A visegrádi országok és a 2008-as válság

Due to their geographical location and historical baackground, the countries of Visegrád offer a great opportunity of comparing their economic indices and their decisions regarding economic policies. The decade of post$socialist transition followed by a relatively favourable economic environment shows dissimilar tendencies in terms of certain macroeconomic indices. The employment, the incurring debts of the state and the private sector, and the data regarding the level of redistribution of the state all appear in the economy's power, in which Hungary’s fallback is clearly observable. The high level of external and internal national debt and the effect of spending on the consumption of the private sector passed soon, and made Hungary vulnerable to external shocks. Naturally, the aforementioned facts influenced the possible answers given to the crisis of 2008, the applicable fiscal and monetary political instruments and it is constricting the originally narrow margin of the economic policies up to this day

A gyermek 4 (1910) 05

A gyermek A Magyar Gyermektanulmányi Társaság közlönye 4. évfolyam, 04. szám Budapest, 1910. A folyóirat 1908-ig a Gyermekvédelmi lap mellékleteként, 1909-től mint önálló lap jelent meg

Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons

Aging contributes to cellular stress and neurodegeneration. Our understanding is limited regarding the tissue-restricted mechanisms providing protection in post-mitotic cells throughout life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric dimethyl arginines (ADMA) and the presence of this posttranslational modification provides protection against environmental stress. We identify Protein aRginine MethylTransferase 8 (PRMT8) as a tissue-restricted enzyme responsible for proper ADMA level in post-mitotic neurons. Male PRMT8 knockout mice display decreased muscle strength with aging due to premature destabilization of neuromuscular junctions. Mechanistically, inhibition of methyltransferase activity or loss of PRMT8 results in accumulation of unrepaired DNA double-stranded breaks and decrease in the CREB1 level. As a consequence, expression of CREB1-mediated pro-survival and regeneration-associated immediate early genes are dysregulated in aging PRMT8 knockout mice. The uncovered role of PRMT8 represents a novel mechanism of stress tolerance in long-lived post-mitotic neurons and identifies PRMT8 as a tissue-specific therapeutic target in the prevention of motoneuron degeneration.SIGNIFICANCE STATEMENTWhile most of the cells in our body have a very short lifespan, post-mitotic neurons must survive for many decades. Longevity of a cell within the organism depends on its ability to properly regulate signaling pathways that counteract perturbations, such as DNA damage, oxidative stress or protein misfolding. Here we provide evidence that tissue-specific regulators of stress tolerance exist in post-mitotic neurons. Specifically, we identify Protein Arginine Methyltransferase 8 (PRMT8) as a cell-type restricted arginine methyltransferase in spinal cord motoneurons. PRMT8-dependent arginine methylationis required for neuroprotection against age-related increased of cellular stress. Tissue-restricted expression and the enzymatic activity of PRMT8 make it an attractive target for drug development to delay the onset of neurodegenerative disorders

4-Aryl-3-arylsulfonyl-quinolines as negative allosteric modulators of metabotropic GluR5 receptors:From HTS hit to development candidate

High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability. One of the most promising compounds (3), showing excellent in vivo efficacy, was selected for preclinical development and subsequent phase I clinical studies

The influence of 5-HT2A activity on a 5-HT2C specific in vivo assay used for early identification of multiple acting SERT and 5-HT2C receptor ligands

As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1- phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2- aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed