the spring following autumn establishment as for age cover crops after soybean [Glycine max (L.) Merr.] grain harvest. Replicated pastures (0.4 ha) were no-till seeded in three consecutive years into soybean stubble in autumn, fertilized, and grazed the following spring near Ithaca, NE, USA. Each pasture (n = 3) was continuously stocked in spring with four yearling steers (380 ± 38 kg) for 17, 32, and 28 d in 2005, 2006, and 2007, respectively. In 2005, average daily gain (ADG) for steers grazing triticale exceeded the ADG for wheat by 0.31 kghd-1d-1. In 2006, wheat ADG exceeded that for triticale by 0.12 kghd-1d-1. In 2007, steers grazing wheat lost weight, while steers grazing triticale gained 0.20 kghd-1d-1. Based on the 3-year average animal gains valued at $1.32 kg-1, mean net return ($ ha-1 yr-1) was $62.15 for triticale and $22.55 for wheat. Since these grazed cover crops provide ecosystem services in addition to forage, grazing could be viewed as a mechanism for recovering costs and adds additional value to the system. Based on this 3-year grazing trial, triticale was superior to wheat and likely will provide the most stable beef yearling performance across years with variable weather for the western Cornbelt USA.

关键词： Cover crops Soybean Triticale Wheat

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