Assessment of LD matrix measures for the analysis of biological pathway association.

Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression (Wang et al., 2008). To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis). In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r=0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.

Regions of the alpha 1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function.

Regions of the hamster alpha 1-adrenergic receptor (alpha 1 AR) that are important in GTP-binding protein (G protein)-mediated activation of phospholipase C were determined by studying the biological functions of mutant receptors constructed by recombinant DNA techniques. A chimeric receptor consisting of the beta 2-adrenergic receptor (beta 2AR) into which the putative third cytoplasmic loop of the alpha 1AR had been placed activated phosphatidylinositol metabolism as effectively as the native alpha 1AR, as did a truncated alpha 1AR lacking the last 47 residues in its cytoplasmic tail. Substitutions of beta 2AR amino acid sequence in the intermediate portions of the third cytoplasmic loop of the alpha 1AR or at the N-terminal portion of the cytoplasmic tail caused marked decreases in receptor coupling to phospholipase C. Conservative substitutions of two residues in the C terminus of the third cytoplasmic loop (Ala293----Leu, Lys290----His) increased the potency of agonists for stimulating phosphatidylinositol metabolism by up to 2 orders of magnitude. These data indicate (i) that the regions of the alpha 1AR that determine coupling to phosphatidylinositol metabolism are similar to those previously shown to be involved in coupling of beta 2AR to adenylate cyclase stimulation and (ii) that point mutations of a G-protein-coupled receptor can cause remarkable increases in sensitivity of biological response.

Quantification of biological aging in young adults.

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

The accuracy and completeness for receipt of colorectal cancer care using Veterans Health Administration administrative data.

BACKGROUND: The National Comprehensive Cancer Network and the American Society of Clinical Oncology have established guidelines for the treatment and surveillance of colorectal cancer (CRC), respectively. Considering these guidelines, an accurate and efficient method is needed to measure receipt of care. METHODS: The accuracy and completeness of Veterans Health Administration (VA) administrative data were assessed by comparing them with data manually abstracted during the Colorectal Cancer Care Collaborative (C4) quality improvement initiative for 618 patients with stage I-III CRC. RESULTS: The VA administrative data contained gender, marital, and birth information for all patients but race information was missing for 62.1% of patients. The percent agreement for demographic variables ranged from 98.1-100%. The kappa statistic for receipt of treatments ranged from 0.21 to 0.60 and there was a 96.9% agreement for the date of surgical resection. The percentage of post-diagnosis surveillance events in C4 also in VA administrative data were 76.0% for colonoscopy, 84.6% for physician visit, and 26.3% for carcinoembryonic antigen (CEA) test. CONCLUSIONS: VA administrative data are accurate and complete for non-race demographic variables, receipt of CRC treatment, colonoscopy, and physician visits; but alternative data sources may be necessary to capture patient race and receipt of CEA tests.

Reliability analysis of flip chip designs via computer simulation

A flip chip component is a silicon chip mounted to a substrate with the active area facing the substrate. This paper presents the results of an investigation into the relationship between a number of important material properties and geometric parameters on the thermal-mechanical fatigue reliability of a standard flip chip design and a flip chip design with the use of microvias. Computer modeling has been used to analyze the mechanical conditions of flip chips under cyclic thermal loading where the Coffin-Manson empirical relationship has been used to predict the life time of the solder interconnects. The material properties and geometry parameters that have been investigated are the Young's modulus, the coefficient of thermal expansion (CTE) of the underfill, the out-of-plane CTE (CTEz) of the substrate, the thickness of the substrate, and the standoff height. When these parameters vary, the predicted life-times are calculated and some of the features of the results are explained. By comparing the predicted lifetimes of the two designs and the strain conditions under thermal loading, the local CTE mismatch has been found to be one of most important factors in defining the reliability of flip chips with microvias.

