Criminal Procedure

Criminal Procedur

Criminal Procedure

Criminal Procedur

The Mechanism of Flexible Controlling as an Innovative Method in Management of Corporate Structures

У статті представлений принцип дії механізму гнучкого контролінгу як інноваційного методу управління корпоративними структурами. Розглянуто принципи застосування даного методу як інструменту ефективного управління корпоративними структурами, що дозволяють забезпечити різноманітність і гнучкість процесів управління для досягнення поставлених цілей. Розглянуто особливості контролінгу в управлінні корпоративними структурами в умовах нестабільного економічного середовища. Подано концепцію механізму контролінгу в управлінні корпоративними структурами, яка дозволяє забезпечити необхідну різноманітність процесів управління для досягнення динамічного комплексу цілей. Розглянуто особливості функціонування корпоративних структур у нестабільному ринковому оточенні. На прикладі механізму гнучкого контролінгу як способу адаптації до реалій сформованої нестабільності в економіці України представлена його здатність оперативно і тонко спрямовувати управління корпоративними структурами для прийняття правильних рішень та погодження роботи всіх підсистем підприємства.В статье представлен принцип действия механизма гибкого контроллинга как инновационного метода управления корпоративными структурами. Рассмотрены принципы применения данного метода как инструмента эффективного управления корпоративными структурами, позволяющие обеспечить разнообразие и гибкость процессов управления для достижения поставленных целей. Рассмотрены особенности контроллинга в управлении корпоративными структурами в условиях нестабильной экономической среды. Представлена концепция механизма контроллинга в управлении корпоративными структурами, которая позволяет обеспечить необходимое разнообразие процессов управления для достижения динамического комплекса целей. Рассмотрены особенности функционирования корпоративных структур в нестабильном рыночном окружении. На примере механизма гибкого контроллинга как способа адаптации к реалиям сложившейся нестабильности в экономике Украины представлена его способность оперативно и тонко направлять управление корпоративными структурами для принятия правильных решений и согласования работы всех подсистем предприятия.This article presents the principle of the mechanism controlling the flexible as an innovative method of managing corporate structures. The principles of this method as a tool for the effective management of corporate structures, allowing for variety and flexibility of management processes to achieve their goals. Features of controlling in management of corporate structures in the conditions of the unstable economic environment are considered. The concept of the mechanism of controlling in management of corporate structures which allows to provide a necessary variety of management processes for achievement of a dynamic complex of the purposes is presented. Features of functioning of corporate structures in an unstable market environment are considered. On the example of controlling a flexible mechanism as a way of adapting to the realities of the current instability in the economy of Ukraine, represented by its ability to quickly and subtly direct the management of the corporate structure to make the right decisions and coordination of all sub-systems of the enterprise

Ligand-Induced Proton Transfer and Low-Barrier Hydrogen Bond Revealed by X-ray Crystallography

Ligand binding can change the pKa of protein residues and influence enzyme catalysis. Herein, we report three sub-Angstrom resolution X-ray crystal structures of CTX-M \u3b2-lactamase, representing three stages of the enzymatic pathway, apo protein (0.79 \uc5), pre-covalent complex (0.89 \uc5), and acylation transition state analog (0.84 \uc5). The binding of a non-covalent ligand induces a proton transfer from the catalytic Ser70 to the general base Glu166, and the formation of a low-barrier hydrogen bond (LBHB) between Ser70 and Lys73. QM/MM reaction path calculations determined the proton transfer barrier between Ser70 and Lys73 to be 1.53 kcal/mol, further confirming the presence of a LBHB. This LBHB is absent in the other two structures. Our data represents the first evidence of a direct and transient LBHB stabilizing a nucleophilic serine, as hypothesized by Cleland and Kreevoy. These results have important implications for the study of enzyme mechanisms as well as protein-inhibitor interactions

2014-2015 Children\u27s Concert

https://spiral.lynn.edu/conservatory_otherseasonalconcerts/1005/thumbnail.jp

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket

Chromosome 10q26-driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD

Sterilization of Exopolysaccharides Produced by Deep-Sea Bacteria: Impact on Their Stability and Degradation

Polysaccharides are highly heat-sensitive macromolecules, so high temperature treatments are greatly destructive and cause considerable damage, such as a great decrease in both viscosity and molecular weight of the polymer. The technical feasibility of the production of exopolysaccharides by deep-sea bacteria Vibrio diabolicus and Alteromonas infernus was previously demonstrated using a bioproduct manufacturing process. The objective of this study was to determine which sterilization method, other than heat sterilization, was the most appropriate for these marine exopolysaccharides and was in accordance with bioprocess engineering requirements. Chemical sterilization using low-temperature ethylene oxide and a mixture of ionized gases (plasmas) was compared to the sterilization methods using gamma and beta radiations. The changes to both the physical and chemical properties of the sterilized exopolysaccharides were analyzed. The use of ethylene oxide can be recommended for the sterilization of polysaccharides as a weak effect on both rheological and structural properties was observed. This low-temperature gas sterilizing process is very efficient, giving a good Sterility Assurance Level (SAL), and is also well suited to large-scale compound manufacturing in the pharmaceutical industry

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases