Targeting histone deacetylases for the treatment of immune, endocrine and metabolic disorders

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as histone acetyltransferases or HATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The proinflammatory environment is increasingly being recognised as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential & current development of histone deacetylases for the treatment of diseases for which a proinflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the proinflammatory environment. © 2009 Bentham Science Publishers Ltd.

Chlorzoxazone, an SK-type potassium channel activator used in humans, reduces excessive alcohol intake in rats

Background Alcoholism imposes a tremendous social and economic burden. There are relatively few pharmacological treatments for alcoholism, with only moderate efficacy, and there is considerable interest in identifying additional therapeutic options. Alcohol exposure alters SK-type potassium channel (SK) function in limbic brain regions. Thus, positive SK modulators such as chlorzoxazone (CZX), a US Food and Drug Administration–approved centrally acting myorelaxant, might enhance SK function and decrease neuronal activity, resulting in reduced alcohol intake. Methods We examined whether CZX reduced alcohol consumption under two-bottle choice (20% alcohol and water) in rats with intermittent access to alcohol (IAA) or continuous access to alcohol (CAA). In addition, we used ex vivo electrophysiology to determine whether SK inhibition and activation can alter firing of nucleus accumbens (NAcb) core medium spiny neurons. Results Chlorzoxazone significantly and dose-dependently decreased alcohol but not water intake in IAA rats, with no effects in CAA rats. Chlorzoxazone also reduced alcohol preference in IAA but not CAA rats and reduced the tendency for rapid initial alcohol consumption in IAA rats. Chlorzoxazone reduction of IAA drinking was not explained by locomotor effects. Finally, NAcb core neurons ex vivo showed enhanced firing, reduced SK regulation of firing, and greater CZX inhibition of firing in IAA versus CAA rats. Conclusions The potent CZX-induced reduction of excessive IAA alcohol intake, with no effect on the more moderate intake in CAA rats, might reflect the greater CZX reduction in IAA NAcb core firing observed ex vivo. Thus, CZX could represent a novel and immediately accessible pharmacotherapeutic intervention for human alcoholism. Key Words: Alcohol intake; intermittent; neuro-adaptation; nucleus accumbens; SK potassium channel

Plan zemelʻnogo uchastka poselka Ėrstmaĭsk N 8 Leninskogo fonda

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Achieving SK Capacity in the Source Model: When Must All Terminals Talk?

In this paper, we address the problem of characterizing the instances of the multiterminal source model of Csiszar and Narayan in which communication from all terminals is needed for establishing a secret key of maximum rate. We give an information-theoretic sufficient condition for identifying such instances. We believe that our sufficient condition is in fact an exact characterization, but we are only able to prove this in the case of the three-terminal source model.

Struktura fizyczna gruntu, zawartość substancji organicznej oraz skład chemiczny gleb w podłożach 21 stanowisk zieleni miejskiej na terenie Poznania. Część III. Zawartość makroelementów: N, P, K, S, Ca i Mg

This article is a continuation of a four-piece work describing the condition of soil in what has been broadly defined as central Poznań. This article presents the content of active forms of six chemical elements which tend to be absorbed by plants in biggest quantities. Relations between these chemical elements are discussed and indications are made of how to counteract the negative effects of deficits as well as overdoses of specific chemical elements in the substrate.

Struktura fizyczna gruntu, zawartość substancji organicznej oraz skład chemiczny gleb w podłożach 21 stanowisk zieleni miejskiej na terenie Poznania. Część IV. Zawartość mikroelementów: Cl, Fe, Mn, Zn, Cu, B oraz Na, Pb i Cd. Wskaźnik zasolenia EC

This article presents the physical structure of the land, organic substances content and the chemical composition of soil comprising subsoil of 21 urban greenery locations in the city of Poznań. As they tend to be commonly underestimated, they have also been presented with view to their vital functions in plants’ life processes. The analysed microelements are referred to their levels, the so-called geo-chemical background of Polish soils and the limit values for field soils with medium levels of nutrients.

Struktura fizyczna gruntu, zawartość substancji organicznej oraz skład chemiczny gleb w podłożach 21 stanowisk zieleni miejskiej na terenie Poznania. Część I. Struktura fizyczna gruntu

This article is the first one in the series of four publications describing the condition of soil environment in the area of broadly understood centre of Poznań. The paper presents the results of studies into a ph ph ph ysical structure of the soil collected around horse chestnuts (Aesculus hippocastanum), growing in various habitats in 21 locations in the area of Poznań. In the majority of cases, 75 per cent of them, the obtained data point to a deficient ph ph ysical structure of subsoils. Only in five cases, out of a general number of 21 locations, the roots of the trees developed in soil conditions that were favourable for the plants, and which enabled them the retention of precipitation water, oxygention of rhizosph ph ere and accumulation of humus.

Próba zastosowania lotniczych termowizyjnych obrazów wideo do wykrywania miejsc nielegalnego składowania odpadów zwierzęcych

Access to the remote sensing data was increasing in Poland since 1989. This procccess had stimulating impact on scientific research in the scope of changes in the environment. Special attention should be given to the thermal imagery methods because of its information potential. Presented paper discusses the possibilities of using information from thermal images for detecting of places of illegal dumping of animal waste in the ground. On the basis of earlier survey and gathered data draft fl ight plan was created, covering the sorroundings of Śmiłowo (around 30 sq km). Theoretical thesis for the subject was an assumption that all disturbances of the ground and soil structure should give visible representation in both thermal and visible images. Moreover the process of decay of animal tissues should be the source of heat, which can be observed through thermal sensor. Several places of potential dumping of animal waste were selected. For detailed ground verifi cation eight of them were chosen. In these location geological drillings were performed and than analysis of the samples. Thermovision is a method with great potential for the monitoing of the environment, but its effectiveness depends on the access to another sources of geoinformation.