Modelling the performance of lead-Free solder interconnects for copper bumped flip-chip devices

Traditionally, before flip chips can be assembled the dies have to be attached with solder bumps. This process involves the deposition of metal layers on the Al pads on the dies and this is called the under bump metallurgy (UBM). In an alternative process, however, Copper (Cu) columns can be used to replace solder bumps and the UBM process may be omitted altogether. After the bumping process, the bumped dies can be assembled on to the printed circuit board (PCB) by using either solder or conductive adhesives. In this work, the reliability issues of flip chips with Cu column bumped dies have been studied. The flip chip lifetime associated with the solder fatigue failure has been modeled for a range of geometric parameters. The relative importance of these parameters is given and solder volume has been identified as the most important design parameter for long-term reliability. Another important problem that has been studied in this work is the dissolution of protection metals on the pad and Cu column in the reflow process. For small solder joints the amount of Cu which dissolves into the molten solder after the protection layers have worn out may significantly affect solder joint properties.

Reliability of power electronic modules

The electric car, the all electric aircraft and requirements for renewable energy are examples of potential technologies needed to address the world problem of global warming/carbon emission etc. Power electronics and packaged modules are fundamental for the underpinning of these technologies and with the diverse requirements for electrical configurations and the range of environmental conditions, time to market is paramount for module manufacturers and systems designers alike. This paper details some of the results from a major UK project into the reliability of power electronic modules using physics of failure techniques. This paper presents a design methodology together with results that demonstrate enhanced product design with improved reliability, performance and value within acceptable time scales

Modelling the reliability of components on flexible substrates

The use of flexible substrates is growing in many applications such as computer peripherals, hand held devices, telecommunications, automotive, aerospace, etc. The drive to adopt flexible circuits is due to their ability to reduce size, weight, assembly time and cost of final product. they also accommodate flexibility by allowing relative movement between component parts and provide a route for three dimensional packaging. This paper will describe some of the current research results from the Flex-No-Lead project, European Commission sponsored programme. The principle aim of this project is to investigate the processing, performance and reliability of flexible substrates when subjected to new environmentally friendly, lead-free soldering technologies. This paper will discuss the impact of specific design variables on performance and reliability. In particular the paper will focus on copper track designs, substrate material, dielectric material and solder mask defined joints

Epilobium parviflorum Schreb. - in vitro study of biological action

Epilobium parviflorum Schreb. (Onagraceae) is used for the treatment of benign prostatic hyperplasia (BPH), which is regarded as an endocrine disorder caused by age-related hormone imbalance and increased oxidative damage [1,2,3]. Epilobium can moderate the obstructive and the irritative symptoms of BPH [1] but its biological action is not entirely identified. E. parviflorum is rich in phytosterols, flavonoids (myricetin, quercetin, kaempferol and their glycosides), phenolic acids, catechins, ellagi- and gallotannins [4]. The potential biological effects of Epilobium parviflorum Schreb. have been investigated, in respect to its antioxidant, anti-inflammatory, enzyme-inhibitory and anti-androgenic effect. The whole-plant water extract showed higher antioxidant effect (IC50=1.65±0.05µg/mL) in DPPH assay than Trolox or ascorbic acid and inhibited the lipid peroxidation examined in TBA assay (IC50=2.31±0.18mg/mL). In concentrations 0.20-15.00µg/mL the extract possessed a protective effect comparable to catalase enzyme (2500 IU/mL), against oxidative damage generated on fibroblast cells. The examination of the COX-inhibitory effect showed that E. parviflorum had an anti-inflammatory effect (IC50=1.38±0.08µg/mL). Investigation of steroid receptor binding ability and the aromatase enzyme-inhibition showed negative results in the concentration range examined.

The use of biological indicators of heavy metal contamination in estuaries. Occasional Publication of the Marine Biological Association 1

The use of the deposit-feeding molluscs Scrobicularia plana and Macoma balthica and the burrowing polychaete Nereis diversicolor as indicators of the biological availability of heavy metals in sediments has been evaluated. Concentrations of Ag, As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Sn and Zn have been measured in organisms and sediments from more than 30 estuaries in south west England and South Wales and indicate that the biological availability of most metals varies by order of magnitude between uncontaminated and contaminated sites. The results have been compared with those obtained with the use of other species of indicator organisms in estuaries.