Contractor Programming

WOSInternational audienceThis paper describes a solver programming method, called "contractor programming", that copes with two issues related to constraint processing over the reals. First, continuous constraints involve an inevitable step of solver design. Existing softwares provide an insufficient answer by restricting users to choose among a list of fixed strategies. Our first contribution is to give more freedom in solver design by introducing programming concepts where only configuration parameters were previously available. Programming consists in applying operators (intersection, composition, etc.) on algorithms called "contractors" that are somehow similar to propagators. Second, many problems with real variables cannot be cast as the search for vectors simultaneously satisfying the set of constraints, but a large variety of different outputs may be demanded from a set of constraints (e.g., a paving with boxes inside and outside of the solution set). These outputs can actually be viewed as the result of different "contractors" working concurrently on the same search space, with a bisection procedure intervening in case of deadlock. Such algorithms (which are not strictly speaking solvers) will be made easy to build thanks to a new branch & prune system, called "paver". Thus, this paper gives a way to deal harmoniously with a larger set of problems while giving a fine control on the solving mechanisms. The contractor formalism and the paver system are the two contributions. The approach is motivated and justified through different cases of study. An implementation of this framework named Quimper is also presented

Upper Bounding in Inner Regions for Global Optimization under Inequality Constraints

International audienceIn deterministic continuous constrained global optimization, upper bounding the objective function generally resorts to local minimization at several nodes/iterations of the branch and bound. We propose in this paper an alternative approach when the constraints are inequalities and the feasible space has a non-null volume. First, we extract an inner region , i.e., an entirely feasible convex polyhedron or box in which all points satisfy the constraints. Second, we select a point inside the extracted inner region and update the upper bound with its cost. We describe in this paper two original inner region extraction algorithms implemented in our interval B&B called IbexOpt. They apply to nonconvex constraints involving mathematical operators like +,x,power,sqrt,exp,log,sin. This upper bounding shows very good performance obtained on medium-sized systems proposed in the COCONUT suite

Rigorous solution techniques for numerical constraint satisfaction problems

A constraint satisfaction problem (e.g., a system of equations and inequalities) consists of a finite set of constraints specifying which value combinations from given variable domains are admitted. It is called numerical if its variable domains are continuous. Such problems arise in many applications, but form a difficult problem class since they are NP-hard. Solving a constraint satisfaction problem is to find one or more value combinations satisfying all its constraints. Numerical computations on floating-point numbers in computers often suffer from rounding errors. The rigorous control of rounding errors during numerical computations is highly desired in many applications because it would benefit the quality and reliability of the decisions based on the solutions found by the computations. Various aspects of rigorous numerical computations in solving constraint satisfaction problems are addressed in this thesis: search, constraint propagation, combination of inclusion techniques, and post-processing. The solution of a constraint satisfaction problem is essentially performed by a search. In this thesis, we propose a new complete search technique (i.e., it can find all solutions within a predetermined tolerance) for numerical constraint satisfaction problems. This technique is general and can be used in place of branching steps in most branch-and-prune methods. Moreover, this new technique speeds up the most recent general search strategy (often by an order of magnitude) and provides a concise representation of solutions. To make a constraint satisfaction problem easier to solve, a major approach, called constraint propagation, in the constraint programming1 field is often used to reduce the variable domains (by discarding redundant value combinations from the domains). Basing on directed acyclic graphs, we propose a new constraint propagation technique and a method for coordinating constraint propagation and search. More importantly, we propose a novel generic scheme for combining multiple inclusion techniques2 in numerical constraint propagation. This scheme allows bringing into the constraint propagation framework the strengths of various techniques coming from different fields. To illustrate the flexibility and efficiency of the generic scheme, we base on this scheme and devise several specific combination strategies for rigorous numerical constraint propagation using interval constraint propagation, interval arithmetic, affine arithmetic, and linear programming. Our experiments show that the new propagation techniques outperform previously available methods by 1 to 4 orders of magnitude or more in speed. We also propose several post-processing techniques for the representation of continuums of solutions. Based on connectedness, they allow grouping each cluster of connected solution subsets into a larger subset, thus allowing getting additional grouping information. Potentially, these techniques enable interval-based solution techniques to be alternatives to bounding-volume techniques in applications such as collision detection and interactive graphics. __________________________________________________ 1 Constraint programming is an approach to programming that relies on both reasoning and computing. 2 An inclusion technique is to include a set of interest into enclosures. It is also called an enclosure technique

Involvement of aberrant chromosome architecture and locus-specific vulnerability to DNA methylation epimutations in bovine large offspring syndrome

