Computational insights into the generation of chromosomal copy number changes

Deviations from a diploid configuration of the human genome, spanning single genes or entire chromosomes, can have wide-ranging impacts on the variation of human phenotypes, including Mendelian and complex forms of diseases. These chromosomal alterations — such as duplications, deletions or copy-neutral loss-of-heterozygosity — are thus important forms of genetic variation for phenotyping populations of individuals as well as populations of cells. Indeed, copy number variants (CNVs) serve as hallmarks of critical changes in the development of particular diseases such as cancer and thus may be used as biomarkers. These CNVs may be either inherited (transmitted by germ cells, originating in meiosis; “germline”) or acquired (originating in mitosis; “somatic mosaicism”). The complex structure and the diverse mechanisms generating CNVs have been studied molecularly, but this has generally not been attempted using population data. This dissertation seeks to provide insights into CNV diversity in two complementary settings: 1) the genesis of germline copy number duplications, and 2) the diversity of acquired CNVs within distinct tumor tissues. First, we develop a novel method to disentangle the haplotype (the specific alleles on an inherited chromosome) composition of de novo germline duplications to characterize the “grandparental origin” of the extra piece of a chromosome. Using large family-based genome-wide association study data, we report the ratio of “bi-allelic” duplications, from inter-chromatid non-allelic homologous recombination (NAHR), to “tri-allelic” duplications, from inter-chromosomal NAHR, as 1.07:1. In addition, our method reveals a third configuration, consisting of both tri-allelic and bi-allelic duplications, which we hypothesize arose from spontaneous inter-chromosomal and inter-chromatid NAHR. The rate of these complex duplications among all the de novo duplications is 6%. Second, we assess tumor heterogeneity of biphasic uterine carcinosarcoma (UCS) from 10 patients by analyzing the data of component-specific tumor samples (carcinomatous, sarcomatous, and normal uterine tissues), generated from multiple platforms (SNP array, DNA target sequencing, and whole transcriptome sequencing). We augment the quantification of tumor heterogeneity by considering the haplotype information within the somatic copy number alterations for each sample to more precisely annotate recurrent copy number changes. Our results imply that the carcinomatous and the sarcomatous components in UCS originate from the same clone and the heterogeneity reflects relatively advanced stages. Our work confirms that profiling of carcinomas and sarcomas separately may offer clinical utility. Overall, this dissertation shows the potential utility of incorporating haplotype information in particular settings in population science and cancer biology

A Pilot Study of Query-Free Adversarial Attack against Stable Diffusion

Despite the record-breaking performance in Text-to-Image (T2I) generation by Stable Diffusion, less research attention is paid to its adversarial robustness. In this work, we study the problem of adversarial attack generation for Stable Diffusion and ask if an adversarial text prompt can be obtained even in the absence of end-to-end model queries. We call the resulting problem 'query-free attack generation'. To resolve this problem, we show that the vulnerability of T2I models is rooted in the lack of robustness of text encoders, e.g., the CLIP text encoder used for attacking Stable Diffusion. Based on such insight, we propose both untargeted and targeted query-free attacks, where the former is built on the most influential dimensions in the text embedding space, which we call steerable key dimensions. By leveraging the proposed attacks, we empirically show that only a five-character perturbation to the text prompt is able to cause the significant content shift of synthesized images using Stable Diffusion. Moreover, we show that the proposed target attack can precisely steer the diffusion model to scrub the targeted image content without causing much change in untargeted image content.Comment: The 3rd Workshop of Adversarial Machine Learning on Computer Vision: Art of Robustnes

Flat Connections from Irregular Conformal Blocks

In this work we study Liouville conformal blocks with degenerate primaries and one operator in an irregular representation of the Virasoro algebra. Using an algebraic approach, we derive modified BPZ equations satisfied by such blocks and subsequently construct corresponding integral representations based on integration over non-compact Lefschetz cycles. The integral representations are then used to derive novel types of flat connections on the irregular conformal block bundle.Comment: 30 page

Performance Analysis of a Four-Switch Three-Phase Grid-Side Converter with Modulation Simplification in a Doubly-Fed Induction Generator-Based Wind Turbine (DFIG-WT) with Different External Disturbances

This paper investigates the performance of a fault-tolerant four-switch three-phase (FSTP) grid-side converter (GSC) in a doubly-fed induction generator-based wind turbine (DFIG-WT). The space vector pulse width modulation (SVPWM) technique is simplified and unified duty ratios are used for controlling the FSTP GSC. Steady DC-bus voltage, sinusoidal three-phase grid currents and unity power factor are obtained. In addition, the balance of capacitor voltages is accomplished based on the analysis of current flows at the midpoint of DC bus in different operational modes. Besides, external disturbances such as fluctuating wind speed and grid voltage sag are considered to test its fault-tolerant ability. Furthermore, the effects of fluctuating wind speed on the performance of DFIG-WT system are explained according to an approximate expression of the turbine torque. The performance of the proposed FSTP GSC is simulated in Matlab/Simulink 2016a based on a detailed 1.5 MW DFIG-WT Simulink model. Experiments are carried out on a 2 kW platform by using a discrete signal processor (DSP) TMS320F28335 controller to validate the reliability of DFIG-WT for the cases with step change of the stator active power and grid voltage sag, respectively