scholarly journals Promiscuity of inhibitors of human protein kinases at varying data confidence levels and test frequencies

RSC Advances ◽  
2017 ◽  
Vol 7 (65) ◽  
pp. 41265-41271 ◽  
Author(s):  
Dagmar Stumpfe ◽  
Annachiara Tinivella ◽  
Giulio Rastelli ◽  
Jürgen Bajorath
Keyword(s):  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Human Protein ◽  
Confidence Levels ◽  
The One ◽  
The Right

Kinase inhibitors from screening data. Shown are two analogs that were tested against 10 (left) and 13 (right) different kinases. The inhibitor on the left was active against a single kinase and the one on the right against three kinases.

scholarly journals An optimal set of inhibitors for Reverse Engineering via Kinase Regularization

2020 ◽  
Author(s):  
Scott Rata ◽  
Jonathan Scott Gruver ◽  
Natalia Trikoz ◽  
Alexander Lukyanov ◽  
Janelle Vultaggio ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Human Protein ◽  
Cellular Phenotype ◽  
Migration Assay ◽  
Machine Learning Methods ◽  
Optimal Subset ◽  
Optimal Set

AbstractWe present a comprehensive resource of 257 kinase inhibitor profiles against 365 human protein kinases using gold-standard kinase activity assays. We show the utility of this dataset with an improved version of Kinome Regularization (KiR) to deconvolve protein kinases involved in a cellular phenotype. We assayed protein kinase inhibitors against more than 70% of the human protein kinome and chose an optimal subset of 58 inhibitors to assay at ten doses across four orders of magnitude. We demonstrate the effectiveness of KiR to identify key kinases by using a quantitative cell migration assay and updated machine learning methods. This approach can be widely applied to biological problems for which a quantitative phenotype can be measured and which can be perturbed with our set of kinase inhibitors.

Mechanisms of Resource Curse and Economic Policy

2007 ◽  
pp. 4-27 ◽  
Author(s):  
V. Polterovich ◽  
V. Popov ◽  
A. Tonis
Keyword(s):  
Real Exchange Rates ◽  
Resource Curse ◽  
Budget Deficits ◽  
Resource Abundance ◽  
Fuel Prices ◽  
Use Of Resources ◽  
Resource Wealth ◽  
The One ◽  
The Right ◽  
Rich Countries

This paper compares various mechanisms of resource curse leading to a potentially inefficient use of resources; it is demonstrated that each of these mechanisms is associated with market imperfections and can be "corrected" with appropriate government policies. Empirical evidence seems to suggest that resource abundant countries have on average lower budget deficits and inflation, and higher foreign exchange reserves. Besides, lower domestic fuel prices that are typical for resource rich countries have a positive effect on long-term growth even though they are associated with losses resulting from higher energy consumption. On top of that resource abundance allows to reduce income inequalities. So, on the one hand, resource wealth turns out to be conducive to growth, especially in countries with strong institutions. However, on the other hand, resource abundance leads to corruption of institutions and to overvalued real exchange rates. On balance, there is no solid evidence that resource abundant countries grow more slowly than the others, but there is evidence that they grow more slowly than could have grown with the right policies and institutions.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

Challenges of Media Education Standards in Georgia

2017 ◽  
Vol 2 (2) ◽  
Author(s):  
Marine Vekua
Keyword(s):  
Working Conditions ◽  
Teaching Methods ◽  
International Standards ◽  
The Other ◽  
Historical Background ◽  
Journalism Education ◽  
Education Standards ◽  
Modern Media ◽  
The One ◽  
The Right

The main goal of this research is to determine whether the journalism education of the leading media schools inGeorgia is adequate to modern media market’s demands and challenges. The right answer to this main questionwas found after analyzing Georgian media market’s demands, on the one hand, and, on the other hand, differentaspects of journalism education in Georgia: the historical background, development trends, evaluation ofeducational programs and curricula designs, reflection of international standards in teaching methods, studyingand working conditions.

The Taubman/Golandsky Approach to the Violin

Public Voices ◽  
2016 ◽  
Vol 12 (2) ◽  
pp. 7
Author(s):  
Sophie Till
Keyword(s):  
The Other ◽  
Technical Approach ◽  
Piano Technique ◽  
Pedagogical Approach ◽  
New Developments ◽  
Body Of Knowledge ◽  
Music Making ◽  
Helping Others ◽  
The One ◽  
The Right

Three years ago Sophie Till started working with pianist Edna Golandsky, the leading exponent of the Taubman Piano Technique, an internationally acclaimed approach that is well known to pianists, on the one hand, for allowing pianists to attain a phenomenal level of virtuosity and on the other, for solving very serious piano-related injuries. Till, a violinist, quickly realized that here was a unique technical approach that could not only identify and itemize the minute movements that underlie a virtuoso technique but could show how these movements interact and go into music making at the highest level. Furthermore, through the work of the Golandsky Institute, she saw a pedagogical approach that had been developed to a remarkable depth and level of clarity. It was an approach that had the power to communicate in a way she had never seen before, despite her own first class violin training from the earliest age. While the geography and “look” on the violin are different from the piano, the laws governing coordinate motion specifically in playing the instrument are the same for pianists and violinists. As a result of Till’s work translating the technique for violin, a new pedagogical approach for violinists of all ages is emerging; the Taubman/Golandsky Approach to the Violin. In reflecting on these new developments, Edna Golandsky wrote, “I have been working with the Taubman Approach for more than 30 years and have worked regularly with other instrumentalists. However, Sophie Till was the first violinist who asked me to teach her with the same depth that I do with pianists. With her conceptual and intellectual agility as well as complete dedication to helping others, she has been the perfect partner to translate this body of knowledge for violinists. Through this collaboration, Sophie is helping develop a new ‘language’ for violinist that will prevent future problems, solve present ones and start beginners on the right road to becoming the best they can be. The implications of this new work for violinists are enormous.”

