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Identification and optimization of a potent and highly selective D3 dopamine receptor agonist

中国药理学与毒理学杂志 2017年第10期31卷 950-951页

作者： amy e moritz R Benjamin FRee Warren WeINeR Muzna BACHANI Trevor DOYLe Noel SOUTHALL Marc FeRReR Jonathan A JAVITCH Joseph STeINeR Ara ABRamyAN Lei SHI Jeffrey AUBé Kevin FRANKOWSKI David R SIBLeY Molecular Neuropharmacology Section National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 University of North Carolina Chapel Hill NC27599 Neurotherapeutic Development Unit National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 National Center for Advancing Translational Sciences Rockville MD 20892 Columbia University New York NY 10032 Computational Chemistry and Molecular Biophysics Unit Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse National Institutes of Health Baltimore MD 21224

OBJeCTIVe Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric *** available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays *** lab employed high throughput screening paradigms to discover highly selective modulators for the *** The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the *** and counter-screens assessed selectivity and mechanisms of *** identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining *** lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BReT)-based β-arrestin recruitment and G-protein activation assays as well as p-eRK *** neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell *** ML417 displays potent,DRD3-selective agonist activity in multiple functional *** and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other ***417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L^(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell *** We have discovered and characterized ML417,a potent and highly selective DRD3 *** compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.

关键词： Dopamine receptor high throughput screening subtype selectivity neuroprotection

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Leveraging the potential of big genomic and phenotypic data for genome-wide association mapping in wheat

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The Crop Journal 2024年第3期12卷 803-813页

作者： moritz Lell Yusheng Zhao Jochen C.Reif Leibniz Institute of Plant Genetics and Crop Plant Research(IPK) Corrensstraße 3D-06466 SeelandGermany

Genome-wide association mapping studies(GWAS)based on Big Data are a potential approach to improve marker-assisted selection in plant *** number of available phenotypic and genomic data sets in which medium-sized populations of several hundred individuals have been studied is rapidly *** these data and using them in GWAS could increase both the power of QTL discovery and the accuracy of estimation of underlying genetic effects,but is hindered by data heterogeneity and lack of *** this study,we used genomic and phenotypic data sets,focusing on Central european winter wheat populations evaluated for heading *** explored strategies for integrating these data and subsequently the resulting potential for *** interoperability between data sets was greatly aided by some overlapping genotypes and a linear relationship between the different phenotyping protocols,resulting in high quality integrated phenotypic *** this context,genomic prediction proved to be a suitable tool to study relevance of interactions between genotypes and experimental series,which was low in our *** to expectations,fewer associations between markers and traits were found in the larger combined data than in the individual experimental ***,the predictive power based on the marker-trait associations of the integrated data set was higher across data ***,the results show that the integration of medium-sized to Big Data is an approach to increase the power to detect QTL in *** results encourage further efforts to standardize and share data in the plant breeding community.

关键词： Big Data Genome-wide association study Data integration Genomic prediction Wheat

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Shifting the paradigm:A critical review of social innovation literature

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International Journal of Innovation Studies 2024年第1期8卷 45-58页

作者： amy Phillips Rosalie Luo Joel Wendland-Liu Social Innovation Program Grand Valley State UniversityGrand Rapids49504USA Ivey School of Business Western UniversityPLondonN6A 0E1Canada Social Innovation Program Grand Valley State UniversityAllendale49401USA

In this review of ten years of social innovation research(2012e2022),we define and explore three paradigms in the field:instrumentalist,strong,and *** investigate how language usage and geography play a central role in identifying which paradigms recently published scholarship falls *** we do not insist that sharp divisions exist between each paradigm,we do find that on the“instrumentalist”side,language tends to abstract or neutralize power ***,these perspectives tend to derive from Western or eurocentric orientations or ***“strong”paradigm accepts the necessity of institutional and stakeholder engagement and seeks to engage socially excluded *** contrast,geographical diversity,attendance to historicized and systemic inequalities,and elevation of the most marginalized communities are more likely to be centered in the“democratic”*** apply this discussion to recent research in arts-related social innovation and the related field of social entrepreneurship.

