Strategies To Design Selective Histone Deacetylase Inhibitors

This review classifies drug-design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class-specific sub-pockets: the side-pocket-, lower-pocket- and foot-pocket-targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.     

Holistic data-driven requirements elicitation in the big data era

Digital transformation stimulates continuous generation of large amounts of digital data, both in organizations and in society at large. As a consequence, there have been growing efforts in the Requirements Engineering community to consider digital data as sources for requirements acquisition, in addition to human stakeholders. The volume, velocity and variety of the data make requirements discovery increasingly dynamic, but also unstructured and complex, which current elicitation methods are unable to consider and manage in a systematic and efficient manner. We propose a framework, in the form of a conceptual metamodel and a method, for continuous and automated acquisition, analysis and aggregation of heterogeneous digital sources that aims to support data-driven requirements elicitation and management. The usability of the framework is partially validated by an in-depth case study from the business sector of video game development.

     

Pepper to fall: a perception method for sweet pepper robotic harvesting

Intelligent Service Robotics - In this paper we propose a robotic system for picking peppers in a structured robotic greenhouse environment. A commercially available robotic manipulator is equipped...     

Lipids and Antiplatelet Therapy: Important Considerations and Future Perspectives

Lipids play an essential role in platelet functions. It is known that polyunsaturated fatty acids play a role in increasing platelet reactivity and that the prothrombotic phenotype plays a crucial role in the occurrence of major adverse cardiovascular events. The ongoing increase in cardiovascular diseases’ incidence emphasizes the importance of research linking lipids and platelet function. In particular, the rebound phenomenon that accompanies discontinuation of clopidogrel in patients receiving dual antiplatelet therapy has been associated with changes in the lipid profile. Our many years of research underline the importance of reduced HDL values for the risk of such a rebound effect and the occurrence of thromboembolic events. Lipids are otherwise a heterogeneous group of molecules, and their signaling molecules are not deposited but formed “on-demand” in the cell. On the other hand, exosomes transmit lipid signals between cells, and the profile of such changes can be monitored by lipidomics. Changes in the lipid profile are organ-specific and may indicate new drug action targets.     

In-situ immobilization of Sr radioactive isotope using nanocrystalline hydroxyapatite

Hydroxyapatite was used as the inert matrix for in-situ immobilization of strontium (Sr) radioactive isotopes at room temperature. A nano-emulsification method was applied to synthesize Sr-substituted calcium hydroxyapatite (Ca_1?xSr_x)₁₀(PO₄)₆(OH)₂. The concentration of incorporated Sr was in the range of 0 ≤ x ≤ 1. Immobilization of Sr was evaluated using a stable isotope instead of radioactive isotope. The effect of strontium concentration on the crystal structure was studied and the results have showed that in the whole concentration range, Sr forms solid solutions with the host hydroxyapatite crystal structure. Powders comprised of nanometre sized particles were obtained and their properties, such as crystallite and particle size, changes in lattice parameters as function of dopant content and thermal stability, were further examined. It was found that the crystal structure of obtained powders is thermally stable at high temperatures. No secondary phases were formed in as-prepared powders or during calcination. The results in this study showed that nano-emulsion strategy provides a simple pathway for synthesis of a single-phase Sr-substituted hydroxyapatite, which can be used for immobilization of Sr radioactive isotopes.     

An Overview,Advantages and Therapeutic Potential of Nonpeptide Positive Allosteric Modulators of Glucagon-Like Peptide-1 Receptor

Due to uncomfortable injection regimens of peptidic agonists of glucagon-like peptide-1 receptor (GLP-1R), orally available nonpeptide positive allosteric modulators (PAMs) of GLP-1Rs are foreseen as the possible future mainstream therapy for type 2 diabetes. Herein, current GLP-1R PAMs are reviewed. Based on the effectiveness and in silico predicted physicochemical properties, pharmacokinetics, and toxicity, possible candidates for further development as oral drugs were selected. The suggestion is that GLP-1R PAMs might be used orally alone or in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors, which could offer an optimal treatment option next to metformin monotherapy in type 2 diabetes mellitus, or in a wider spectrum of indications. Quercetin acts as a GLP-1R PAM and DPP-4 inhibitor, and therefore, might be considered as a pioneering agent with a dual mechanism of action, in terms of GLP-1R positive allosteric modulation and DPP-4 inhibition for potentiating GLP-1 dependent effects.