Study of Alpha Mangostin as a Chemoprotective Agent for Breast Cancer via Activation of the P53 Pathway

Breast carcinoma is the most frequently diagnosed cancer among women and causes over 400,000 deaths each year worldwide. Current treatments such as chemotherapy are not selective for cancerous tissues but are destructive to normal tissues as well. This causes a range of side effects including pain, nausea, hair loss, weakness, and more. Inactivation of p53 is a very common mutation within human cancer cells. The ability to activate the p53 pathway, which protects cells from tumor formation, is lost in 50% of cancers. Due to the prevalence of this mutation, p53 is a uniquely valuable target for applied research. Alpha mangostin is an extract from a southeast Asian fruit, Garcinia mangostana. It has potential to be an effective p53 activator in which the small molecule disrupts the binding of p53 to MDM2, a negative regulator, inducing the p53 cascade, which results in cell cycle arrest for low level stressors. This protects the cells from paclitaxel, a chemotherapy agent that only kills actively dividing cells. Here, we hypothesized that alpha mangostin protects wild-type, but not p53 (-/- ), MCF10A breast cancer cells from the chemotherapeutic agent paclitaxel. When MCF10A wild-type cells were cotreated with alpha mangostin and paclitaxel, alpha mangostin exhibited a protective effect on the cells. However, when MCF10A P53 knockout cells were treated with alpha mangostin, cell viability decreased, indicating a loss of protective effect in the p53 distressed cancer cells. These results further support treatments that target chemoprotection via p53 pathway in wild-type cells, and the use of alpha mangostin warrants further study

Study of Alpha Mangostin as a Chemoprotective Agent for Breast Cancer via Activation of the P53 Pathway

Breast carcinoma is the most frequently diagnosed cancer among women and causes over 400,000 deaths each year worldwide. Current treatments such as chemotherapy are not selective for cancerous tissues but are destructive to normal tissues as well. This causes a range of side effects including pain, nausea, hair loss, weakness, and more. Inactivation of p53 is a very common mutation within human cancer cells. The ability to activate the p53 pathway, which protects cells from tumor formation, is lost in 50% of cancers. Due to the prevalence of this mutation, p53 is a uniquely valuable target for applied research. Alpha mangostin is an extract from a southeast Asian fruit, Garcinia mangostana. It has potential to be an effective p53 activator in which the small molecule disrupts the binding of p53 to MDM2, a negative regulator, inducing the p53 cascade, which results in cell cycle arrest for low level stressors. This protects the cells from paclitaxel, a chemotherapy agent that only kills actively dividing cells. Here, we hypothesized that alpha mangostin protects wild-type, but not p53 (-/- ), MCF10A breast cancer cells from the chemotherapeutic agent paclitaxel. When MCF10A wild-type cells were cotreated with alpha mangostin and paclitaxel, alpha mangostin exhibited a protective effect on the cells. However, when MCF10A P53 knockout cells were treated with alpha mangostin, cell viability decreased, indicating a loss of protective effect in the p53 distressed cancer cells. These results further support treatments that target chemoprotection via p53 pathway in wild-type cells, and the use of alpha mangostin warrants further study

N348 en de Douwelerkolk te Deventer; ecologie en gebruik na aanleg van de N348

De N348 is de verbinding Zutphen, Deventer en Raalte. Voor het gedeelte Deventer-Wesepe is de aanleg thans in voorbereiding. Dit gedeelte loopt langs het gebied van de Douwelerkolk in Deventer. Voor het gedeelte Zutphen-Deventer-Raalte is door Rijkswaterstaat eind jaren tachtig reeds een milieueffectrapportage (MER) opgesteld. Ondertussen is het tracé een provinciale aangelegenheid geworden. Alterra heeft voor de MER aanvullend onderzoek uitgevoerd naar de effecten van de N348 op de Douwelerkolk en de nabijgelegen woonwijken. Tevens werden in de opdracht de autonome ontwikkelingen van de verstedelijking meegenomen en zijn mitigerende maatregelen voorgesteld om de effecten op natuur, beleving en gebruik van de Douwelerkolk te verzachten

