Clinical application of high throughput molecular screening techniques for pharmacogenomics.

Genetic analysis is one of the fastest-growing areas of clinical diagnostics. Fortunately, as our knowledge of clinically relevant genetic variants rapidly expands, so does our ability to detect these variants in patient samples. Increasing demand for genetic information may necessitate the use of high throughput diagnostic methods as part of clinically validated testing. Here we provide a general overview of our current and near-future abilities to perform large-scale genetic testing in the clinical laboratory. First we review in detail molecular methods used for high throughput mutation detection, including techniques able to monitor thousands of genetic variants for a single patient or to genotype a single genetic variant for thousands of patients simultaneously. These methods are analyzed in the context of pharmacogenomic testing in the clinical laboratories, with a focus on tests that are currently validated as well as those that hold strong promise for widespread clinical application in the near future. We further discuss the unique economic and clinical challenges posed by pharmacogenomic markers. Our ability to detect genetic variants frequently outstrips our ability to accurately interpret them in a clinical context, carrying implications both for test development and introduction into patient management algorithms. These complexities must be taken into account prior to the introduction of any pharmacogenomic biomarker into routine clinical testing

Conditions for describing triplet states in reduced density matrix functional theory

We consider necessary conditions for the one-body-reduced density matrix (1RDM) to correspond to a triplet wave-function of a two electron system. The conditions concern the occupation numbers and are different for the high spin projections, $S_z=\pm 1$, and the $S_z=0$ projection. Hence, they can be used to test if an approximate 1RDM functional yields the same energies for both projections. We employ these conditions in reduced density matrix functional theory calculations for the triplet excitations of two-electron systems. In addition, we propose that these conditions can be used in the calculation of triplet states of systems with more than two electrons by restricting the active space. We assess this procedure in calculations for a few atomic and molecular systems. We show that the quality of the optimal 1RDMs improves by applying the conditions in all the cases we studied

ASSESSMENT OF MOLECULAR GENETIC DIVERSITY OF ECUADORIAN RICE CULTIVARS USING SIMPLE SEQUENCE REPEAT MARKERS

Molecular markers are useful tools for evaluating genetic diversity and determining cultivar identity. Thirty simple-sequence-repeat (SSR) markers were selected in order to evaluate the genetic diversity within 76 cultivars of the Ecuadorian Rice Program for breeding. One-hundred-ninety-four alleles were detected in 22 SSR polymorphic markers, number of alleles per marker ranging from 2 to 24, with an average of 9 alleles per locus. The sizes of the alleles varied between 62 to 280 bp, with an average polymorphism information content value of 0.624, ranging from 0.202 (RM125) to 0.943 (RM413), indicating significant genetic diversity among and within the rice accessions. The average observed heterozygosity (Ho) was 0.086, while average expected genetic diversity (He) was 0.667. A set of eight of the polymorphic SSR markers produced seventeen unique alleles for the genotypes studied and could distinguish released cultivars from the rest of accessions. A dendrogram constructed using the unweighted pair-group method with arithmetic means (UPGMA) grouped the 76 rice materials in four well differentiated major clusters whereas the Structure program without any a priori information provided support for the existence of three genetically distinct clusters (K =3D 3). Additional key words: Cluster analysis, molecular marker, Oryza sativa, rice breeding, variability. ABSTRACT Los marcadores moleculares son herramientas \ufatiles para evaluar la diversidad gen\ue9tica y determinar la identidad del cultivar. Se seleccionaron 30 marcadores de secuencia simple repetida (SSR) para evaluar la diversidad gen\ue9tica en setenta y seis cultivares del Programa de Arroz Ecuatoriano con fines de mejoramiento. Se detect\uf3 un total de 194 alelos en 22 marcadores polim\uf3rficos SSR, el n\ufamero de alelos por marcador oscil\uf3 entre 2 y 24, con un promedio de 9 alelos por locus. Los tama\uf1os de los alelos variaron entre 62 y 280 pb, con un valor de contenido de informaci\uf3n polim\uf3rfica promedio de 0,624, variando entre 0,202 (RM125) y 0,943 (RM413), lo que indic\uf3 diversidad gen\ue9tica significativa entre y dentro de las accesiones de arroz. La heterocigosidad observada promedio (Ho) fue 0,086, mientras que la diversidad gen\ue9tica esperada promedio (He) fue 0,667. Un conjunto de ocho de los marcadores SSR polim\uf3rficos produjo diecisiete alelos \ufanicos para los genotipos estudiados y pudo distinguir los cultivares liberados del resto de las accesiones. Un dendrograma construido utilizando el m\ue9todo de pares no ponderados con medios aritm\ue9ticos (UPGMA) agrup\uf3 los 76 materiales de arroz en cuatro grupos principales bien diferenciados, mientras que el programa Structure sin informaci\uf3n a priori proporcion\uf3 soporte para la existencia de tres grupos gen\ue9ticamente distintos (K =3D 3). Palabras clave adicionales: An\ue1lisis de conglomerados, marcador molecular; mejoramiento de arroz; Oryza sativa, variabilidad. <br