关键词： Social innovation Culture Arts Social entrepreneurship ethnocentrism

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Hydraulic properties and drought response of a tropical bamboo (Cephalostachyum pergracile)

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Plant Diversity 2024年第3期46卷 406-415页

作者： Wanwalee Kongjarat Lu Han amy Ny Aina Aritsara Shu-Bin Zhang Gao-Juan Zhao Yong-Jiang Zhang Phisamai Maenpuen Ying-Mei Li Yi-Ke Zou Ming-Yi Li Xue-Nan Li Lian-Bin Tao Ya-Jun Chen CAS Key Laboratory of Tropical Forest ecology Xishuangbanna Tropical Botanical GardenChinese Academy of SciencesYunnan 666303China University of the Chinese Academy of Sciences Beijing 100049China T-STAR Core Team Xishuangbanna Tropical Botanical GardenChinese Academy of SciencesYunnan 666303China School of Biology and ecology University of MaineOronoMEUSA Climate Change Institute University of MaineOronoME 04469USA School of Biological and Chemical Science Pu’er UniversityXueyuan RoadYunnan 665000China Institute of ecology and Geobotany School of Ecology and Environmental SciencesYunnan UniversityKunmingYunnan 650091China School of ecology and environment Southwest Forestry UniversityKunmingYunnan 650224China Yuanjiang Savanna ecosystem Research Station Xishuangbanna Tropical Botanical GardenChinese Academy of SciencesYuanjiangYunnan 653300China

Bamboo plants are an essential component of tropical ecosystems,yet their vulnerability to climate extremes,such as drought,is poorly understood due to limited knowledge of their hydraulic *** pergracile,a commonly used tropical bamboo species,exhibited a substantially higher mortality rate than other co-occurring bamboos during a severe drought event in 2019,but the underlying mechanisms remain *** study investigated the leaf and stem hydraulic traits related to drought responses,including leaf-stem embolism resistance(P50leaf;P50stem) estimated using optical and X-ray microtomography methods,leaf pressure-volume and water-releasing ***,we investigated the seasonal water potentials,native embolism level(PLC) and xylem water source using stable *** found that *** exhibited strong resistance to embolism,showing low P50leaf,P50stem,and turgor loss point,despite its rapid leaf water ***,its leaves displayed greater resistance to embolism than its stem,suggesting a lack of effective hydraulic vulnerability segmentation(HVS) to protect the stem from excessive xylem *** the dry season,approximately 49% of the water was absorbed from the upper 20-cm-deep soil ***,significant diurnal variation in leaf water potentials and an increase in midday PLC from 5.87±2.33% in the wet season to 12.87±4.09%in the dry season were *** summary,this study demonstrated that the rapid leaf water loss,high reliance on surface water,and a lack of effective HVS in *** accelerated water depletion and increased xylem embolism even in the typical dry season,which may explain its high mortality rate during extreme drought events in 2019.

关键词： Climate change Drought Hydraulic safety Hydraulic vulnerability segmentation Stable isotope Tree mortality

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Heightened condition dependent expression of structural coloration in the faces,but not wings,of male and female flies

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Current Zoology 2022年第5期68卷 600-607页

作者： Thomas e White amy Locke Tanya Latty School of Life and environmental Sciences The University of SydneySydney 2106Australia