Freedom of Expression versus Privacy and the Right to Reputation

2017 ◽  
Author(s):  
Dirk Voorhoof
Keyword(s):  
Public Interest ◽  
Freedom Of Expression ◽  
Media Freedom ◽  
Investigative Journalism ◽  
The Public ◽  
The Right Of Privacy ◽  
The One ◽  
Grand Chamber ◽  
The Right ◽  
The Impact

The normative perspective of this chapter is how to guarantee respect for the fundamental values of freedom of expression and journalistic reporting on matters of public interest in cases where a (public) person claims protection of his or her right to reputation. First it explains why there is an increasing number and expanding potential of conflicts between the right to freedom of expression and media freedom (Article 10 ECHR), on the one hand, and the right of privacy and the right to protection of reputation (Article 8 ECHR), on the other. In addressing and analysing the European Court’s balancing approach in this domain, the characteristics and the impact of the seminal 2012 Grand Chamber judgment in Axel Springer AG v. Germany (no. 1) are identified and explained. On the basis of the analysis of the Court’s subsequent jurisprudence in defamation cases it evaluates whether this case law preserves the public watchdog-function of media, investigative journalism and NGOs reporting on matters of public interest, but tarnishing the reputation of public figures.

scholarly journals MAPPING AND ENHANCING DESIGN STUDIES WITH PSI META-THEORETIC DESIGN FRAMEWORK

2021 ◽  
Vol 1 ◽  
pp. 2007-2016
Author(s):  
Yoram Reich ◽  
Eswaran Subrahmanian
Keyword(s):  
Design Research ◽  
The Other ◽  
Design Studies ◽  
Abstraction Level ◽  
Follow Up Studies ◽  
The One ◽  
The Right ◽  
Abstract Framework ◽  
Tools And Methods

AbstractDesign research as a field has been studied from diverse perspectives starting from product inception to their disposal. The product of these studies includes knowledge, tools, methods, processes, frameworks, approaches, and theories. The contexts of these studies are innumerable. The unit of these studies varies from individuals to organizations, using a variety of theoretical tools and methods that have fragmented the field, making it difficult to understand the map of this corpus of knowledge across this diversity.In this paper, we propose a model-based approach that on the one hand, does not delve into the details of the design object itself, but on the other hand, unifies the description of design problem at another abstraction level. The use of this abstract framework allows for describing and comparing underlying models of published design studies using the same language to place them in the right context in which design takes place and to enable to inter-relate them, to understand the wholes and the parts of design studies.Patterns of successful studies could be generated and used by researchers to improve the design of new studies, understand the outcome of existing studies, and plan follow-up studies.

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

Filippov solutions of vector Dirichlet problems

2020 ◽  
Vol 70 (2) ◽  
pp. 401-416
Author(s):  
Hana Machů
Keyword(s):  
Differential Equations ◽  
The State ◽  
State Variables ◽  
Dirichlet Problems ◽  
Filippov Solutions ◽  
Natural Notion ◽  
Growth Restrictions ◽  
The One ◽  
The Right ◽  
Effective Growth

Abstract If in the right-hand sides of given differential equations occur discontinuities in the state variables, then the natural notion of a solution is the one in the sense of Filippov. In our paper, we will consider this type of solutions for vector Dirichlet problems. The obtained theorems deal with the existence and localization of Filippov solutions, under effective growth restrictions. Two illustrative examples are supplied.

The State Policy towards the Homeless in Moldova between the ‘Left Hand’ and the ‘Right Hand’. The Case of Chișinău Shelter

Südosteuropa ◽  
2019 ◽  
Vol 67 (2) ◽  
pp. 175-195
Author(s):  
Petru Negură
Keyword(s):  
Homeless People ◽  
Severe Disabilities ◽  
The State ◽  
Small Scale ◽  
Left Hand ◽  
Right Hand ◽  
Binary Approach ◽  
The One ◽  
The Right ◽  
Depth Interviews

Abstract The Centre for the Homeless in Chișinău embodies on a small scale the recent evolution of state policies towards the homeless in Moldova (a post-Soviet state). This institution applies the binary approach of the state, namely the ‘left hand’ and the ‘right hand’, towards marginalised people. On the one hand, the institution provides accommodation, food, and primary social, legal assistance and medical care. On the other hand, the Shelter personnel impose a series of disciplinary constraints over the users. The Shelter also operates a differentiation of the users according to two categories: the ‘recoverable’ and those deemed ‘irrecoverable’ (persons with severe disabilities, people with addictions). The personnel representing the ‘left hand’ (or ‘soft-line’) regularly negotiate with the employees representing the ‘right hand’ (‘hard-line’) of the institution to promote a milder and a more humanistic approach towards the users. This article relies on multi-method research including descriptive statistical analysis with biographical records of 810 subjects, a thematic analysis of in-depth interviews with homeless people (N = 65), people at risk of homelessness (N = 5), professionals (N = 20) and one ethnography of the Shelter.

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