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Diverse Structures (diverse + structure)
Selected AbstractsA novel method to identify gene,gene effects in nuclear families: the MDR-PDTGENETIC EPIDEMIOLOGY, Issue 2 2006E.R. Martin Abstract It is now well recognized that gene,gene and gene,environment interactions are important in complex diseases, and statistical methods to detect interactions are becoming widespread. Traditional parametric approaches are limited in their ability to detect high-order interactions and handle sparse data, and standard stepwise procedures may miss interactions that occur in the absence of detectable main effects. To address these limitations, the multifactor dimensionality reduction (MDR) method [Ritchie et al., 2001: Am J Hum Genet 69:138,147] was developed. The MDR is wellsuited for examining high-order interactions and detecting interactions without main effects. The MDR was originally designed to analyze balanced case-control data. The analysis can use family data, but requires a single matched pair be selected from each family. This may be a discordant sib pair, or may be constructed from triad data when parents are available. To take advantage of additional affected and unaffected siblings requires a test statistic that measures the association of genotype with disease in general nuclear families. We have developed a novel test, the MDR-PDT, by merging the MDR method with the genotype-Pedigree Disequilibrium Test (geno-PDT)[Martin et al., 2003: Genet Epidemiol 25:203,213]. MDR-PDT allows identification of single-locus effects or joint effects of multiple loci in families of diverse structure. We present simulations to demonstrate the validity of the test and evaluate its power. To examine its applicability to real data, we applied the MDR-PDT to data from candidate genes for Alzheimer disease (AD) in a large family dataset. These results show the utility of the MDR-PDT for understanding the genetics of complex diseases. Genet. Epidemiol. 2006. © 2005 Wiley-Liss, Inc. [source] Can management compensate for atmospheric nutrient deposition in heathland ecosystems?JOURNAL OF APPLIED ECOLOGY, Issue 4 2006WERNER HÄRDTLE Summary 1Atmospheric nutrient deposition has contributed to widespread changes in heathlands throughout Europe. As a consequence, management is now being considered as a potential tool with which to compensate for increased nutrient loads. Currently, only limited information is available on the extent to which management measures could compensate for atmospheric nutrient deposition. We hypothesized that low-intensity management measures are not sufficient to counterbalance current nutrient inputs, particularly of nitrogen (N). 2In order to improve heathland management schemes, we evaluated the effectiveness of different management measures in reducing the impact of ongoing atmospheric nutrient loads. We compared the effects of mowing, prescribed burning (low-intensity management) and sod-cutting (high-intensity management) on heathland nutrient budgets [N, calcium (Ca), potassium (K), magnesium (Mg) and phosphorus (P)] in the Lueneburg Heath nature reserve (north-west Germany). Nutrient balances were calculated by analysing the present-day input, the output as a result of the removal of biomass/humus horizons, and changes in leaching rates. 3Nutrient losses by increased leaching following management measures were negligible compared with nutrient losses caused by the removal of above-ground biomass or humus horizons. The total quantities of nutrients removed by sod-cutting were equivalent to between 37 and 176 years of atmospheric input (for N, 89 years). 4In contrast, the quantities of N removed by mowing and prescribed burning were equivalent to only 5 years of atmospheric input. Thus, heathlands subjected to such treatments will accumulate N in the long term. In addition, output,input ratios for phosphorus (P) exceeded those for N in the mowing and sod-cutting experiments. It is therefore likely that heathlands currently (co-) limited by N will shift to being more P-limited in the long term. This will promote species that are well adapted to P-limited sites (e.g. Molinia caerulea). 5Synthesis and applications. This study shows that low-intensity management cannot compensate for atmospheric N loads in the long term. Consequently, high-intensity management measures are an indispensable tool in preserving a long-term balanced N budget in heathlands. In order to maintain a diverse structure, managers need to combine low- and high-intensity management measures. Prescribed burning proved to be the best means of avoiding an increasing P shortage, because this measure causes very low P outputs. [source] Characterisation of the effects of potassium channel modulating agents on mouse intestinal smooth muscleJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2002Chi-Kong Yeung The actions of agents which modulate ATP-sensitive potassium (KATP) channels in excitable cells were investigated in an in-vitro preparation of mouse ileum from which the mucosa was removed. A range of potassium channel openers of diverse structure, cromakalim (0.1,100 ,M), pinacidil (0.1,200 ,M) and its analogue P1060 (0.1,200 ,M), SDZ PCO400 ((-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent-1-enyloxy)-2H -1-benzopyran-6-carbonitrile) (0.3,60 ,M), caused concentration-related reduction in twitch height of electrical field stimulated ileum. P1060 and SDZ PCO400 were the most potent agents; diazoxide (0.1,100 ,M) was without effect. The order of inhibitory potency, based on EC50 values (concentration of a relaxant producing 50% of the maximum inhibition of twitch) was: P1060 = SDZ PCO400 > cromakalim > pinacidil. The relaxant effect of the potassium channel openers was antagonised by the sulfonylureas glibenclamide (0.1-1.0 ,M) and glipizide (3,30 ,M) but the nature of the antagonism differed. Antagonism of P1060 and SDZ PCO400 by glibenclamide appeared to be competitive