Molecular effect of an OPTN common variant associated to Paget's disease of bone

Paget's disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains several candidate genes for metabolic bone diseases. We focused our analysis in the most significantly associated variant with PDB, within the Optineurin (OPTN) gene, i.e. the common variant rs1561570. Although it was previously shown to be strongly associated with PDB in several populations, its contribution to PDB pathogenesis remains unclear. In this study we have shown that rs1561570 may contribute to PDB since its Tallele results in the loss of a methylation site in patients' DNA, leading to higher levels of OPTN gene expression and a corresponding increase in protein levels in patients' osteoclasts. This increase in OPTN expression leads to higher levels of NF-KB translocation into the nucleus and increasing expression of its target genes, which may contribute to the overactivity of osteoclasts observed in PDB. We also reported a tendency for a more severe clinical phenotype in the presence of a haplotype containing the rs1561570 T allele, which appear to be re-enforced with the presence of the SQSTM1/P392L mutation. In conclusion, our work provides novel insight towards understanding the functional effects of this variant, located in OPTN intron 7, and its implication in the contribution to PDB pathogenesis.national funds from Foundation for Science and Technology (FCT) [UID/Multi/04326/2013]; Canadian Institutes for Health Research, Canada [MOP130457]; CHU de Quebec Foundation; Canadian Foundation for Innovation; Fonds de recherche du Quebec-sante; Laval University; CHU de Quebec-Universite Laval Research Centre; FCT [SFRH/BD/77227/2011, SFRH/BPD/111898/2015]; Fonds de recherche Quebec-Sante (FRQ-S), Quebec, Canad

Detection, attribution, and sensitivity of trends toward earlier streamflow in the Sierra Nevada

Observed changes in the timing of snowmelt dominated streamflow in the western United States are often linked to anthropogenic or other external causes. We assess whether observed streamflow timing changes can be statistically attributed to external forcing, or whether they still lie within the bounds of natural (internal) variability for four large Sierra Nevada (CA) basins, at inflow points to major reservoirs. Streamflow timing is measured by “center timing” (CT), the day when half the annual flow has passed a given point. We use a physically based hydrology model driven by meteorological input from a global climate model to quantify the natural variability in CT trends. Estimated 50-year trends in CT due to natural climate variability often exceed estimated actual CT trends from 1950 to 1999. Thus, although observed trends in CT to date may be statistically significant, they cannot yet be statistically attributed to external influences on climate. We estimate that projected CT changes at the four major reservoir inflows will, with 90% confidence, exceed those from natural variability within 1–4 decades or 4–8 decades, depending on rates of future greenhouse gas emissions. To identify areas most likely to exhibit CT changes in response to rising temperatures, we calculate changes in CT under temperature increases from 1 to 5°. We find that areas with average winter temperatures between −2°C and −4°C are most likely to respond with significant CT shifts. Correspondingly, elevations from 2000 to 2800 m are most sensitive to temperature increases, with CT changes exceeding 45 days (earlier) relative to 1961–1990

High density p-type Bi0.5Sb1.5Te3 nanowires by electrochemical templating through ion-track lithography

High density p-type Bi0.5Sb1.5Te3 nanowire arrays are produced by a combination of electrodeposition and ion-track lithography technology. Initially, the electrodeposition of p-type wBi(0.5)Sb(1.5)Te(3) films is investigated to find out the optimal conditions for the deposition of nanowires. Polyimide-based Kapton foils are chosen as a polymer for ion track irradiation and nanotemplating Bi0.5Sb1.5Te3 nanowires. The obtained nanowires have average diameters of 80 nm and lengths of 20 mu m, which are equivalent to the pore size and thickness of Kapton foils. The nanowires exhibit a preferential orientation along the {110} plane with a composition of 11.26 at.% Bi, 26.23 at.% Sb, and 62.51 at.% Te. Temperature dependence studies of the electrical resistance show the semiconducting nature of the nanowires with a negative temperature coefficient of resistance and band gap energy of 0.089 +/- 0.006 eV

Modeling Relationships Using The Relational And Object-Oriented Data Models

We compare the performance of naive data modelers in modeling association, generalization, and aggregation relationships with the relational and object-oriented data models. We first develop research hypotheses based on the properties of expressiveness, minimality, and unique semantic interpretation to analyze the effectiveness of the two models. We then test our hypotheses in anexperiment with 22 naive modelers. The findings of our study support the notion that, to be effective, a data model should satisfy these three propertie

Modifications of the Bonferroni-Holm procedure for a multi-way ANOVA

This paper aims at constructing stepwise test procedures based on the Bonferroni-Holm principle for a multi-way ANOVA. Especially for the two-way ANOVA it is shown, that the procedures keep the multiple level alpha. These theoretical results are supplemented by a simulation study to compare the multiple procedures regarding two power concepts and to learn about which of the introduced procedures is the best