Szénhidrát-szulfonsav típusú sziálsav-mimetikumok szintézise és neuraminidáz gátló hatásuk vizsgálata = Synthesis of sulfonic acid analogues of sialic acids and investigation of their neuraminidase inhibitory effect

Előállítottuk az N-acetil-neuraminsav szulfonsav mimetikumait L-fukózból kiindulva; az egyik analogon mérsékelten gátolta a Clostridium perfringens neuramidázt. Előállítottuk a szialil Lewis X és szialil Lewis A tetraszacharidok új szulfonsav-mimetikumait különböző módszerekkel (glikozilezés 1-dezoxi-1-etoxiszulfonátometil heptulózokkal; nukleofil szubsztitúció tioacetáttal majd oxidáció). Elsőként szintetizáltunk tio-click reakcióval sziálsav-tartalmú oligoszacharidokat. Az alkin-tiol addícióval nyert, egy vagy két tio-sziálsav egységet hordozó galaktozid és laktozid származékok potenciálisan antivirális és antibakteriális hatásúak. Új típusú antikoaguláns hatású heparinoid pentaszacharid-szulfonsavakat szintetizáltunk, melyek a természetes szulfátészterek helyett bioizoszter szulfonátometil-csoportokat tartalmaznak. Előállítottunk egy heparinoid pentaszacharid-diszulfonsavat, és egy pentaszacharid-triszulfonsavat. Humán plazmán végzett in vitro vizsgálatokban a diszulfonsav kiváló antikoaguláns hatást mutatott, felülmúlva az irodalomból ismert legjobb véralvadásgátló szer hatását. Difenilmetilén-acetálok LiAlH4-AlCl3 reagenssel végrehajtott regioszelektív nyitását vizsgáltuk kinetikai és in silico módszerekkel, és javaslatot tettünk a reakció mechanizmusára. Tanulmányoztuk naftilmetilén- és antracenilmetilén-acetálok rekcióit; a naftilmetilének regioszelektív gyűrűnyitásával nyálkagomba-glikoprotein pentaszacharidok szintézisét valósítottuk meg. | Sulfonic acid mimetics of N-acetyl-neuraminic acid were prepared from L-fucose, one of them displayed a moderate neuraminidase inhibitory activity. New sulfonic acid analogues of the sialyl Lewis X and Lewis A tetrasaccharides were prepared using different methods such as glycosylation with 1-deoxy-1-sulfonatomethyl heptuloses and substitution with thioacetate followed by oxidation. Thio-click reaction was utilised for the first time to prepare sialylated oligosaccharides. The applied alkyne-thiol addition reaction resulted in galactosides and lactosides carrying one or two 2-thio-sialic acid residues, the products might possess antiviral and antibacterial activities. Novel blood-anticoagulant heparionid pentasaccharides were prepared by substituting the natural sulfate ester groups with bioisosteric sulfonatomethyl moieties. The anticoagulant activity of the prepared pentasaccharide disulfonic acid and pentasaccharide trisulfonic acid was tested in an in vitro assay using human plasma. The disulfonic acid derivative displayed higher activity than idraparinux, the best synthetic anticoagulant pentasaccharide. Kinetic and in silico studies on regioselective ring-opening reaction of diphenylmethylene acetals using LiAlH4-AlCl3 reagents were carried out to lay down the mechanism. Transformation of naphthylmethylene and anthracenylmethylene acetals of carbohydrates were investigated and applied for the synthesis of pentasaccharides of mould glycoprotein origin

Initial temperature and EoS of quark matter from direct photons

The time evolution of the quark gluon plasma created in gold-gold collisions of the Relativistic Heavy Ion Collider (RHIC) can be described by hydrodynamical models. Distribution of hadrons reflects the freeze-out state of the matter. To investigate the time evolution one needs to analyze penetrating probes, such as direct photon spectra. Distributions of low energy photons was published in 2010 by PHENIX. In this paper we analyze a 3+1 dimensional solution of relativistic hydrodynamics and calculate momentum distribution of direct photons. Using earlier fits of this model to hadronic spectra, we compare photon calculations to measurements and find that the initial temperature of the center of the fireball is at least 519+-12 MeV, while for the equation of state we get c_s= 0.36+-0.02.Comment: Talk at the VI Workshop on Particle Correlations and Femtoscopy, Kiev, September 14-18, 2010. 6 pages, 1 figure. This work was supported by the OTKA grant NK73143 and M. Csanad's Bolyai scholarshi