Structurally colored sexual signals are a conspicuous and widespread class of ornament used in mate choice,though the extent to which they encode information on the quality of their bearers is not fully *** predicts that signaling traits under strong sexual selection as honest indicators should evolve to be more developmentally integrated and exaggerated than nonsexual traits,thereby leading to heightened condition ***,we test this prediction through examination of the sexually dimorphic faces and wings of the cursorial fly Lispe *** and females possess structural UV-white and golden faces,respectively,and males present their faces and wings to females during close-range,ground-based courtship displays,thereby creating the opportunity for mutual *** a field-collected sample of individuals,we found that the appearance of the faces of both sexes scaled positively with individual condition,though along separate *** in better condition expressed brighter faces as modeled according to conspecific flies,whereas condition scaled with facial saturation in *** found no such relationships for their wing interference pattern nor abdomens,with the latter included as a nonsexual *** results suggest that the structurally colored faces,but not the iridescent wings,of male and female *** are reliable guides to individual quality and support the broader potential for structural colors as honest *** also highlight the potential for mutual mate choice in this system,while arguing for 1 of several alternate signaling roles for wing interferences patterns among the myriad taxa which bear them.

关键词： honest signal iridescent mate choice sexual selection wing interference pattern

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A sting in the tail： the N-terminal domain of the androgen receptor as a drug target

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Asian Journal of Andrology 2016年第5期18卷 687-694页

作者： amy e Monaghan Iain J Mcewan School of Medicine Medical Sciences and Nutrition Institute of Medical Sciences University of Aberdeen Foresterhill Aberdeen AB25 2ZD United Kingdom.

The role of androgen receptor （AR） in the initiation and progression of prostate cancer （PCa） is well established. Competitive inhibition of the AR ligand-binding domain （LBD） has been the staple of antiandrogen therapies employed to combat the disease in recent years. However, their efficacy has often been limited by the emergence of resistance, mediated through point mutations, and receptor truncations. As a result, the prognosis for patients with malignant castrate resistant disease remains poor. The amino-terminal domain （NTD） of the AR has been shown to be critical for AR function. Its modular activation function （AF-1） is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been dismissed in the past. The recent emergence of the small molecule ePI-O01 has provided evidence that AR-NTD can be targeted therapeutically, independent of the LBD. Targeting of AR-NTD has the potential to disrupt multiple intermolecular interactions between AR and its coregulatory binding partners, in addition to intramolecular cross-talk between the domains of the AR. Therapeutics targeting these protein-protein interactions or NTD directly should also have efficacy against emerging AR splice variants which may play a role in PCa progression. This review will discuss the role of intrinsic disorder in AR function and illustrate how emerging therapies might target NTD in PCa.

关键词： androgen receptor inhibitor intrinsically disordered structure N-terminal domain prostate cancer small molecules

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Black hairy tongue syndrome

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World Journal of Gastroenterology 2014年第31期20卷 10845-10850页

作者： Grigoriy e Gurvits amy Tan Department of Gastroenterology New York University School of Medicine/Langone Medical Center New York University School of Medicine

Black hairy tongue (BHT) is a benign medical condition characterized by elongated filiform lingual papillae with typical carpet-like appearance of the dorsum of the tongue. Its prevalence varies geographically, typically ranging from 0.6% to 11.3%. Known predisposing factors include smoking, excessive coffee/black tea consumption, poor oral hygiene, trigeminal neuralgia, general debilitation, xerostomia, and medication use. Clinical presentation varies but is typically asymptomatic, although aesthetic concerns are common. Differential diagnosis includes pseudo-BHT, acanthosis nigricans, oral hairy leukoplakia, pigmented fungiform papillae of the tongue, and congenital melanocytic/melanotic nevi/macules. Clinical diagnosis relies on visual observation, detailed history taking, and occasionally microscopic evaluation. Treatment involves identification and discontinuation of the offending agent, modifications of chronic predisposing factors, patient’s re-assurance to the benign nature of the condition, and maintenance of adequate oral hygiene with gentle debridement to promote desquamation. Complications of BHT (burning mouth syndrome, halitosis, nausea, gagging, dysgeusia) typically respond to therapy. Prognosis is excellent with treatment of underlying medical conditions. BHT remains an important medical condition which may result in additional burden on the patient and health care system and requires appropriate prevention, recognition and treatment.

关键词： Black hairy tongue Hyperkeratosis of the tongue Lingua villosa nigra

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Alternatives for large-scale production of cultured beef: A review

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Journal of Integrative Agriculture 2015年第2期14卷 208-216页

作者： Matilda S M moritz Sanne e L Verbruggen Mark J Post Department of Physiology Maastricht UniversityMaastricht 6229 ER The Netherlands Department of Physics Chemistry and Biology Linkping UniversityLinkping SE-581 83 Sweden

Cultured beef is a method where stem cells from skeletal muscle of cows are cultured in vitro to gain edible muscle tissue. For large-scale production of cultured beef, the culture technique needs to become more efficient than today＇s 2-dimensional（2D） standard technique that was used to make the first cultured hamburger. Options for efficient large-scale production of stem cells are to culture cells on microcarriers, either in suspension or in a packed bed bioreactor, or to culture aggregated cells in suspension. We discuss the pros and cons of these systems as well as the possibilities to use the systems for tissue culture. either of the production systems needs to be optimized to achieve an efficient production of cultured beef. It is anticipated that the optimization of large-scale cell culture as performed for other stem cells can be translated into successful protocols for bovine satellite cells resulting in resource and cost efficient cultured beef.

关键词： cultured beef microcarriers aggregated cells packed bed bioreactor cell culture

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Impacts of bovine spongiform encephalopathy and avian influenza on U.S. meat demand

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Journal of Integrative Agriculture 2015年第6期14卷 1130-1141页

作者： Jianhong e Mu Bruce A McCarl amy Hagerman David Bessler Department of Applied economics Oregon State University Department of Agricultural economics Texas A&M University Center for epidemiology and Animal Health Veterinary Services Animal and Plant Health Inspection Service United States Department of Agriculture

This paper examines the U.S. meat demand impacts of the announced outbreaks of bovine spongiform encephalopathy（BSe） and avian influenza（AI）. Findings indicate that beef and chicken demand was negatively affected by BSe and AI disease outbreaks. Specifically, in the short run, U.S. consumers shift demand due to both outbreaks but more so due to domestic disease outbreaks than for outbreaks occurring overseas-the impact of U.S. AI outbreaks is about 0.5% for beef and the impact of U.S. BSe cases is around –0.42% for beef and 0.4% for pork, respectively. Regarding the BSe shock on meat demand, there is a high rate of beef demand adjusted from disturbance to the long-run equilibrium and a lower adjustment rate for chicken demand because of the repeated outbreaks of AI worldwide. In the long run, information related to severe, persistently recurring overseas animal disease outbreaks changes U.S. consumers＇ meat consumption patterns. Although effects of animal diseases on U.S. meat demand were statistically significant, the magnitudes were small-the impact of WHO reported human death numbers for AI is 0.005% for beef, –0.002% for pork, and –0.006% for chicken and the impact of U.S. BSe cases is 1.1% for pork and –0.7% for chicken.

关键词： spongiform avian chicken bovine encephalopathy overseas disturbance adjustment pathogenic deaths

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A case for systemic environmental analysis of cultured meat

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Journal of Integrative Agriculture 2015年第2期14卷 249-254页

作者： Carolyn S Mattick amy e Landis Braden R Allenby University of Texas School of Public Health 1200 Hermann Pressler DriveHouston TX 77030 USA School of Sustainable engineering and the Built environment Arizona State UniversityTempe AZ PO Box 875306 USA

The environmental implications of cultured meat are profound. An anticipatory life cycle assessment of cultured meat published in 2011 suggested it could have a smaller impact than agricultural meat in all categories except energy consumption. As with most technologies, cultured meat will almost certainly be accompanied by unintended consequences as well as unforeseen costs and benefits that accrue disproportionately to different stakeholders. Uncertainty associated with new engineered products cannot be completely eliminated prior to introduction, but ongoing environmental assessments of the technologies as they advance can serve to reduce unforeseen risks. Given the pace at which tissue engineering is advancing, systemic assessments of the technology will be pivotal in mitigating unintended environmental consequences.

关键词： cultured meat in vitro meat factory-grown food anticipatory life cycle assessment systemic environmental implications of emerging technologies

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