Contribution to fusion research from IAEA coordinated research projects and joint experiments

The paper presents objectives and activities of IAEA Coordinated Research Projects 'Conceptual development of steady-state compact fusion neutron sources' and 'Utilisation of a network of small magnetic confinement fusion devices for mainstream fusion research'. The background and main projects of the CRP on FNS are described in detail, as this is a new activity at IAEA. Recent activities of the second CRP, which continues activities of previous CRPs, are overviewed

Formation of convective cells in the scrape-off layer of the CASTOR tokamak

Understanding of the scrape-off layer (SOL) physics in tokamaks requires diagnostics with sufficient temporal and spatial resolution. This contribution describes results of experiments performed in the SOL of the CASTOR tokamak (R=40 cm, a = 6 cm) by means of a ring of 124 Langmuir probes surrounding the whole poloidal cross section. The individual probes measure either the ion saturation current of the floating potential with the spatial resolution up to 3 mm. Experiments are performed in a particular magnetic configuration, characterized by a long parallel connection length in the SOL, L_par ~q2piR. We report on measurements in discharges, where the edge electric field is modified by inserting a biased electrode into the edge plasma. In particular, a complex picture is observed, if the biased electrode is located inside the SOL. The poloidal distribution of the floating potential appears to be strongly non-uniform at biasing. The peaks of potential are observed at particular poloidal angles. This is interpreted as formation of a biased flux tube, which emanates from the electrode along the magnetic field lines and snakes q times around the torus. The resulting electric field in the SOL is 2-dimensional, having the radial as well as the poloidal component. It is demonstrated that the poloidal electric field E_pol convects the edge plasma radially due to the E_pol x B_T drift either inward or outward depending on its sign. The convective particle flux is by two orders of magnitude larger than the fluctuation-induced one and consequently dominates.Comment: 12th International Congress on Plasma Physics, 25-29 October 2004, Nice (France

Prokaryotic homologs of Argonaute proteins are predicted to function as key components of a novel system of defense against mobile genetic elements

<p>Abstract</p> <p>Background</p> <p>In eukaryotes, RNA interference (RNAi) is a major mechanism of defense against viruses and transposable elements as well of regulating translation of endogenous mRNAs. The RNAi systems recognize the target RNA molecules via small guide RNAs that are completely or partially complementary to a region of the target. Key components of the RNAi systems are proteins of the Argonaute-PIWI family some of which function as slicers, the nucleases that cleave the target RNA that is base-paired to a guide RNA. Numerous prokaryotes possess the CRISPR-associated system (CASS) of defense against phages and plasmids that is, in part, mechanistically analogous but not homologous to eukaryotic RNAi systems. Many prokaryotes also encode homologs of Argonaute-PIWI proteins but their functions remain unknown.</p> <p>Results</p> <p>We present a detailed analysis of Argonaute-PIWI protein sequences and the genomic neighborhoods of the respective genes in prokaryotes. Whereas eukaryotic Ago/PIWI proteins always contain PAZ (oligonucleotide binding) and PIWI (active or inactivated nuclease) domains, the prokaryotic Argonaute homologs (pAgos) fall into two major groups in which the PAZ domain is either present or absent. The monophyly of each group is supported by a phylogenetic analysis of the conserved PIWI-domains. Almost all pAgos that lack a PAZ domain appear to be inactivated, and the respective genes are associated with a variety of predicted nucleases in putative operons. An additional, uncharacterized domain that is fused to various nucleases appears to be a unique signature of operons encoding the short (lacking PAZ) pAgo form. By contrast, almost all PAZ-domain containing pAgos are predicted to be active nucleases. Some proteins of this group (e.g., that from <it>Aquifex aeolicus</it>) have been experimentally shown to possess nuclease activity, and are not typically associated with genes for other (putative) nucleases. Given these observations, the apparent extensive horizontal transfer of pAgo genes, and their common, statistically significant over-representation in genomic neighborhoods enriched in genes encoding proteins involved in the defense against phages and/or plasmids, we hypothesize that pAgos are key components of a novel class of defense systems. The PAZ-domain containing pAgos are predicted to directly destroy virus or plasmid nucleic acids via their nuclease activity, whereas the apparently inactivated, PAZ-lacking pAgos could be structural subunits of protein complexes that contain, as active moieties, the putative nucleases that we predict to be co-expressed with these pAgos. All these nucleases are predicted to be DNA endonucleases, so it seems most probable that the putative novel phage/plasmid-defense system targets phage DNA rather than mRNAs. Given that in eukaryotic RNAi systems, the PAZ domain binds a guide RNA and positions it on the complementary region of the target, we further speculate that pAgos function on a similar principle (the guide being either DNA or RNA), and that the uncharacterized domain found in putative operons with the short forms of pAgos is a functional substitute for the PAZ domain.</p> <p>Conclusion</p> <p>The hypothesis that pAgos are key components of a novel prokaryotic immune system that employs guide RNA or DNA molecules to degrade nucleic acids of invading mobile elements implies a functional analogy with the prokaryotic CASS and a direct evolutionary connection with eukaryotic RNAi. The predictions of the hypothesis including both the activities of pAgos and those of the associated endonucleases are readily amenable to experimental tests.</p> <p>Reviewers</p> <p>This article was reviewed by Daniel Haft, Martijn Huynen, and Chris Ponting.</p