Szénhidrát alapú C- és CH2-szulfonsavak szintézise és biológiai vizsgálata, továbbá cukorszulfopeptidek előállítása = Synthesis and biological investigation of carbohydrate containing C- and CH2- sulfonic and that of the sugar sulfopeptides

Ötéves célkitűzésünk alatt 16 nemzetközi közleményt publikáltunk. Mindenekelőtt a szénhidrátszulfonsavak előállításának különböző lehetőségeit vizsgáltuk. Eredményesen valósítottuk meg az intra- és intermolekuláris nukleofil reakciókat. Legfontosabb célkitűzésünk, a a cukorszulfonsavak előállítására alkalmas reakciók vizsgálata, pl. az 1-tio-2-O-mezil-beta-D-glükozidok és 1-tio-2-O-mezil-alfa-D-mannozidok transzformációja 1,2-transz-D-manno- ill. glükopiranoziddá. Kiemelhető az exo-metilén csoport bevezetése és szulfonometil-csoporttá alakítása szulfit addícióval. Az izolált vegyületek konfigurációjának és konformációjának meghatározása 1H- és 13C-NMR segítségével, ill. oldat és szilárd fázisú chiroptikai módszerrel történt. Az N-acetilneuraminsav analógok szinétzisét L-fukózból kiindulva valósítottuk meg. A vegyület gyűrű-rendszere biológiai aktivitást mutat. A vegyületek hiányzó anomer protona következtében távolható NMR mérések és molekuláris számítások (QM) elengedhetetlenül szükségesek voltak. Magasabb tagszámú 3,6 elágazású arabinogalaktán oligoszacharidok (tetra és hexa) előállítását megvalósítottuk. A Mycobacterium avium 19-es szerovariáns sejtfelszíni pentaszacharidjának szintézisét a közelmúltban valósítottuk meg. A legvonzóbb eredmény a szulfonsavtartalmú heparinoid mono- és oligoszacharidok szintézise. Valamennyi építőelem alkalmas védőcsoportként kezelhető. Jelenleg 6 diszacharid egység a közeli jövőben pentaszacharidig teljesíthető. | As a result of our OTKA project, aimed, primarily, at the investigation of the possibilities for the preparation carbohydrate sulfonic acids, 16 papers were published in international journals. We realized the transformation of 1-thio-2-O-mesyl-beta-D-glucopyranosides and 1-thio-2-O-mesyl-alpha-D-mannopyranosides into 1,2-trans-D-manno- and glucopyranosides. An important result is the introduction of the exo-methylene group and its conversion into sulfonatomethyl moiety by sulfit addition. The determination of the configuration and conformation of the isolated compounds was carried out with NMR techniques, as well as by means of solution- and solid-phase chiroptical methods. The N-acetylneuraminic acid analogues were synthesized from L-fucose. The prepared compounds, carrying the demanded ring-system, showed biological activity. Due to the missing anomeric proton of such ketoses, long-range NMR coupling measurements and molecular calculatios (QM) were established. Our research group performed the preparation of 3.6-branched arabinogalactan oligosaccharides. The synthesis of the pentasaccharide of the Mycobact. avium serovar 19 was recently accomplished. Our most attractive results include those which are in connection with the sulfonatomethyl mono- and oligosaccharide analogues of heparin. The disaccharides of the required heparin-pentasaccharides have been synthesized

Introduction of a New Variable and the Problem of Complexity in Determining Impact Speeds in Vehicle–Pedestrian Accidents

Reconstruction and analysis of road traffic accidents represent an inherently complex task. This is especially true for one of the most significant accident categories, vehicle-pedestrian collisions. Forensic traffic and vehicle technical experts must determine the relevant impact speeds in virtually all cases, based on a wide variety of objective traces. The most relevant evidence and information can be obtained on-site within a limited period following the occurrence of the accident. These indispensable sources of information cannot be reproduced later or can only be reproduced to a very minimal extent. Therefore, it is essential to uncover as many traces at the accident site as possible and as soon as possible. In certain cases, the so-called rapid expert calculations may need to be performed on-site. In this paper, we seek solutions related to these rapid calculations and to facilitating the determination of speeds that play a critical role in vehicle-pedestrian accidents. The proposed approach may simplify the daily work of forensic traffic and vehicle technical experts

