Approaches to grid-based SAT solving

In this work we develop techniques for using distributed computing resources to efficiently solve instances of the propositional satisfiability problem (SAT). The computing resources considered in this work are assumed to be geographically distributed and connected by a non-dedicated network. Such systems are typically referred to as computational grid environments. The time a modern SAT solver consumes while solving an instance varies according to a random distribution. Unlike many other methods for distributed SAT solving, this work identifies the random distribution as a valuable resource for solving-time reduction. The methods which use randomness in the run times of a search algorithm, such as the ones discussed in this work, are examples of multi-search. The main contribution of this work is in developing and analyzing the multi-search approach in SAT solving and showing its efficiency with several experiments. For the purpose of the analysis, the work introduces a grid simulation model which captures several of the properties of a grid environment which are not observed in more traditional parallel computing systems. The work develops two algorithmic frameworks for multi-search in SAT. The first, SDSAT, is based on using properties of the distribution of the solving time so that the expected time required to solve an instance is reduced. Based on the analysis of SDSAT, the work proposes an algorithm for efficiently using large number of computing resources simultaneously to solve collections of SAT instances. The analysis of SDSAT also motivates the second algorithmic framework, CL-SDSAT. The framework is used to efficiently solve many industrial SAT instances by carefully combining information learned in the distributed SAT solvers. All methods described in the work are directly applicable in a wide range of grid environments and can be used together with virtually unmodified state-of-the-art SAT solvers. The methods are experimentally verified using standard benchmark SAT instances in a production-level grid environment. The experiments show that using the relatively simple methods developed in the work, SAT instances which cannot be solved efficiently in sequential settings can be now solved in a grid environment

Modelling timing in blood cancers

Dysregulation of biological processes in normal cells can lead to the abnormal growth of tumours. Oncogenesis requires the acquisition of advantageous mutations to expand in a fluctuating environment. Cancer cells gain these genetic and epigenetic alterations at different timing in their development, resulting in the formation of heterogeneous cell populations which interact and compete with each others inside tumours. At later stages, by escaping the immune system and acquiring malignant properties, some cancer cells manage to evade the primary tumour and spread in different organs to form metastases. Hence, tumour development in healthy tissues endure several biological changes whilst progressing and the order between these molecular and cellular events may modify prognosis. This thesis addresses the influence of biological event timing on blood cancer progression and clinical outcomes. It first investigates the therapeutic efficacy of p53 restoration in a lymphoma mouse model. While several therapy schedules are tested, all fail due to resistance emergence. Computational modelling establishes the cell dynamics in these tumours and how to use it to propose alternative treatment strategies. Data availability leads this work to explore the impact of molecular evolution in myeloid malignancies. Notably, one study has found that Myeloproliferative Neoplasms patients with both JAK2 and TET2 mutations have different disease characteristics with distinct mutation order. My analyses identify HOXA9 as a potential prognosis marker and biological switch responsible for patient stratification in these patients and in Acute Myeloid Leukemia. Additionally, a molecular network identifies the hematopoietic regulators involved in the branching evolution of Myeloproliferative Neoplasms. Further investigations of the Acute Myeloid Leukemia data show the possible involvement of APP, a gene associated to Alzheimer disease, in early cell fate commitment in hematopoiesis and in poor survival prognosis in undifferentiated leukemia when lowly expressed. Finally, this thesis examines the regulatory dynamics behind three clusters of Acute Myeloid Leukemia patients with distinct levels of HOXA9 and APP expression. By building a program inferring molecular motifs from biological observations, genes which may interact with HOXA9 and APP are identified.Microsoft Research and the MRC Cancer Unit