A detailed description of the uncertainty analysis for High Area Ratio Rocket Nozzle tests at the NASA Lewis Research Center

A preliminary uncertainty analysis has been performed for the High Area Ratio Rocket Nozzle test program which took place at the altitude test capsule of the Rocket Engine Test Facility at the NASA Lewis Research Center. Results from the study establish the uncertainty of measured and calculated parameters required for the calculation of rocket engine specific impulse. A generalized description of the uncertainty methodology used is provided. Specific equations and a detailed description of the analysis are presented. Verification of the uncertainty analysis model was performed by comparison with results from the experimental program's data reduction code. Final results include an uncertainty for specific impulse of 1.30 percent. The largest contributors to this uncertainty were calibration errors from the test capsule pressure and thrust measurement devices

A new method for the estimation of variance matrix with prescribed zeros in nonlinear mixed effects models

We propose a new method for the Maximum Likelihood Estimator (MLE) of nonlinear mixed effects models when the variance matrix of Gaussian random effects has a prescribed pattern of zeros (PPZ). The method consists in coupling the recently developed Iterative Conditional Fitting (ICF) algorithm with the Expectation Maximization (EM) algorithm. It provides positive definite estimates for any sample size, and does not rely on any structural assumption on the PPZ. It can be easily adapted to many versions of EM.Comment: Accepted for publication in Statistics and Computin

Transport of Cytoplasmically Synthesized Proteins into the Mitochondria in a Cell Free System from Neurospora crassa

Synthesis and transport of mitochondrial proteins were followed in a cell-free homogenate of Neurospora crassa in which mitochondrial translation was inhibited. Proteins synthesized on cytoplasmic ribosomes are transferred into the mitochondrial fraction. The relative amounts of proteins which are transferred in vitro are comparable to those transferred in whole cells. Cycloheximide and puromycin inhibit the synthesis of mitochondrial proteins but not their transfer into mitochondria. The transfer of immunoprecipitable mitochondrial proteins was demonstrated for matrix proteins, carboxyatractyloside-binding protein and cytochrome c. Import of proteins into mitochondria exhibits a degree of specificity. The transport mechanism differentiates between newly synthesized proteins and preexistent mitochondrial proteins, at least in the case of matrix proteins. In the cell-free homogenate membrane-bound ribosomes are more active in the synthesis of mitochondrial proteins than are free ribosomes. The finished translation products appear to be released from the membrane-bound ribosomes into the cytosol rather than into the membrane vesicles. The results suggest that the transport of cytoplasmically synthesized mitochondrial proteins is essentially independent of cytoplasmic translation; that cytoplasmically synthesized mitochondrial proteins exist in an extramitochondrial pool prior to import; that the site of this pool is the cytosol for at least some of the mitochondrial proteins; and that the precursors in the extramitochondrial pool differ in structure or conformation from the functional proteins in the mitochondria

Are ribosomal DNA clusters rearrangement hotspots? A case study in the genus Mus (Rodentia, Muridae)

<p>Abstract</p> <p>Background</p> <p>Recent advances in comparative genomics have considerably improved our knowledge of the evolution of mammalian karyotype architecture. One of the breakthroughs was the preferential localization of evolutionary breakpoints in regions enriched in repetitive sequences (segmental duplications, telomeres and centromeres). In this context, we investigated the contribution of ribosomal genes to genome reshuffling since they are generally located in pericentromeric or subtelomeric regions, and form repeat clusters on different chromosomes. The target model was the genus <it>Mus </it>which exhibits a high rate of karyotypic change, a large fraction of which involves centromeres.</p> <p>Results</p> <p>The chromosomal distribution of rDNA clusters was determined by <it>in situ </it>hybridization of mouse probes in 19 species. Using a molecular-based reference tree, the phylogenetic distribution of clusters within the genus was reconstructed, and the temporal association between rDNA clusters, breakpoints and centromeres was tested by maximum likelihood analyses. Our results highlighted the following features of rDNA cluster dynamics in the genus <it>Mus</it>: i) rDNA clusters showed extensive diversity in number between species and an almost exclusive pericentromeric location, ii) a strong association between rDNA sites and centromeres was retrieved which may be related to their shared constraint of concerted evolution, iii) 24% of the observed breakpoints mapped near an rDNA cluster, and iv) a substantial rate of rDNA cluster change (insertion, deletion) also occurred in the absence of chromosomal rearrangements.</p> <p>Conclusions</p> <p>This study on the dynamics of rDNA clusters within the genus <it>Mus </it>has revealed a strong evolutionary relationship between rDNA clusters and centromeres. Both of these genomic structures coincide with breakpoints in the genus <it>Mus</it>, suggesting that the accumulation of a large number of repeats in the centromeric region may contribute to the high level of chromosome repatterning observed in this group. However, the elevated rate of rDNA change observed in the chromosomally invariant clade indicates that the presence of these sequences is insufficient to lead to genome instability. In agreement with recent studies, these results suggest that additional factors such as modifications of the epigenetic state of DNA may be required to trigger evolutionary plasticity.</p

Non-compartment model to compartment model pharmacokinetics transformation meta-analysis – a multivariate nonlinear mixed model

Background To fulfill the model based drug development, the very first step is usually a model establishment from published literatures. Pharmacokinetics model is the central piece of model based drug development. This paper proposed an important approach to transform published non-compartment model pharmacokinetics (PK) parameters into compartment model PK parameters. This meta-analysis was performed with a multivariate nonlinear mixed model. A conditional first-order linearization approach was developed for statistical estimation and inference. Results Using MDZ as an example, we showed that this approach successfully transformed 6 non-compartment model PK parameters from 10 publications into 5 compartment model PK parameters. In simulation studies, we showed that this multivariate nonlinear mixed model had little relative bias (<1%) in estimating compartment model PK parameters if all non-compartment PK parameters were reported in every study. If there missing non-compartment PK parameters existed in some published literatures, the relative bias of compartment model PK parameter was still small (<3%). The 95% coverage probabilities of these PK parameter estimates were above 85%. Conclusions This non-compartment model PK parameter transformation into compartment model meta-analysis approach possesses valid statistical inference. It can be routinely used for model based drug development

Advantages of the single delay model for the assessment of insulin sensitivity from the intravenous glucose tolerance test

The Minimal Model, (MM), used to assess insulin sensitivity (IS) from Intra-Venous Glucose-Tolerance Test (IVGTT) data, suffers from frequent lack of identifiability (parameter estimates with Coefficients of Variation (CV) less than 52%). The recently proposed Single Delay Model (SDM) is evaluated as a practical alternative

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Genetic Association Studies of Copy-Number Variation: Should Assignment of Copy Number States Precede Testing?

Recently, structural variation in the genome has been implicated in many complex diseases. Using genomewide single nucleotide polymorphism (SNP) arrays, researchers are able to investigate the impact not only of SNP variation, but also of copy-number variants (CNVs) on the phenotype. The most common analytic approach involves estimating, at the level of the individual genome, the underlying number of copies present at each location. Once this is completed, tests are performed to determine the association between copy number state and phenotype. An alternative approach is to carry out association testing first, between phenotype and raw intensities from the SNP array at the level of the individual marker, and then aggregate neighboring test results to identify CNVs associated with the phenotype. Here, we explore the strengths and weaknesses of these two approaches using both simulations and real data from a pharmacogenomic study of the chemotherapeutic agent gemcitabine. Our results indicate that pooled marker-level testing is capable of offering a dramatic increase in power (-fold) over CNV-level testing, particularly for small CNVs. However, CNV-level testing is superior when CNVs are large and rare; understanding these tradeoffs is an important consideration in conducting association studies of structural variation

Genetic variance in fitness indicates rapid contemporary adaptive evolution in wild animals

Funding: Hoge Veluwe great tits: the NIOO-KNAW, ERC, and numerous funding agencies; Wytham great tits: Biotechnology and Biological Sciences Research Council, ERC, and the UK Natural Environment Research Council (NERC).The rate of adaptive evolution, the contribution of selection to genetic changes that increase mean fitness, is determined by the additive genetic variance in individual relative fitness. To date, there are few robust estimates of this parameter for natural populations, and it is therefore unclear whether adaptive evolution can play a meaningful role in short-term population dynamics. We developed and applied quantitative genetic methods to long-term datasets from 19 wild bird and mammal populations and found that, while estimates vary between populations, additive genetic variance in relative fitness is often substantial and, on average, twice that of previous estimates. We show that these rates of contemporary adaptive evolution can affect population dynamics and hence that natural selection has the potential to partly mitigate effects of current environmental change.PostprintPeer reviewe