Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology

The Clinical Laboratory Improvement Amendments (CLIA) of 1988 requires that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a CLIA-accredited laboratory. As no known reference materials were available, DNA samples that were from Coriell Cell Repositories (Camden, NJ) were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other CLIA-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays

A Resource and Information Guide for the Aspiring Doubler of Orchestral Tenor and Bass Trombones

A survey of professional musicians who double on both tenor and bass trombone leads to a guide for selecting helpful equipment as well as selected etudes, solos, and orchestral excerpts that can aid the development of the orchestral trombonist wishing to begin doubling between both tenor and bass trombone.</p

Selected Orchestral Excerpts to Aid the Aspiring Doubler of Orchestral Tenor and Bass Trombones

The following selected orchestral excerpts can aid the development of the orchestral trombonist wishing to begin doubling between both tenor and bass trombone.</p

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging

The metabolic environment of the developing embryo: A multidisciplinary approach on oilseed rapeseed

Brassicaceae seeds consist of three genetically distinct structures: the embryo, endosperm and seed coat, all of which are involved in assimilate allocation during seed development. The complexity of their metabolic interrelations remains unresolved to date. In the present study, we apply state-of-the-art imaging and analytical approaches to assess the metabolic environment of the Brassica napus embryo. Nuclear magnetic resonance imaging (MRI) provided volumetric data on the living embryo and endosperm, revealing how the endosperm envelops the embryo, determining endosperm's priority in assimilate uptake from the seed coat during early development. MRI analysis showed higher levels of sugars in the peripheral endosperm facing the seed coat, but a lower sugar content within the central vacuole and the region surrounding the embryo. Feeding intact siliques with 13C-labeled sucrose allowed tracing of the post-phloem route of sucrose transfer within the seed at the heart stage of embryogenesis, by means of mass spectrometry imaging. Quantification of over 70 organic and inorganic compounds in the endosperm revealed shifts in their abundance over different stages of development, while sugars and potassium were the main determinants of osmolality throughout these stages. Our multidisciplinary approach allows access to the hidden aspects of endosperm metabolism, a task which remains unattainable for the small-seeded model plant Arabidopsis thaliana

A new Late Pliocene large provannid gastropod associated with hydrothermal venting at Kane Megamullion, Mid-Atlantic Ridge

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Taylor & Francis for personal use, not for redistribution. The definitive version was published in Journal of Systematic Palaeontology 10 (2012): 423-433, doi:10.1080/14772019.2011.607193.A new gastropod, Kaneconcha knorri gen et sp. nov., was found in marlstone dredged from the surface of Adam Dome at Kane Megamullion on the flank of the Mid-Atlantic Ridge in an area of former hydrothermal activity. The snail is interpreted as a large provannid similar to the chemosymbiotic genera Ifremeria and Alviniconcha. This is the first record of presumably chemosymbiotic provannids from the Atlantic Ocean and also the first fossil record of such large provannids associated with hydrothermal venting. Extant Alviniconcha and Ifremeria are endemic to hydrothermal vents in the Pacific and Indian oceans. Kaneconcha differs from Ifremeria in having no umbilicus and a posterior notch, and it differs from Alviniconcha in having the profile of the whorl slightly flattened and having no callus on the inner lip. A dark layer covering the Kaneconcha shell is interpreted here as a fossilized periostracum. The shell/periostracum interface shows fungal traces attributed to the ichnospecies Saccomorpha clava. We hypothesize that large chemosymbiotic provannids (i.e., Kaneconcha, Ifremeria, and Alviniconcha) form a clade that possibly diverged from remaining provannids in the Late Jurassic, with the Late Jurassic/Early Cretaceous Paskentana being an early member.R/V Knorr Cruise 180- 2 to Kane Megamullion was supported by National Science Foundation grant OCE- 0118445. A. Kaim acknowledges support from the Alexander von Humboldt Foundation. B. Tucholke acknowledges support from an Andrew W. Mellon Foundation Award for Innovative Research and from the Deep Ocean Exploration Institute at Woods Hole Oceanographic Institution

Performance Evaluation of a High Bandwidth Liquid Fuel Modulation Valve for Active Combustion Control

