Neutral Networks of Real-World Programs and their Application to Automated Software Evolution

The existing software development ecosystem is the product of evolutionary forces, and consequently real-world software is amenable to improvement through automated evolutionary techniques. This dissertation presents empirical evidence that software is inherently robust to small randomized program transformations, or \u27mutations. Simple and general mutation operations are demonstrated that can be applied to software source code, compiled assembler code, or directly to binary executables. These mutations often generate variants of working programs that differ significantly from the original, yet remain fully functional. Applying successive mutations to the same software program uncovers large \u27neutral networks\u27 of fully functional variants of real-world software projects. These properties of \u27mutational robustness\u27 and the corresponding \u27neutral networks\u27 have been studied extensively in biology and are believed to be related to the capacity for unsupervised evolution and adaptation. As in biological systems, mutational robustness and neutral networks in software systems enable automated evolution. The dissertation presents several applications that leverage software neutral networks to automate common software development and maintenance tasks. Neutral networks are explored to generate diverse implementations of software for improving runtime security and for proactively repairing latent bugs. Next, a technique is introduced for automatically repairing bugs in the assembler and executables compiled from off-the-shelf software. As demonstration, a proprietary executable is manipulated to patch security vulnerabilities without access to source code or any aid from the software vendor. Finally, software neutral networks are leveraged to optimize complex nonfunctional runtime properties. This optimization technique is used to reduce the energy consumption of the popular PARSEC benchmark applications by 20% as compared to the best available public domain compiler optimizations. The applications presented herein apply evolutionary computation techniques to existing software using common software engineering tools. By enabling evolutionary techniques within the existing software development toolchain, this work is more likely to be of practical benefit to the developers and maintainers of real-world software systems

Unveiling combinatorial regulation through the combination of ChIP information and in silico cis-regulatory module detection

Computationally retrieving biologically relevant cis-regulatory modules (CRMs) is not straightforward. Because of the large number of candidates and the imperfection of the screening methods, many spurious CRMs are detected that are as high scoring as the biologically true ones. Using ChIP-information allows not only to reduce the regions in which the binding sites of the assayed transcription factor (TF) should be located, but also allows restricting the valid CRMs to those that contain the assayed TF (here referred to as applying CRM detection in a query-based mode). In this study, we show that exploiting ChIP-information in a query-based way makes in silico CRM detection a much more feasible endeavor. To be able to handle the large datasets, the query-based setting and other specificities proper to CRM detection on ChIP-Seq based data, we developed a novel powerful CRM detection method 'CPModule'. By applying it on a well-studied ChIP-Seq data set involved in self-renewal of mouse embryonic stem cells, we demonstrate how our tool can recover combinatorial regulation of five known TFs that are key in the self-renewal of mouse embryonic stem cells. Additionally, we make a number of new predictions on combinatorial regulation of these five key TFs with other TFs documented in TRANSFAC

Identification of the mRNA targets of tRNA-specific regulation using genome-wide simulation of translation

FUNDING Biotechnology and Biological Sciences Research Council (BBSRC) [BB/I020926/1 to I.S.]; BBSRC PhD studentship award [C103817D to I.S. and M.C.R.]; Scottish Universities Life Science Alliance PhD studentship award (to M.C.R. and I.S.]. Funding for open access charge: BBSRC. Conflict of interest statement. None declared.Peer reviewedPublisher PD

Discovering and Understanding High Performance Materials using Density Functional Theory: Quantum Mechanical Simulations and the Consequences of Symmetry

There are two primary ways that atomic level modeling data is used: materials prediction and understanding materials properties. This dissertation work encom- passes two studies, each of which explore one application. Both studies rely on the highly successful density functional theory (DFT) formalism but differ in that two different implementations of DFT are used on two different high performance materials. The first study on bulk magnesium (Mg) metal alloys explores materials prediction and relies on VASP, a commercially maintained plane-wave DFT code which has been used extensively to successfully study a wide range of materials. [1] The approach used in this first study is to ‘experiment’ within computational quantum mechanical simulations to improve the elastic properties of bulk Mg by altering its HCP lattice structure. We systematically study the influence of adding lithium (Li) as an alloy for two reasons: to maintain the lightweight benefits of Mg, and Li naturally occurs in a body centered cubic (BCC) crystal structure. The hypothesis is that an alloy with a more symmetric crystal structure will show im- proved properties, however we do not place any symmetry restrictions on the results of the structure search. We find that the addition of Li to Mg does improve the elastic properties of the resulting alloys; however it does not necessarily increase the symmetry. Five structures are found which belong to the convex hull, three of which are previously unreported. The second DFT study seeks to understand the electronic environment within lead sulfur (PbS) semiconductor nano-structures and utilizes the open-source Octopus code, designed for electron-ion dynamics in finite systems using time-dependent DFT in real time and real space and which has also been bench-marked extensively [2]. The aim of the second study is to understand at the most fundamental levels the impact reduced symmetry has on the electronic states and transitions at the level of the individual IR-light-absorbing quantum dot. We employ three toy models to isolate the impacts of reduced coordination, Pb-rich structures, and Peierls distortions. An in-depth analysis of the bonding through the charge density and electron localization function shows that the metavalent bonding observed in bulk PbS persists in the nanoscale regime. Changing the stoichiometry too far away from Pb:S = 1:1 results in the loss of semiconducting character and an overall metallic character prevails. When we place particular attention on the effects of atomic coordination, we observe enhanced electron localization clustered around the lowest coordinated atoms. Peierls distortions intensify the clustering behavior which lowers the energy of the occupied electronic states and increases the energy of the unoccupied states as deduced from density of states plots. The change in the electron localization is substantial only for a significant amount of low-coordinated atoms. A conclusion is made with an outlook to future work