whereas the antagonism of relaxation induced by cromakalim and pinacidil was apparently not competitive. Both phentolamine (1,10 ,M) and tolbutamide (100,300 ,M) showed competitive antagonism of the actions of pinacidil while yohimbine (1,20 ,M) did not antagonise relaxation and appeared to have actions at sites other than the KATP channel in this preparation. The relative effectiveness of the antagonists on pinacidil-induced relaxation was found to be: glibenclamide >phentolamine >tolbutamide >yohimbine, which is in agreement with studies in other tissues. The results show that many structurally diverse potassium channel openers are potent relaxants of mouse ileum. These observations are consistent with the existence of ATP-dependent K+ channels in murine intestinal muscle which, however, differ somewhat in properties from those reported for vascular muscle and pancreatic ,-cells. [source] Toward the development of new medicinal leads with selectivity for protein kinase C isozymesTHE CHEMICAL RECORD, Issue 4 2005Kazuhiro Irie Abstract Tumor promoters such as phorbol esters bind strongly to protein kinase C (PKC) isozymes to induce their activation. Since each PKC isozyme is involved in diverse biological events in addition to tumor promotion, the isozymes serve as promising therapeutic targets. Tumor promoters bind to the C1A and/or C1B domain of conventional (,, ,I, ,II, and ,) and novel PKC isozymes (,, ,, ,, and ,). As these C1 domains play differential roles in PKC activation and their translocation in cells, the development of agents with binding selectivity for individual C1 domains is a pressing need. For this purpose, we established a synthetic C1 peptide library of all PKC isozymes. The library enabled us to identify indolactam-V (1) as a promising lead compound. Our diverse structure,activity studies on 1 indicated that the position of the hydrophobic substituent on the indole ring dominates the PKC isozyme- and C1 domain-selective binding rather than conformation of the nine-membered lactam. Moreover, we suggested that the indole ring of 1 could be involved in the CH/, interaction with Pro-11 of the C1B domain of PKC,. This invaluable information will lead to the structural optimization of the PKC, ligand as exemplified by the design and synthesis of naphtholactam-V8 (21). © 2005 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 5: 185,195; 2005: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20044 [source] A Facile and Efficient Synthesis of Dihydroisobenzofuran Derivatives via Tandem Palladium-Catalyzed Coupling, Propargyl-Allenyl Rearrangement, [4+2],Cycloaddition and Aromatization ReactionADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 18 2008Ruwei Shen Abstract A variety of dihydroisobenzofuran derivatives has been prepared in good yields via an interesting sequential reaction consisting of palladium-catalyzed coupling, propargyl-allenyl rearrangement, [4+2],cycloaddition and aromatization. A double-coupling, rearrangement, [4+2],cycloaddition and aromatization process is also described for the synthesis of more complex and diverse structures. [source] In silico prediction and screening of ,-secretase inhibitors by molecular descriptors and machine learning methodsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2010Xue-Gang Yang Abstract ,-Secretase inhibitors have been explored for the prevention and treatment of Alzheimer's disease (AD). Methods for prediction and screening of ,-secretase inhibitors are highly desired for facilitating the design of novel therapeutic agents against AD, especially when incomplete knowledge about the mechanism and three-dimensional structure of ,-secretase. We explored two machine learning methods, support vector machine (SVM) and random forest (RF), to develop models for predicting ,-secretase inhibitors of diverse structures. Quantitative analysis of the receiver operating characteristic (ROC) curve was performed to further examine and optimize the models. Especially, the Youden index (YI) was initially introduced into the ROC curve of RF so as to obtain an optimal threshold of probability for prediction. The developed models were validated by an external testing set with the prediction accuracies of SVM and RF 96.48 and 98.83% for ,-secretase inhibitors and 98.18 and 99.27% for noninhibitors, respectively. The different feature selection methods were used to extract the physicochemical features most relevant to ,-secretase inhibition. To the best of our knowledge, the RF model developed in this work is the first model with a broad applicability domain, based on which the virtual screening of ,-secretase inhibitors against the ZINC database was performed, resulting in 368 potential hit candidates. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Morphology and metamorphosis of Eupsophus calcaratus tadpoles (anura: Leptodactylidae)JOURNAL OF MORPHOLOGY, Issue 2 2005M.F. Vera Candioti Abstract Eupsophus calcaratus, a leptodactyloid frog from the austral Andean forests of Argentina and Chile, has endotrophic, nidicolous tadpoles. We studied a metamorphic series from Stages 31 to 46 of Gosner's developmental table (1960). Other than the scarce pigmentation, proportionately large eyes, and massive developing hindlimbs, the remaining external characters are similar to those of generalized, exotrophic larvae. At the same time, internal morphology does not reveal any character state attributable to the endotrophic-nidicolous way of life; conversely, structures such as the hyobranchial skeleton and the mandibular cartilages are similar to those of exotrophic-macrophagous tadpoles. The metamorphic process is characterized by the delayed development of diverse structures (e.g., ethmoid region, palatoquadrate, and hyobranchial apparatus), and the retention of some larval characters (e.g., parietal fenestrae, overall absence of ossification) with the absence of development of some "juvenile" characters (e.g., adult otic process, several