481 research outputs found

    Bicovariant Differential Geometry of the Quantum Group SLh(2)SL_h(2)

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    There are only two quantum group structures on the space of two by two unimodular matrices, these are the SLq(2)SL_q(2) and the SLh(2)SL_h(2) [9-13] quantum groups. One can not construct a differential geometry on SLq(2) SL_q(2), which at the same time is bicovariant, has three generators, and satisfies the Liebnitz rule. We show that such a differential geometry exists for the quantum group SLh(2)SL_h(2) and derive all of its properties

    Fuzzy sphere bimodule, ABS construction to the exact soliton solutions

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    In this paper, we set up the bi-module of the algebra A{\cal A} on fuzzy sphere. Based on the differential operators in moving frame, we generalize the ABS construction into fuzzy sphere case. The applications of ABS construction are investigated in various physical systems.Comment: Latex file without figure, 13 page

    Conversational correlates of children's acquisition of mental verbs and a theory of mind

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    The purpose of this study was to conduct a detailed examination of the ways mothers use mental verbs in conversations with three- and four-year-old children, and to link these usages to the children's developing understanding of mental verbs and a theory of mind. Sixty three- and four-year-olds, either attending preschool (PS) or not (NPS) were given tasks assessing mental verb distinctions and false belief. Their mothers' mental verb use was coded for (a) frequency, (b) type of utterance, (c) type of subordinate clause, (d) the person of the subject of the verb, and (e) the certainty of think. Within the three-year-olds, the NPS children performed significantly better on the mental verb comprehension task; moreover, compared to the PS mothers, the NPS mothers were found to use: (1) less statements and more questions, (2) less first person utterances and more second person utterances, and (3) think in its `very certain' form less often. In regression analyses, children's mental verb and false belief performance were positively predicted by maternal mental verb 1) questions, and 2) single clause utterances; the children's performance was negatively predicted by statements. These findings indicate how maternal input has the potential to promote or hinder children's understanding of the mind.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

    Creative and Stylistic Devices Employed by Children During a Storybook Narrative Task: A Cross-Cultural Study

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    Purpose: The purpose of this study was to analyze the effects of culture on the creative and stylistic features children employ when producing narratives based on wordless picture books. Method: Participants included 60 first- and second-grade African American, Latino American, and Caucasian children. A subset of narratives based on wordless picture books collected as part of a larger study was coded and analyzed for the following creative and stylistic conventions: organizational style (topic centered, linear, cyclical), dialogue (direct, indirect), reference to character relationships (nature, naming, conduct), embellishment (fantasy, suspense, conflict), and paralinguistic devices (expressive sounds, exclamatory utterances). Results: Many similarities and differences between ethnic groups were found. No significant differences were found between ethnic groups in organizational style or use of paralinguistic devices. African American children included more fantasy in their stories, Latino children named their characters more often, and Caucasian children made more references to the nature of character relationships. Conclusion: Even within the context of a highly structured narrative task based on wordless picture books, culture influences children’s production of narratives. Enhanced understanding of narrative structure, creativity, and style is necessary to provide ecologically valid narrative assessment and intervention for children from diverse cultural backgrounds

    Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations

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    The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2

    Validation of the MEDFICTS dietary questionnaire: A clinical tool to assess adherence to American Heart Association dietary fat intake guidelines