Age-friendly Transport: Traffic Safety for All

The elderly make up an increasing percentage of the European population and, with it, of the Hungarian population. Modern society is built around mobility. These two factors together lead to an increasing proportion of elderly drivers on the roads. Given the high proportion of people with chronic neurological conditions (stroke, Parkinson's disease, dementia), particular care should be taken to regularly check their fitness to drive. At present, there is no standardized, well-established protocol for the objective assessment of fitness to drive in the case of these diseases. Our paper discusses this matter

Modelling and Forecasting Health Expectancy

Life expectancy of a human population measures the expected (or average) remaining years of life at a given age. Life expectancy can be defined by two forms of measurement: the period and the cohort life expectancy. The period life expectancy represents the mortality conditions at a specific moment in time, in comparison to the cohort life expectancy, which depicts the life history of a specific group of individuals (born in the same year). Period life expectancies are frequently utilized when assessing and monitoring the health status of a population over time. Currently, the life expectancy of the Western world population is much greater than in prior decades. The dramatic increase over the last century is considered as one of the great achievements of modern societies. Between 1970 and 2009 the average length of life in the old EU member states increased from 68.7 to 78.0 among men and from 74.9 to 83.5 among women. Similar trends were witnessed among the elderly. Although there are many differences in the health service organization, national wealth, culture and associated individual behaviours between these countries, within a broader European perspective the upward trends are remarkably alike. In the first half of the twentieth century eradication of infectious diseases caused unprecedented improvements in mortality, particularly at young ages. As the risk of dying from infectious diseases was reduced, those saved from dying at younger ages survived to middle and older ages. A second wave of mortality improvement was achieved mainly at the adult life. Since the 1970s ischemic heart disease mortality has decreased in most Western countries contributing to the majority of the declines in age-specific death rates. It has been suggested that the decline in cardiovascular disease mortality is due to the combination of better treatment and changes in risk factors such as: lower blood pressure, reduced tobacco consumption, diets containing lower cholesterol, and increased physical activity within the population. There are of course more distal influences that contributed to the gains in overall mortality. The most important elements include increasing welfare, greater access to and better quality of health care, rising living standards and improvements in the level of education. In comparison with mortality, health is difficult to measure and estimates of population health are usuall

Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a

USP2a is a deubiquitinase responsible for stabilization of cyclin D1 – a crucial regulatorbof cell cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCAHA, inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted, both p53-expressing and p53-defective cancer types

Alterations of the Hippocampal Networks in Valproic Acid-Induced Rat Autism Model

Autism Spectrum Disorder (ASD) is one of the most frequently diagnosed neurodevelopmental disorders, characterized among others by impairments in social interactions and repetitive behavior. According to one of the leading hypotheses about its origin, ASD is caused by the imbalance of excitatory and inhibitory circuit activity. ASD-related morphological and functional changes can be observed in several brain regions i.e., in the prefrontal cortex and the hippocampus. It is well-established that prenatal valproic-acid (VPA) exposure of rats on day 12.5 leads to neurodevelopmental alterations with autism-like clinical and behavioral symptoms. The aim of this study was to investigate potential changes in the excitability of neuronal networks and individual neurons of the hippocampus elicited by prenatal VPA treatment. As there are marked sex differences in ASD, offspring of both sexes were systematically tested, using two different age groups, to elucidate eventual differences in neurodevelopment after VPA treatment. Excitatory connections and long-term synaptic plasticity as well as intrinsic excitability of CA1 pyramidal cells were examined. Pregnant female Wistar rats received saline or 500 mg/kg VPA i. p. on gestation day 12.5. Brain slices of 6-week-old and 3-month-old offspring were investigated using extra- and intracellular electrophysiological techniques. Field potential- and whole-cell patch clamp recordings were carried out to measure network excitability and single cell activity in the CA1 region hippocampus. Enhanced excitability of hippocampal networks was detected in the 6-week-old VPA-treated male rats; however, this change could not be observed in 3-month-old males. Intrinsic excitability of single neurons, however, was increased in 3-month-old males. In 6-week-old treated females, the most prominent effect of VPA was an increase in voltage sag, to a similar degree to the neurons of the older age group. In 3-month-old females, a network excitability increase could be demonstrated, in a lesser degree than in younger males. It can be concluded, that VPA treatment had diverse effects on hippocampal excitability depending on the sex and the age of the animals. We found that certain alterations manifested in 6-week-old rats were compensated later, on the other hand, other changes persisted until the age of 3 months