scholarly journals MDM2 case study: Computational protocol utilizing protein flexibility and data mining improves ligand binding mode predictions

2016 ◽  
Keyword(s):  
Data Mining ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
A Priori ◽  
Critical Role ◽  
Binding Mode ◽  
Cancer Therapies ◽  
Targeted Cancer Therapies

AbstractRecovery of the P53 tumor suppressor pathway via small molecule inhibitors of oncoprotein MDM2 highlights the critical role of computational methodologies in targeted cancer therapies. Molecular docking programs in particular, have become essential during computer-aided drug design by providing a quantitative ranking of predicted binding geometries of small ligands to proteins based on binding free energy. In this study, we found improved ligand binding mode predictions of small medicinal compounds to MDM2 based on RMSD values using AutoDock and AutoDock Vina employing protein binding site flexibility. Additional analysis suggests a data mining protocol using linear regression can isolate the particular flexible bonds necessary for future optimum docking results. The implementation of a flexible receptor protocol based on ‘a priori’ knowledge obtained from data mining will improve accuracy and reduce costs of high throughput virtual screenings of potential cancer drugs targeting MDM2.

Friends of Rose Canyon

2018 ◽  
Vol 95 (3) ◽  
pp. 2-20 ◽  
Author(s):  
Andrew Wiese
Keyword(s):  
Open Space ◽  
Critical Role ◽  
First Century ◽  
Grassroots Politics ◽  
History Of ◽  
University City ◽  
Participant Observer ◽  
The Rose

Place-based activism has played a critical role in the history of urban and environmental politics in California. This article explores the continuing significance of environmental place making to grassroots politics through a case study of Friends of Rose Canyon, an environmental group in San Diego. Based in the fast-growing University City neighborhood, Friends of Rose Canyon waged a long, successful campaign between 2002 and 2018 to prevent construction of a bridge in the Rose Canyon Open Space Park in their community. Using historical and participant observer methodologies, this study reveals how twenty-first-century California urbanites claimed and created meaningful local places and mobilized effective politics around them. It illuminates the critical role of individual activists; suggests practical, replicable strategies for community mobilization; and demonstrates the significant impact of local activism at the urban and metropolitan scales.

Case Study: The Critical Role of Sealants in the Repair of a Fluid-Applied Roofing Membrane

2015 ◽  
pp. 328-348
Author(s):  
Kyle D. Magnuson ◽  
W. Joseph Macicak ◽  
Otto C. Guedelhoefer ◽  
David M. VanDommelen
Keyword(s):  
Critical Role

scholarly journals Role of POT1 in Human Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2739 ◽  
Author(s):  
Yangxiu Wu ◽  
Rebecca C. Poulos ◽  
Roger R. Reddel
Keyword(s):  
Human Cancer ◽  
Cell Types ◽  
Cancer Therapies ◽  
Telomeric Dna ◽  
Targeted Cancer Therapies ◽  
Length Regulation ◽  
Tumor Types ◽  
Different Cell Types ◽  
Essential Subunit

Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.

scholarly journals Structural problems for reductionism

2019 ◽  
Vol 177 (11) ◽  
pp. 3571-3593
Author(s):  
Stephan Leuenberger
Keyword(s):  
A Priori ◽  
Humean Supervenience ◽  
Structural Problems ◽  
Promising Strategy ◽  
The World

AbstractUniversal reductionism—the sort of project pursued by Carnap in the Aufbau, Lewis in his campaign on behalf of Humean supervenience, Jackson in From Metaphysics to Ethics, and Chalmers in Constructing the World—aims to reduce everything to some specified base, more or less austere as it may be. In this paper, I identify two constraints that a promising strategy to argue for universal reductionism needs to satisfy: the exhaustion constraint and the chaining constraint. As a case study, I then consider Chalmers’ Constructing the World, in which a priori implication, or “scrutability”, plays the role of reduction. Chalmers first divides up the total vocabulary of our language into different families, and then argues, for each family separately, that truths involving expressions in that family are scrutable from the putative base. He does not systematically address the question whether “cross-family sentences”—sentences involving expressions from more than one family—are scrutable. I shall argue that this lacuna cannot be filled, since scrutability does not allow for the exhaustion constraint and the chaining constraint to be jointly satisfied. I further suggest that Carnap’s account, in which definability plays the role of reduction, has better prospects of meeting these constraints.

scholarly journals Individual variables with an impact on knowledge sharing: the critical role of employees’ ignorance

2015 ◽  
Vol 19 (6) ◽  
pp. 1109-1123 ◽  
Author(s):  
John Israilidis ◽  
Evangelia Siachou ◽  
Louise Cooke ◽  
Russell Lock
Keyword(s):  
Knowledge Sharing ◽  
Critical Role ◽  
Multinational Organization ◽  
Content Type ◽  
External Threats ◽  
Communication In Organizations ◽  
Organizational Ability ◽  
Individual Variables

Purpose – The purpose of this paper is to identify individual variables with an impact on knowledge sharing and explore the under-discussed construct of employees’ ignorance. This can enhance the knowledge-sharing process and facilitate the development of greater intellectual capital. Design/methodology/approach – Eighty-four dependent variables affecting knowledge sharing are analyzed and classified into 11 categories. In addition, the direct effect of employees’ ignorance on knowledge sharing is introduced and empirically investigated in a case study of a multinational organization operating within the aerospace and defense industry. Findings – The findings suggest that employees’ ignorance may negatively affect their intention to share knowledge, thus leading to poor decision-making and communication in organizations. Employees’ ignorance could also limit the organizational ability to repel external threats, implement innovation and manage future risks. Originality/value – A classification scheme based on different categories of employees’ ignorance is developed, providing tailor-made recommendations for practitioners facing different types of ill-informed organizational scenarios. Further, the need to shift the emphasis away from the management of knowledge to the management of ignorance is also an important contribution of this paper.

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