Identification of an ortholog of the eukaryotic RNA polymerase III subunit RPC34 in Crenarchaeota and Thaumarchaeota suggests specialization of RNA polymerases for coding and non-coding RNAs in Archaea

One of the hallmarks of eukaryotic information processing is the co-existence of 3 distinct, multi-subunit RNA polymerase complexes that are dedicated to the transcription of specific classes of coding or non-coding RNAs. Archaea encode only one RNA polymerase that resembles the eukaryotic RNA polymerase II with respect to the subunit composition. Here we identify archaeal orthologs of the eukaryotic RNA polymerase III subunit RPC34. Genome context analysis supports a function of this archaeal protein in the transcription of non-coding RNAs. These findings suggest that functional separation of RNA polymerases for protein-coding genes and non-coding RNAs might predate the origin of the Eukaryotes

Error estimates for solid-state density-functional theory predictions: an overview by means of the ground-state elemental crystals

Predictions of observable properties by density-functional theory calculations (DFT) are used increasingly often in experimental condensed-matter physics and materials engineering as data. These predictions are used to analyze recent measurements, or to plan future experiments. Increasingly more experimental scientists in these fields therefore face the natural question: what is the expected error for such an ab initio prediction? Information and experience about this question is scattered over two decades of literature. The present review aims to summarize and quantify this implicit knowledge. This leads to a practical protocol that allows any scientist - experimental or theoretical - to determine justifiable error estimates for many basic property predictions, without having to perform additional DFT calculations. A central role is played by a large and diverse test set of crystalline solids, containing all ground-state elemental crystals (except most lanthanides). For several properties of each crystal, the difference between DFT results and experimental values is assessed. We discuss trends in these deviations and review explanations suggested in the literature. A prerequisite for such an error analysis is that different implementations of the same first-principles formalism provide the same predictions. Therefore, the reproducibility of predictions across several mainstream methods and codes is discussed too. A quality factor Delta expresses the spread in predictions from two distinct DFT implementations by a single number. To compare the PAW method to the highly accurate APW+lo approach, a code assessment of VASP and GPAW with respect to WIEN2k yields Delta values of 1.9 and 3.3 meV/atom, respectively. These differences are an order of magnitude smaller than the typical difference with experiment, and therefore predictions by APW+lo and PAW are for practical purposes identical.Comment: 27 pages, 20 figures, supplementary material available (v5 contains updated supplementary material