A Pathogenic Mosaic TP53 Mutation in Two Germ Layers Detected by Next Generation Sequencing.

Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described

Reads in NGS Are Distributed over a Sequence Very Inhomogeneously

Distribution of read starts over a sequences genetic entity is studied. Key question was whether the starts are distributed uniformly and homogeneously along a sequence, or there exist some spots of the increased local density of the starts. To answer the question, 15 bacterial genomes have been studied. It was found that some genomes exhibit extremely far distribution pattern, from an homogeneity, while others show lower level of the inhomogeneity. The inhomogeneity level was determined through the Kullback-Leibler distance between the real string distribution, and that one bearing the most probable continuations of the shorter strings. © 2019, Springer Nature Switzerland AG

Adaptations of neutrality tests

Most of the genetic variation observed within a biological species is generally thought to be evolutionary “neutral” in the sense that it is irrelevant for an individuum whether its genome contains one particular variant or another. Evolutionary biologists, and in the case of the human species anthropologists and medical scientists as well, are by contrast interested in variants which do influence on an individual’s survival and/or its ability to reproduce. Population geneticists try to find such variants by purely statistical methods in the form of tests on neutrality or shortly neutrality tests. In this thesis four publications are reprinted and discussed which are concerned with modifications of existing neutrality tests. Three of them deal with a class of tests relying on the so-called site frequency spectrum. It was shown previously that some of these tests, originally designed on models of constant population size, can be adapted to allow for changes in population size. This is generalized in the first publication to all tests of similar structure. Another aspect of these tests is that they are ignorant with respect to which variant in a sample might evolve non-neutrally. If instead a particular variant is suspected a priori, the tests have to allow for this information by conditioning on the existence of a variant with the observed frequency. The second and third article introduce the concept of a conditional frequency spectrum and derive its first resp. second moments which are necessary for an appropriate extension of the above-mentioned class of tests. The fourth article presents an algorithmic improvement of a neutrality test of a different kind. Here, primarily computational speed was of concern, in order to bear comparison with competing software. Solely applications on human data are presented, which is available in unrivalled abundance, owing to several large-scale genotyping and sequencing projects. The applicability of neutrality tests, however, is not confined to any particular species

Modelling of behaviour of metals at high strain rates

The aim of the work presented in this thesis was to produce the improvement of the existing simulation tools used for the analysis of materials and structures, which are dynamically loaded and subjected to the different levels of temperatures and strain rates. The main objective of this work was development of tools for modelling of strain rate and temperature dependant behaviour of aluminium alloys, typical for aerospace structures with pronounced orthotropic properties, and their implementation in computer codes. Explicit finite element code DYNA3D has been chosen as numerical test-bed for implementation of new material models. Constitutive model with an orthotropic yield criterion, damage growth and failure mechanism has been developed and implemented into DYNA3D. Second important aspect of this work was development of relatively simple experimental methods for characterization of engineering materials, and extensive experimental work has been undertaken. Tensile test has been used for the characterisation of two aluminium alloys, at different levels of the strain rates and temperatures, and for three different orientations of materials. The results from these tests allowed derivation of material constants for constitutive models and lead to a better understanding of aluminium alloy behaviour. Procedures for derivation of parameters for temperature and strain rate dependant strength models were developed and parameters for constitutive relations were derived on the basis of uniaxial tensile tests. Taylor cylinder impact test was used as a validation experiment. This test was used to validate the implementation, and accuracy of material model in computer code. At the end of each incremental development, validation of the constitutive material model has been performed through numerical simulations of Taylor cylinder impact test, where simulation results have been compared with the experimental post-test geometries in terms of major and minor side profiles and impact-interface footprints. Plate impact test has been used to determine the material properties at high strain rate, and to investigate damage evolution in impact-loaded material. Initially the material model has been designed as a temperature and strain rate dependant strength model in a simple isotopic form, which then has been tested and verified against the experimental results. Coupling of the Hill’s orthotropic yield criterion with isotropic, temperature and strain rate dependant, hardening material model, has been chosen to suit the orthotropic behaviour. Method for calibration of orthotropic yield criterion has been developed and parameters have been identified for the orthotropic model under the associated flow rule assumption and in case of plane stress on the basis of tensile and cylinder impact tests. The complexity of the model has been further increased through coupling of hardening model with orthotropic yield criterion including damage evolution and failure criteria. The constitutive model was developed within the general framework of continuum thermodynamics for irreversible processes, and plate impact test and tensile tests have been used for determination of parameters for damage part of the new material model