QTL Fine Mapping by Measuring and Testing for Hardy-Weinberg and Linkage Disequilibrium at a Series of Linked Marker Loci in Extreme Samples of Populations

It has recently been demonstrated that fine-scale mapping of a susceptibility locus for a complex disease can be accomplished on the basis of deviations from Hardy-Weinberg (HW) equilibrium at closely linked marker loci among affected individuals. We extend this theory to fine-scale localization of a quantitative-trait locus (QTL) from extreme individuals in populations, by means of HW and linkage-disequilibrium (LD) analyses. QTL mapping and/or linkage analyses can establish a large genomic region (∼30 cM) that contains a QTL. The QTL can be fine mapped by examination of the degree of deviation from HW and LD at a series of closely linked marker loci. The tests can be performed for samples of individuals belonging to either high or low percentiles of the phenotype distribution or for combined samples of these extreme individuals. The statistical properties (the power and the size) of the tests of this fine-mapping approach are investigated and are compared extensively, under various genetic models and parameters for the QTL and marker loci. On the basis of the results, a two-stage procedure that uses extreme samples and different tests (for HW and LD) is suggested for QTL fine mapping. This two-step procedure is economic and powerful and can accurately narrow a genomic region containing a QTL from ∼30–1 cM, a range that renders physical mapping feasible for identification of the QTL. In addition, the relationship between parameterizations of complex diseases, by means of penetrance, and those of complex quantitative traits, by means of genotypic values, is outlined. This means that many statistical genetic methods developed for searching for susceptibility loci of complex diseases can be directly adopted and/or extended to QTL mapping for quantitative traits

First-Principles Investigation of Anistropic Hole Mobilities in Organic Semiconductors

We report a simple first-principles-based simulation model (combining quantum mechanics with Marcus−Hush theory) that provides the quantitative structural relationships between angular resolution anisotropic hole mobility and molecular structures and packing. We validate that this model correctly predicts the anisotropic hole mobilities of ruberene, pentacene, tetracene, 5,11-dichlorotetracene (DCT), and hexathiapentacene (HTP), leading to results in good agreement with experiment

Tunable light and drug induced depletion of target proteins

Biological processes in development and disease are controlled by the abundance, localization and modification of cellular proteins. We have developed versatile tools based on recombinant E3 ubiquitin ligases that are controlled by light or drug induced heterodimerization for nanobody or DARPin targeted depletion of endogenous proteins in cells and organisms. We use this rapid, tunable and reversible protein depletion for functional studies of essential proteins like PCNA in DNA repair and to investigate the role of CED-3 in apoptosis during Caenorhabditis elegans development. These independent tools can be combined for spatial and temporal depletion of different sets of proteins, can help to distinguish immediate cellular responses from long-term adaptation effects and can facilitate the exploration of complex networks

Simulation of Microstructure during Laser Rapid Forming Solidification Based on Cellular Automaton

The grain microstructure of molten pool during the solidification of TC4 titanium alloy in the single point laser cladding was investigated based on the CAFE model which is the cellular automaton (CA) coupled with the finite element (FE) method. The correct temperature field is the prerequisite for simulating the grain microstructure during the solidification of the molten pool. The model solves the energy equation by the FE method to simulate the temperature distribution in the molten pool of the single point laser cladding. Based on the temperature field, the solidification microstructure of the molten pool is also simulated with the CAFE method. The results show that the maximum temperature in the molten pool increases with the laser power and the scanning rate. The laser power has a larger influence on the temperature distribution of the molten pool than the scanning rate. During the solidification of the molten pool, the heat at the bottom of the molten pool transfers faster than that at the top of the molten pool. The grains rapidly grow into the molten pool, and then the columnar crystals are formed. This study has a very important significance for improving the quality of the structure parts manufactured through the laser cladding forming