At the NASA Glenn Research Center, a characterization rig was designed and constructed for the purpose of evaluating high bandwidth liquid fuel modulation devices to determine their suitability for active combustion control research. Incorporated into the rig s design are features that approximate conditions similar to those that would be encountered by a candidate device if it were installed on an actual combustion research rig. The characterized dynamic performance measures obtained through testing in the rig are planned to be accurate indicators of expected performance in an actual combustion testing environment. To evaluate how well the characterization rig predicts fuel modulator dynamic performance, characterization rig data was compared with performance data for a fuel modulator candidate when the candidate was in operation during combustion testing. Specifically, the nominal and off-nominal performance data for a magnetostrictive-actuated proportional fuel modulation valve is described. Valve performance data were collected with the characterization rig configured to emulate two different combustion rig fuel feed systems. Fuel mass flows and pressures, fuel feed line lengths, and fuel injector orifice size was approximated in the characterization rig. Valve performance data were also collected with the valve modulating the fuel into the two combustor rigs. Comparison of the predicted and actual valve performance data show that when the valve is operated near its design condition the characterization rig can appropriately predict the installed performance of the valve. Improvements to the characterization rig and accompanying modeling activities are underway to more accurately predict performance, especially for the devices under development to modulate fuel into the much smaller fuel injectors anticipated in future lean-burning low-emissions aircraft engine combustors

Association Rate Constants of Ras-Effector Interactions Are Evolutionarily Conserved

Evolutionary conservation of protein interaction properties has been shown to be a valuable indication for functional importance. Here we use homology interface modeling of 10 Ras-effector complexes by selecting ortholog proteins from 12 organisms representing the major eukaryotic branches, except plants. We find that with increasing divergence time the sequence similarity decreases with respect to the human protein, but the affinities and association rate constants are conserved as predicted by the protein design algorithm, FoldX. In parallel we have done computer simulations on a minimal network based on Ras-effector interactions, and our results indicate that in the absence of negative feedback, changes in kinetics that result in similar binding constants have strong consequences on network behavior. This, together with the previous results, suggests an important biological role, not only for equilibrium binding constants but also for kinetics in signaling processes involving Ras-effector interactions. Our findings are important to take into consideration in system biology approaches and simulations of biological networks

The associations between QCT-based vertebral bone measurements and prevalent vertebral fractures depend on the spinal locations of both bone measurement and fracture

Summary We examined how spinal location affects the relationships between quantitative computed tomography (QCT)-based bone measurements and prevalent vertebral fractures. Upper spine (T4–T10) fractures appear to be more strongly related to bone measures than lower spine (T11–L4) fractures, while lower spine measurements are at least as strongly related to fractures as upper spine measurements. Introduction Vertebral fracture (VF), a common injury in older adults, is most prevalent in the mid-thoracic (T7–T8) and thoracolumbar (T12–L1) areas of the spine. However, measurements of bone mineral density (BMD) are typically made in the lumbar spine. It is not clear how the associations between bone measurements and VFs are affected by the spinal locations of both bone measurements and VF. Methods A community-based case–control study includes 40 cases with moderate or severe prevalent VF and 80 age- and sex-matched controls. Measures of vertebral BMD, strength (estimated by finite element analysis), and factor of risk (load:strength ratio) were determined based on QCT scans at the L3 and T10 vertebrae. Associations were determined between bone measures and prevalent VF occurring at any location, in the upper spine (T4–T10), or in the lower spine (T11–L4). Results Prevalent VF at any location was significantly associated with bone measures, with odds ratios (ORs) generally higher for measurements made at L3 (ORs = 1.9–3.9) than at T10 (ORs = 1.5–2.4). Upper spine fracture was associated with these measures at both T10 and L3 (ORs = 1.9–8.2), while lower spine fracture was less strongly associated (ORs = 1.0–2.4) and only reached significance for volumetric BMD measures at L3. Conclusions Closer proximity between the locations of bone measures and prevalent VF does not strengthen associations between bone measures and fracture. Furthermore, VF etiology may vary by region, with VFs in the upper spine more strongly related to skeletal fragility.National Institutes of Health (U.S.) (Grants R01AR053986, R01AR/AG041398, T32AG023480, and F31AG041629)National Heart, Lung, and Blood Institute. Framingham Heart Study (NIH/NHLBI Contract N01-HC-25195