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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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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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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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Prediction of spatial heterogeneity in nutrient-limited sub-tropical maize yield:Implications for precision management in the eastern Indo-Gangetic Plains

Artificial Intelligence in Agriculture

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Artificial Intelligence in Agriculture 2024年第3期13卷 100-116页

作者： Zia Uddin Ahmed Timothy j.Krupnik jagadish Timsinab Saiful Islam Khaled Hossain A.S.M.Alanuzzaman Kurishi Shah-Al Emran M.Harun-Ar-Rashid Andrew j.mcdonald Mahesh K.Gathala University at Buffalo New YorkUSA International Maize and Wheat Improvement Center Dhaka 1213Bangladesh Global Ever Greening Alliance 1 Vision DriveBurwood EastMelbourneAustralia Department of Crop Sciences University of Illinois at Urbana-ChampaignUrbanaILUSA SAARC Agriculture Centre DhakaBangladesh Cornell University School of Integrative Plant Science Soil and Crop Sciences SectionNYUSA

Knowledge of the factors influencing nutrient-limited subtropical maize yield and subsequent prediction is crucial for effective nutrientmanagement,maximizing profitability,ensuring food security,and promoting environmental *** data fromnutrient omission plot trials(NOPTs)conducted in 324 farmers'fields across ten agroecological zones(AEZs)in the Eastern Indo-Gangetic Plains(EIGP)of Bangladesh to explain maize yield variability and identify variables controlling nutrient-limited *** additive main effect and multiplicative interaction(AMMI)model was used to explain maize yield variability with nutrient *** machine learning(ML)algorithms in automatic machine learning(AutoML)frameworks were subsequently used to predict attainable yield relative nutrient-limited yield(RY)and to rank variables that control *** stack-ensemble model was identified as the best-performing model for predicting RYs of N,P,and *** contrast,deep learning outperformed all base learners for predicting *** best model's square errors(RMSEs)were 0.122,0.105,0.123,and 0.104 for RY_(N),RY_(P),RY_(K),and RY_(Zn),*** permutation-based feature importance technique identified soil pH as the most critical variable controlling RY_(N)and RY_(P).The RY_(K)showed lower in the eastern longitudinal *** N and Zn were associated with *** predicted median RY of N,P,K,and Zn,representing average soil fertility,was 0.51,0.84,0.87,and 0.97,accounting for 44,54,54,and 48%upland dry season crop area of Bangladesh,*** are needed to update databases cataloging variability in land type inundation classes,soil characteristics,and INS and combine them with farmers'crop management information to develop more precise nutrient guidelines for maize in the EIGP.

关键词： Relative yield Additive Main effect and multiplicative interaction (AMMI) Quantile regression autoML Stack-ensemble Partial dependency plots

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When will it end? Long-lived intracontinental reactivation in central Australia

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Geoscience Frontiers 2019年第1期10卷 149-164页

作者： Raphael Quentin de Gromard Christopher L.Kirkland Heather M.Howard Michael T.D.Wingate Fred jourdan Brent I.A.Mc Innes Martin Danisik Noreen j.Evans Bradley j.mcdonald R.Hugh Smithies Geological Survey of Western Australia Department of Mines Industry Regulation and Safety School of Earth and Planetary Science/john de Laeter Centre/TIGeR Curtin University

The post-Mesoproterozoic tectonometamorphic history of the Musgrave Province, central Australia, has previously been solely attributed to intracontinental compressional deformation during the 580 -520 Ma Petermann Orogeny. However, our new structurally controlled multi-mineral geochronology results,from two north-trending transects, indicate protracted reactivation of the Australian continental interior over ca. 715 million years. The earliest events are identified in the hinterland of the orogen along the western transect. The first tectonothermal event, at ca. 715 Ma, is indicated by40 Ar/39 Ar muscovite and U e Pb titanite ages. Another previously unrecognised tectonometamorphic event is dated at ca. 630 Ma by Ue Pb analyses of metamorphic zircon rims. This event was followed by continuous cooling and exhumation of the hinterland and core of the orogen along numerous faults, including the Woodroffe Thrust,from ca. 625 Ma to 565 Ma as indicated by muscovite, biotite, and hornblende40 Ar/39 Ar cooling ages. We therefore propose that the Petermann Orogeny commenced as early as ca. 630 Ma. Along the eastern transect,40 Ar/39 Ar muscovite and zircon(Ue Th)/He data indicate exhumation of the foreland fold and thrust system to shallow crustal levels between ca. 550 Ma and 520 Ma, while the core of the orogen was undergoing exhumation to mid-crustal levels and cooling below 600-660℃. Subsequent cooling to 150 -220℃ of the core of the orogen occurred between ca. 480 Ma and 400 Ma(zircon [Ue Th]/He data)during reactivation of the Woodroffe Thrust, coincident with the 450 -300 Ma Alice Springs *** of the footwall of the Woodroffe Thrust to shallow depths occurred at ca. 200 Ma. More recent tectonic activity is also evident as on the 21 May, 2016(Sydney date), a magnitude 6.1 earthquake occurred, and the resolved focal mechanism indicates that compressive stress and exhumation along the Woodroffe Thrust is continuing to the present day. Overall, these results

关键词： Intracontinental deformation Thermochronology Petermann orogen Musgrave Province Plate tectonics Cratonization

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Transhiatal versus transthoracic esophagectomy for esophageal cancer

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World journal of Gastroenterology 2010年第30期16卷 3804-3810页

作者： j Camilo Barreto mitchell C Posner Section of General Surgery and Surgical Oncology Department of SurgeryUniversity of Chicago Pritzker School of Medicine5841 S. Maryland AveMC 5094ChicagoIL 60637United States

Esophageal cancer continues to represent a formidable challenge for both patients and clinicians. Relative 5-year survival rates for patients have improved over the past three decades, probably linked to a combination of improved surgical outcomes, progress in systemic chemotherapy and radiotherapy, and the increasing acceptance of multimodality treatment. Surgical treatment remains a fundamental component of the treatment of localized esophageal adenocarcinoma. Multiple approaches have been described for esophagectomy, which can be thematically grouped under two major categories: either transthoracic or transhiatal. The main controversy rests on whether a more extended resection through thoracotomy provides superior oncological outcomes as opposed to resection with relatively limited morbidity and mortality through a transhiatal approach. After numerous trials have addressed these issues, neither approach has consistently proven to be superior to the other one, and both can provide excellent short-term results in the hands of experienced surgeons. Moreover, the available literature suggests that experience of the surgeonand hospital in the surgical management of esophageal cancer is an important factor for operative morbidity and mortality rates, which could supersede the type of approach selected. Oncological outcomes appear to be similar after both procedures.

关键词： Esophageal cancer Transhiatal esophageal resection Transthoracic esophageal resection

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