bones) in metamorphosed individuals. These heterochronic processes and truncation of larval development are related to a shorter larval life (when compared to other species of the austral Andean region) and to the small size at metamorphosis. J. Morphol. © 2005 Wiley-Liss, Inc. [source] Machine learning approaches for predicting compounds that interact with therapeutic and ADMET related proteinsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2007H. Li Abstract Computational methods for predicting compounds of specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) property are useful for facilitating drug discovery and evaluation. Recently, machine learning methods such as neural networks and support vector machines have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic and ADMET property. These methods are particularly useful for compounds of diverse structures to complement QSAR methods, and for cases of unavailable receptor 3D structure to complement structure-based methods. A number of studies have demonstrated the potential of these methods for predicting such compounds as substrates of P-glycoprotein and cytochrome P450 CYP isoenzymes, inhibitors of protein kinases and CYP isoenzymes, and agonists of serotonin receptor and estrogen receptor. This article is intended to review the strategies, current progresses and underlying difficulties in using machine learning methods for predicting these protein binders and as potential virtual screening tools. Algorithms for proper representation of the structural and physicochemical properties of compounds are also evaluated. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2838,2860, 2007 [source] Recent cancer drug development with xanthone structuresJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2009Younghwa Na Abstract Objectives Xanthones are simple three-membered ring compounds that are mainly found as secondary metabolites in higher plants and microorganisms. Xanthones have very diverse biological profiles, including antihypertensive, antioxidative, antithrombotic and anticancer activity, depending on their diverse structures, which are modified by substituents on the ring system. Although several reviews have already been published on xanthone compounds, few of them have focused on the anticancer activity of xanthone derivatives. In this review we briefly summarize natural and synthetic xanthone compounds which have potential as anticancer drugs. Key findings The interesting structural scaffold and pharmacological importance of xanthone derivatives have led many scientists to isolate or synthesize these compounds as novel drug candidates. In the past, extensive research has been conducted to obtain xanthone derivatives from natural resources as well as through synthetic chemistry. Xanthones interact with various pharmacological targets based on the different substituents on the core ring. The anticancer activities of xanthones are also dramatically altered by the ring substituents and their positions. Summary The biological activities of synthetic xanthone derivatives depend on the various substituents and their position. Study of the biological mechanism of action of xanthone analogues, however, has not been conducted extensively compared to the diversity of xanthone compounds. Elucidation of the exact biological target of xanthone compounds will provide better opportunities for these compounds to be developed as potent anticancer drugs. At the same time, modification of natural xanthone derivatives aimed at specific targets is capable of expanding the biological spectrum of xanthone compounds. [source] Design of Multi-Component Reactions: From Libraries of Compounds to Libraries of ReactionsMOLECULAR INFORMATICS, Issue 5-6 2006Maxim Abstract Multi-Component Reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules similar to natural. Due to the large number of accessible compounds and other advantages, this type of chemistry has become very popular in the community of combinatorial chemists. In the last 5 years combinatorial chemistry is has evolved from the synthesis of libraries based on one scaffold to the synthesis of structurally diverse compounds, better known as diversity-oriented synthesis. Following this trend, the design of MCRs is becoming a tool kit for chemists to explore chemistry space broadly with complex and diverse structures. Various approaches to the creation of novel MCRs including "union of MCRs", "substrate design", and "reaction operator" are discussed here. [source] Analysis of water solubility data on the basis of HYBOT descriptorsMOLECULAR INFORMATICS, Issue 9-10 2003Part 2. Abstract Solubility data of 787 organic liquids (electrolytes and non-electrolytes) with diverse structures has been quantitatively described by physicochemical property descriptors. Special effects like intra - and intermolecular hydrogen bonds have been shown to be very important for water solubility. It is found that an important part of the solute-solvent interaction is neglected in all correlations of logS with (only) logP, as in this case the solute H-bond donor effect is not considered. As expected intramolecular hydrogen bonds lead to reduced solubility, whereas intermolecular hydrogen bonds (both HB donors and acceptors) of solutes result in higher solubility. An exception to the latter rule are carboxylic acids which due to intermolecular HB-induced dimerization in the pure liquid phase of acids show a three times lower solubility as expected on the basis of their molecular properties. A volume-related term (molecular polarizability ,) was found to have an essential negative contribution to solubility. For the first time the solubility increasing effect of partial ionization of weak acids and bases in saturated aqueous solutions has been quantitatively considered for sets of compounds by exact calculation of the pH determined by the solutes aqueous solubility and pKa value(s). [source] | |||||||||||||