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    BACKGROUND: Dietary assessment tools are often too long, difficult to quantify, expensive to process, and largely used for research purposes. A rapid and accurate assessment of dietary fat intake is critically important in clinical decision-making regarding dietary advice for coronary risk reduction. We assessed the validity of the MEDFICTS (MF) questionnaire, a brief instrument developed to assess fat intake according to the American Heart Association (AHA) dietary "steps". METHODS: We surveyed 164 active-duty US Army personnel without known coronary artery disease at their intake interview for a primary prevention cardiac intervention trial using the Block food frequency (FFQ) and MF questionnaires. Both surveys were completed on the same intake visit and independently scored. Correlations between each tools' assessment of fat intake, the agreement in AHA step categorization of dietary quality with each tool, and the test characteristics of the MF using the FFQ as the gold standard were assessed. RESULTS: Subjects consumed a mean of 36.0 ± 13.0% of their total calories as fat, which included saturated fat consumption of 13.0 ± 0.4%. The majority of subjects (125/164; 76.2%) had a high fat (worse than AHA Step 1) diet. There were significant correlations between the MF and the FFQ for the intake of total fat (r = 0.52, P < 0.0001) and saturated fat (r = 0.52, P < 0.0001). Despite these modest correlations, the currently recommended MF cutpoints correctly identified only 29 of 125 (23.3%) high fat (worse than AHA Step 1) diets. Overall agreement for the AHA diet step between the FFQ and MF (using the previously proposed MF score cutoffs of 0–39 [AHA Step 2], 40–70 [Step 1], and >70 [high fat diet]) was negligible (kappa statistic = 0.036). The MF was accurate at the extremes of fat intake, but could not reliably identify the 3 AHA dietary classifications. Alternative MF cutpoints of <30 (Step 2), 30–50 (Step 1), and >50 (high fat diet) were highly sensitive (96%), but had low specificity (46%) for a high fat diet. ROC curve analysis identified that a MF score cutoff of 38 provided optimal sensitivity 75% and specificity 72%, and had modest agreement (kappa = 0.39, P < 0.001) with the FFQ for the identification of subjects with a high fat diet. CONCLUSIONS: The MEDFICTS questionnaire is most suitable as a tool to identify high fat diets, rather than discriminate AHA Step 1 and Step 2 diets. Currently recommended MEDFICTS cutpoints are too high, leading to overestimation of dietary quality. A cutpoint of 38 appears to be providing optimal identification of patients who do not meet AHA dietary guidelines for fat intake

    WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop

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    beta-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity2617993FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/50724-5; 2016/17469-0M.B.M. acknowledges support from the NIH (RO1-CA187799 and U24-DK116204-01). M.J.A. received financial support from NIH T32 Predoctoral Training Grants in Pharmacology (T32-GM007040-43 and T32-GM007040-42), an Initiative for Maximizing Student Diversity Grant (R25-GM055336-16), and the NIH National Cancer Institute (NCI) NRSA Predoctoral Fellowship to Promote Diversity in Health-Related Research (F31CA228289). M.P.W. received support from the Lymphoma Research Foundation (337444) and the NIH (T32-CA009156-35). Y.N. was supported by grants-in-aid from the Japan Society for the Promotion of Science (JSPS) (15KK0356 and 16K11493). T.T. was supported by the Howard Hughes Medical Institute Gilliam Fellowship for Advanced Study. M.V.G. was supported by Cancer Research UK (grants C7379/A15291 and C7379/A24639 to Mariann Bienz). The UNC Flow Cytometry Core Facility is supported in part by Cancer Center Core Support Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center, and research reported in this publication was supported by the Center for AIDS Research (award number 5P30AI050410), and the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Eshelman Institute for Innovation, Genome Canada, the Innovative Medicines Initiative (European Union [EU]/European Federation of Pharmaceutical Industries and Associations [EFPIA]) (ULTRA-DD grant no. 115766), Janssen, Merck & Company, Merck KGaA, Novartis Pharma AG, the Ontario Ministry of Economic Development and Innovation, Pfizer, the São Paulo Research Foundation (FAPESP) (2013/50724-5), Takeda, and the Wellcome Trust (106169/ZZ14/Z). R.R.R. received financial support from FAPESP (2016/17469-0). We would also like to thank Claire Strain-Damerell and Pavel Savitsky for cloning various mutants of AAK1 and BMP2K proteins that were used in the crystallization trials. Additionally, we thank Dr. Sean Conner for providing the AAK1 plasmids, Dr. Stephane Angers for kindly providing the HEK293T DVL TKO cells, and Dr. Mariann Bienz for providing comments and feedback. We would like to thank members of the Major laboratory for their feedback and expertise regarding experimental design and project directio
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