Published in No1. Ranked journal in the field of genetics. First Genome wide association study in Slovenian population performed by Slovenian scientists! We have used next-generation sequencing (NGS) approach for deep sequencing of 56 genes previously associated with Crohn disease (CD) through genome-wide association studies (GWAS) and discovered new causal rare mutations in genes NOD2/CARD15, IL23R, CARD9, IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. The assotiation between mutation and disease was confirmed in followup genotyping of 12 000 Inflammatory bowel disease patients and more than 10000 controls, icluding 250 Slovenian IBD patients and 250 Slo controls. We extended the results of successful Genome wide association study GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
COBISS.SI-ID: 15421974
We used quantum-chemical methods to study seven possible mechanisms of monoamine oxidase (MAO) inhibition by acetylenic inhibitors, considering neutral, cationic, anionic and radical mechanisms. MAO is a flavoenzyme responsible for the metabolism of the important neurotransmitters noradrenaline, serotonin and dopamine. It exists in two isoforms: MAO A and MAO B. Selective MAO A inhibitors are used in the treatment of depression, whereas selective MAO B inhibitors such as rasagiline and selegiline are used to relieve symptoms of Parkinson disease. Rasagiline and selegiline are irreversible MAO B inhibitors, each forming a covalent bond with the enzyme's flavin adenine dinucleotide (FAD) cofactor upon inhibition. Although widely used, they both exhibit numerous adverse effects. Our calculations, performed at the B3LYP/6-311++G(2d,2p)//B3LYP/6-31+G(d) level of theory, with application of the CPCM solvent reaction field with ? = 4 to mimic the polar environment, found that a polar anionic mechanism, involving deprotonation of the inhibitor molecule at the terminal acetylene carbon atom, is the most plausible. The calculated free energies of activation for rasagiline and selegiline by this mechanistic pathway are 19.9 and 23.7 kcal?mol-1, respectively, in very good agreement withexperimentally determined values of 20.8 and 21.3 kcal?mol-1,respectively. Together with additional experimental and theoretical work, the results presented here could lead to better understanding of the nature of MAO inhibition and possible design of new antiparkinsonians as improved MAO B inhibitors. Some ideas on the strategy to achieve that and perspectives for future work are also given.
COBISS.SI-ID: 4788506
Apoptosis and necroptosis are highly regulated, interconnected forms of a celldeath. The distinction between them is critical, because necroptosis may cause significant cell loss and local inflammation, whereas apoptosis is essential for tissue homeostasis. The same stimulus can induce both apoptosis and necroptosis. Both forms of a cell death were detected in various pathologies, including pathologies in the central nervous system. Astrocytes are a large, heterogeneous cell population in the central nervous system, withmany supportive, developmental functions. Although their demise may seriously impair normal functions of the central nervous system, it is still poorly understood. In this study, apoptosis and necroptosis were induced in cultured rat astrocytes by staurosporine. When a low concentration (10-7 M) ofstaurosporine was applied, a significantly increased proportion of early apoptotic cells was detected after regeneration in a staurosporine free medium. The proportion of necroptotic cells was already increased without regeneration after 3 hours of exposure to staurosporine. When a higher (10-6 M) concentration of staurosporine was applied, further significantly increasednecroptosis was detected after regeneration in a staurosporine free medium. Necroptosis was significantly reduced when RIP1 kinase was inhibited by necrostatin-1, whereas inhibition of caspases with z-vad-fmk, an irreversible pan-caspase inhibitor, did not prevent necroptosis. This report of necroptosis induced by staurosporine represents a simple approach for the in vitro induction and detection of apoptosis and necroptosis.
COBISS.SI-ID: 29083097