Quantitative traits for the tail suspension test: automation, optimization, and BXD RI mapping

Immobility in the tail suspension test (TST) is considered a model of despair in a stressful situation, and acute treatment with antidepressants reduces immobility. Inbred strains of mouse exhibit widely differing baseline levels of immobility in the TST and several quantitative trait loci (QTLs) have been nominated. The labor of manual scoring and various scoring criteria make obtaining robust data and comparisons across different laboratories problematic. Several studies have validated strain gauge and video analysis methods by comparison with manual scoring. We set out to find objective criteria for automated scoring parameters that maximize the biological information obtained, using a video tracking system on tapes of tail suspension tests of 24 lines of the BXD recombinant inbred panel and the progenitor strains C57BL/6J and DBA/2J. The maximum genetic effect size is captured using the highest time resolution and a low mobility threshold. Dissecting the trait further by comparing genetic association of multiple measures reveals good evidence for loci involved in immobility on chromosomes 4 and 15. These are best seen when using a high threshold for immobility, despite the overall better heritability at the lower threshold. A second trial of the test has greater duration of immobility and a completely different genetic profile. Frequency of mobility is also an independent phenotype, with a distal chromosome 1 locus

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Thermodynamic properties of magnetic liquid metals in undercooled region

371-374The experimental study of the thermodynamic properties of liquid metals has been confined usually to the stable liquid range of temperature and pressure. Nevertheless, there is a significant range between the melting point and the glass transition over which the liquid state can exist in a metastable equilibrium provided that crystallization can be avoided. The specific heat of undercooled liquid metals is a very important thermodynamic parameter. Appropriate knowledge of ΔCp¹⁻x i.e. the difference of specific heats of undercooled liquid and the corresponding crystalline solid can be utilized to derive accurate results for the parameters like ΔG, ΔS and ΔH. However, the experimental determination of Cp in undercooled system is difficult due to its metastable nature. Still, it is possible to arrive at an expression for the ΔCp¹⁻x, if the value of ΔCpm i.e. specific heat difference at melting point and the nature of variation of ΔCp¹⁻x in undercooled region can be estimated. In the present paper, ΔG for pure liquid Co and Ni have been estimated using linear temperature dependence of ΔCp in the undercooled region. Further, a general expression has been used which is valid in a large temperature range. The calculated results for ΔG are in excellent agreement with experimental data. Other thermodynamic parameters like ΔS and ΔH are also evaluated

Gibbs free energy difference in bulk metallic glass forming alloys

The Gibbs Free Energy Difference between the solid and liquid phases (DG) is related to nucleation frequency and has played an important role in predicting the glass forming ability (GFA) of multicomponent metallic alloys. This is due to the fact that the maximum energy for nucleus formation i.e. the activation barrier for nucleation has an inverse square relation with DG. The Gibbs Free Energy Difference of three multi-component bulk metallic glasses namely Mg65Cu25Y10, Zr57Cu15.4Ni12.6Al10Nb5 and Zr52.5Cu17.9Ni14.6Al10Ti5 have been evaluated using two new expressions. The results show that the DG values calculated assuming DCp to be constant lie closer to the experimental values for the Mg based system while in the case of two Zr based systems, DG computed using the hyperbolic variation of DCp show improved agreement with the experimental data

Kinetic analysis of crystallization processes in amorphous 2826A (Ni₃₆Fe₃₂Cr₁₄P₁₂ B₆) metallic glass

390-393The crystallization processes of 2826A (Ni₃₆Fe₃₂Cr₁₄P₁₂B₆) metallic glass were investigated using differential scanning calorimetry (DSC) at various heating rates. The thermograms at all scanning rates show two exothermic events. Different methods of kinetic analysis were employed at non-isothermal condition to derive important kinetic parameters namely activation energy of crystallization (E), frequency factor (A) and Avrami exponent (n) for the two exothermic peaks. The obtained values of E for peaks 1 and 2 are 298 and 457 (kJ/mol), respectively. The obtained Avrami exponent values 2.2(peak1) and 1.6(peak2) indicate one-dimensional and surface crystallization, respectively