SRSF2 Is Essential For Hematopoiesis and Its Mutations Dysregulate Alternative RNA Splicing In MDS

Abstract Myelodysplastic syndromes (MDS) are a group of neoplasms that are ineffective in generating multiple lineages of myeloid cells and have various risks to progress to acute myeloid leukemia. Recent genome-wide sequencing studies reveal that mutations in genes of splicing factors are commonly associated with MDS. However, the importance of these splicing factors in hematopoiesis has been unclear and the causal effect of their mutations on MDS development remains to be determined. One of these newly identified genes is SRSF2, and its mutations have been linked to poor survival among MDS patients. Interestingly, most of SRSF2 mutations occur at proline 95 and the majority of these mutations change this proline to histidine (P95H). Given that SRSF2 is a well-characterized splicing factor involved in both constitutive and regulated splicing, we hypothesize that SRSF2 plays an important role in normal hematopoiesis and the SRSF2 mutations induce specific changes in alternative splicing that favor disease progression. We first examined the role of SRSF2 in hematopoiesis by generating Srsf2 null mutation in mouse blood cells via crossing conditional Srsf2 knockout mice (Srsf2f/f) with blood cell-specific Cre transgenic mice (Vav-Cre). The mutant mice produced significantly fewer definitive blood cells (10% of wild type controls), exhibited increased apoptosis in the remaining blood cells, and died during embryonic development. Importantly, we detected no hematopoietic stem/progenitor cells (lineage-/cKit+) in E14 fetal livers of Vav-Cre/Srsf2f/f mice. These results indicate that SRSF2 is essential for hematopoiesis during embryonic development. We next examined the role of SRSF2 in adult hematopoiesis by injecting polyIC into mice that carry a polyIC inducible Cre expression unit. Unexpectedly, after multiple polyIC treatments, the Srsf2f/f mice stayed alive during several months of observation. Time course genotyping analyses of polyIC treated mice revealed an increased rate of incomplete Srsf2 deletion in peripheral blood cells. These observations suggest that Srsf2 ablation did not cause immediate cell lethality in differentiated blood cells, but the gene is indispensable for the function of blood stem/progenitor cells. Since mutations of splicing factors are generally heterozygous in MDS patients, we also examined mice with Srsf2+/- blood cells. No obvious defect of hematopoiesis was observed under normal conditions or in response to stress with 5-FU treatment and sublethal irradiation. To gain molecular insight into the splicing activity of MDS-associated mutant forms of SRSF2, we performed large-scale alternative splicing surveys by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq) previously developed in our lab, which offers a robust and cost-effective platform for splicing profiling. Compared to vector transduction controls, we found that overexpression of both wild type and P95H SRSF2 induced many, but distinct changes in alternative splicing in lineage-negative bone marrow cells, and importantly, we noted several changes in genes with known roles in hematopoietic malignancies that were uniquely induced by the mutant SRSF2. To further link the mutations to altered splicing in MDS patients, we also applied RASL-seq to a large number of MDS patient samples with or without mutations in SRSF2 or other splicing regulators. The data revealed a specific set of alternative splicing events that are commonly linked to MDS with splicing factor mutations. These findings strongly suggest that many of these mutations in splicing regulators are gain-of-function mutations that are causal to MDS. In conclusion, we report that SRSF2 plays an essential role in hematopoietic stem/progenitor cells and that the MDS-associated mutations in SRSF2 have a dominant effect on RNA alternative splicing. These findings provide functional information and molecular basis of SRSF2 and its MDS-related mutations in hematopoiesis and related clinical disorders. Disclosures: No relevant conflicts of interest to declare

Frontiers, challenges, and solutions in modeling of swift heavy ion effects in materials