Assessing non-market benefits of seagrass restoration in the Gulf of Gdańsk

Seagrass meadows (Zostera marina) are an important ecosystem in the coastal environment of the Baltic Sea. This study employs a discrete choice experiment to value a set of non-market benefits provided by seagrass meadows in the Gulf of Gdańsk, Poland. The benefits valued in this study are a reduction of filamentous algae in the water and on the beach; access to seagrass meadows for boaters and divers; and improved water clarity. Results show significant willingness to pay for each attribute and differences of value estimates across different groups of survey respondents. It is discussed how to link choice attributes and estimated values with established ecosystem benefit categories in order to facilitate value transfer.

SK-HEP cells and lentiviral vector for production of human recombinant factor VIII

Hemophilia A is caused by a deficiency in coagulation factor VIII. Recombinant factor VIII can be used as an alternative although it is unavailable for most patients. Here, we describe the production of a human recombinant B-domain-deleted FVIII (rBDDFVIII) by the human cell line SK-HEP-1, modified by a lentiviral vector rBDDFVIII was produced by recombinant SK-HEP cells (rSK-HEP) at 1.5-2.1 IU/10(6) in 24 h. The recombinant factor had increased in vitro stability when compared to commercial pdFVIII. The functionality of rBDDFVIII was shown by its biological activity and by tail-clip challenge in hemophilia A mice. The rSK-HEP cells grew in a scalable system and produced active rBDDFVIII, indicating that this platform production can be optimized to meet the commercial production scale needs.

Increased cytotoxicity of cisplatin in SK-MEL 28 melanoma cells upon down-regulation of melanoma inhibitor of apoptosis protein

BACKGROUND: Malignant melanoma is a highly metastatic cutaneous cancer and typically refractory to chemotherapy. Deregulated apoptosis has been identified as a major cause of cancer drug resistance, and upregulated expression of the inhibitor of apoptosis protein melanom, an inhibitor of apoptosis (ML-IAP) is frequent in melanoma. METHODS: Based on the conclusion that ML-IAP expression contributes to a malignant phenotype, we down-regulated the ML-IAP mRNA using sequence optimized antisense oligonucleotides. RESULTS: As measured by real-time PCR, oligonucleotides M706 and M711 inhibited ML-IAP mRNA expression by 47% and 52%, respectively in the highly metastatic and drug resistant SK-MEL28 cell line. Oligonucleotide M706, which was previously evaluated in G361 cells as the most efficient inhibitor of ML-IAP expression, was chosen to compare cell viability and drug sensitivity of these two melanoma cell lines with different p53 functionality. Protein expression was reduced by oligonucleotide M706 to 49% of the normal level and resulted in a dose-dependent specific reduction of cell viability with a maximum of 39% at 600 nM. Typical morphological changes showed that loss of viability was mainly due to cell death. In combination experiments, the use of oligonucleotide M706 resulted in a two-fold increase of cisplatin cytotoxicity at different concentrations of oligonucleotide and cisplatin (P<0.05). This is in line with our previous findings in G361 melanoma cell line, in which oligonucleotide M706 caused a 3-fold increase in cisplatin cytotoxicity. CONCLUSION: Our data suggest the use of ML-IAP antisense oligonucleotides to overcome drug resistance in metastatic melanoma, in spite of its p53 status.

Architektura a ideologie. Výchovné instituce Adolfa Hitlera v protektorátu Čechy a Morava a v Říšské župě Sudety

This article examines the architecture of the Nazi regime in two occupied cities of Czechoslovakia, Praha/Prag and Jihlava/Iglau (the latter being one of the traditionally German-speaking island in the bohemia country), and focuses specifically on the process by which Hitler youth organisations (Hitlerjugend) in case of ‘education’ and indoctrination of youth were or were not successfully established in these cities. As comparison, he takes the political-administrative centres of the Sudeten Reichsgau, Ústí/Aussig, Opava/Troppau, Karlovy Vary/Karlsbad and Liberec/Reichenberg. Drawing on Czech and German archive materials, the extensive body of modern analytical literature, and propagandist literature from the period studied, the author examines the extent to which architecture served as a projection screen for Fascist propaganda in the Occupied Eastern territories. He describes the role played by the Reichsstelle für Raumordnung and shows how the Reich’s propagandist objectives came to be reflected in a high specific typology and stylistic lexicon/configuration for the architecture of Hitler youth hostels and homes He examines the process by which these organisations were powerful implanted into the space of occupied Czechoslovakia (and Sudeten) too, a topic that has not yet been addressed in (art) history too. The building projects developed for the Protectorate (published here for the first time) and managed by the Reich’s Hitler Youth Leadership in Berlin (Kulturamt, Reichsjugendführung, RJF, Abteilung HJ) reveal the ties that existed between the construction authorities in the Reich and the Protectorate, including the Planning Committee for the City of Prague. The author asks how many German and Czech architects participated for their own profit in the Nazi system, and for future research raises the hitherto taboo question of guilt and collaboration with the Nazis and the perception of this phenomenon in art history, i.e. the measure of active cooperation of not just German but also Czech architects who contributed to the planning and implementation of projects and thereby unequivocally had a hand in consolidating the totalitarian regime and de facto in the forced „Germanification” of their own people under occupation.