Since a few breakthroughs in the fundamental understanding of the effects of swift heavy ions (SHI) decelerating in the electronic stopping regime in the matter have been achieved in the last decade, it motivated us to review the state-of-the-art approaches in the modeling of SHI effects. The SHI track kinetics occurs via several well-separated stages: from attoseconds in ion-impact ionization depositing energy in a target, to femtoseconds of electron transport and hole cascades, to picoseconds of lattice excitation and response, to nanoseconds of atomic relaxation, and even longer macroscopic reaction. Each stage requires its own approaches for quantitative description. We discuss that understanding the links between the stages makes it possible to describe the entire track kinetics within a multiscale model without fitting procedures. The review focuses on the underlying physical mechanisms of each process, the dominant effects they produce, and the limitations of the existing approaches as well as various numerical techniques implementing these models. It provides an overview of ab-initio-based modeling of the evolution of the electronic properties; Monte Carlo simulations of nonequilibrium electronic transport; molecular dynamics modeling of atomic reaction on the surface and in the bulk; kinetic Mote Carlo of atomic defect kinetics; finite-difference methods of tracks interaction with chemical solvents describing etching kinetics. We outline the modern methods that couple these approaches into multiscale multidisciplinary models and point to their bottlenecks, strengths, and weaknesses. The analysis is accompanied by examples of important results improving the understanding of track formation in various materials. Summarizing the most recent advances in the field of the track formation process, the review delivers a comprehensive picture and detailed understanding of the phenomena.Comment: to be submitte

Chromosome segregation drives division site selection in Streptococcus pneumoniae.

Accurate spatial and temporal positioning of the tubulin-like protein FtsZ is key for proper bacterial cell division. <i>Streptococcus pneumoniae</i> (pneumococcus) is an oval-shaped, symmetrically dividing opportunistic human pathogen lacking the canonical systems for division site control (nucleoid occlusion and the Min-system). Recently, the early division protein MapZ was identified and implicated in pneumococcal division site selection. We show that MapZ is important for proper division plane selection; thus, the question remains as to what drives pneumococcal division site selection. By mapping the cell cycle in detail, we show that directly after replication both chromosomal origin regions localize to the future cell division sites, before FtsZ. Interestingly, Z-ring formation occurs coincidently with initiation of DNA replication. Perturbing the longitudinal chromosomal organization by mutating the condensin SMC, by CRISPR/Cas9-mediated chromosome cutting, or by poisoning DNA decatenation resulted in mistiming of MapZ and FtsZ positioning and subsequent cell elongation. Together, we demonstrate an intimate relationship between DNA replication, chromosome segregation, and division site selection in the pneumococcus, providing a simple way to ensure equally sized daughter cells

Global Warming and the Problem of Policy Innovation: Lessons From the Early Environmental Movement

When it comes to influencing government decisions, special interests have some built-in advantages over the general public interest. When the individual members of special interest groups have a good deal to gain or lose as a result of government action, special interests can organize more effectively, and generate benefits for elected officials, such as campaign contributions and other forms of political support. They will seek to use those advantages to influence government decisions favorable to them. The public choice theory of government decision making sometimes comes close to elevating this point into a universal law, suggesting that the general public interest can never prevail over powerful special interests. In the period of the late 1960s and early 1970s, however, Congress enacted numerous significant environmental laws, laws that continue to form the backbone of federal policies toward environmental problems. These laws were truly innovative in their policies and their designs, and they pitted the general public interest in improving environmental quality against powerful, special interests. In each case, the general public interest was able to prevail. This policy “window” did not stay open for long. It was quickly succeeded by an extended period in which enacting additional innovative statutes has proven nearly impossible, which continues to this day. Yet we need innovative approaches to address continuing and emerging environmental problems more than ever. This is self-evidently true with respect to the problem of global warming and climate change. The questions worth asking are whether we can identify the factors that once made policy innovation possible in the late 1960s and early 1970s and if those factors can be produced once again. For the public’s David to be able to stand up against the special interest Goliaths, a broad base of the public must first be mobilized, and then that mobilization must be sustained, which typically occurs when the public embraces a sense of great urgency. Urgency can be generated when the public appreciates that failure to address a problem threatens them or their loved ones with significant harm. Media attention plays a key role in creating the public’s awareness of any urgent problem. These factors can succeed in putting general concerns of the public on the public agenda, at which time acceptable proposals for workable solutions need to be available. When the first window for policy innovation opened up in the late 1960s and early 1970s, each of these favorable factors was present for many of our conventional pollution problems. At the same time, the strength of the special interests was at a low ebb. This Essay argues that under current circumstances, the conditions for policy innovation are not yet as favorable as they were in this earlier period. Strong presidential leadership may be capable of altering those conditions, but as yet the public’s concern about the adverse effects of climate change does not appear to have achieved the same strength or intensity as comparable concerns over conventional pollution problems had earlier