Large/abnormal offspring syndrome (LOS/AOS) and Beckwith-Wiedemann syndrome (BWS) are similar congenital overgrowth syndromes which occur naturally in ruminants and humans, respectively. The incidence of these syndromes increases when offspring are conceived with the use of assisted reproductive technologies (ART; i.e. in vitro oocyte maturation, in vitro fertilization, and embryo culture). Molecular defects reported in both syndromes include global gene misregulation, DNA methylome epimutations, and disruption of genomic imprinting (parental-allele-specific gene expression). Although we have reported that bovine LOS occurs spontaneously (SLOS) based on phenotypic similarities to ART-LOS, to date no study has been conducted to determine if SLOS has the same methylome epimutations as ART-LOS. One goal of my dissertation research is to characterize DNA methylation profiles in bovine SLOS and ART-LOS to determine whether there are conserved genomic loci with DNA methylation defects between these overgrowth conditions. In addition, while it is known that LOS is characterized by global alterations in DNA methylation, it is largely unknown how altered DNA methylation drives the development of LOS, as the methylation errors (i.e., differentially methylated regions; DMRs) observed in the syndrome only explain [less than] 4 percent of the gene misregulation in short range (the flanking 20,000 DNA bases from the DMR). Therefore, another goal of my dissertation research is to determine whether long-range regulatory mechanisms of gene expression, such as chromosome architecture, is altered in LOS as a result of aberrant DNA methylation. In this dissertation, Chapter 1 is the literature review and will introduce epigenetic regulation of gene expression including chromosome architecture and clinical features and molecular findings of LOS and BWS. Chapter 2 and 3 are the research chapters. In Chapter 2, I characterize allele-specific chromosome architecture of IGF2R imprinted domain in fibroblast cells derived from control bovine fetuses and identified disrupted chromosome architecture in LOS. I also observed genomic location-based clustering tendency of misregulated genes in LOS. This study has been published in the Journal iScience (https://doi.org/10.1016/j.isci.2022.104269) (Li et al., 2022). In Chapter 3, I determined that bovine SLOS has DNA methylation defects with some similarities and differences when compared to ART-LOS. I also identified vulnerable genomic loci for DNA methylation defects in LOS, which could serve as molecular markers for the diagnosis of the syndrome during early pregnancy. This study has been published in the journal Epigenetics (https://doi.org/10.1080/15592294.2022.2067938). Chapter 4 is the general discussion in which my research findings are incorporated into the general knowledge of the field and implications and directions of future studies are discussed. In Appendix 1, I briefly introduce our ongoing Hi-C (global chromosome architecture), methylome and transcriptome project in which samples from LOS and BWS will be analyzed together to further shed light into the etiology of these syndromes, knowledge that will equally help Agriculture and Biomedicine. I anticipate submitting this manuscript for peer review and publication in July of 2022, thus becoming the third primary literature manuscript from my dissertation research. Appendix 2 is a review paper in which I am main contributor author published in Veterinary Clinics of North America: Food Animal Practice in 2019 (PMID: 31103180, https://doi.org/10.1016/j.cvfa.2019.02.007). This review summarized clinical and molecular findings in LOS and for the first time reported the existence of SLOS. Lastly, Appendix 3 summarizes my contributions of five other publications in which I collaborated with groups in the Division, at Mizzou, and other Academic institutions in the USA during my tenure as a PhD student.Includes bibliographical references

Modifying Anthocyanins Biosynthesis in Tomato Hairy Roots:A Test Bed for Plant Resistance to Ionizing Radiation and Antioxidant Properties in Space

Gene expression manipulation of specific metabolic pathways can be used to obtain bioaccumulation of valuable molecules and desired quality traits in plants. A single-gene approach to impact different traits would be greatly desirable in agrospace applications, where several aspects of plant physiology can be affected, influencing growth. In this work, MicroTom hairy root cultures expressing a MYB-like transcription factor that regulates the biosynthesis of anthocyanins in Petunia hybrida (PhAN4), were considered as a testbed for bio-fortified tomato whole plants aimed at agrospace applications. Ectopic expression of PhAN4 promoted biosynthesis of anthocyanins, allowing to profile 5 major derivatives of delphinidin and petunidin together with pelargonidin and malvidin-based anthocyanins, unusual in tomato. Consistent with PhAN4 features, transcriptomic profiling indicated upregulation of genes correlated to anthocyanin biosynthesis. Interestingly, a transcriptome reprogramming oriented to positive regulation of cell response to biotic, abiotic, and redox stimuli was evidenced. PhAN4 hairy root cultures showed the significant capability to counteract reactive oxygen species (ROS) accumulation and protein misfolding upon high-dose gamma irradiation, which is among the most potent pro-oxidant stress that can be encountered in space. These results may have significance in the engineering of whole tomato plants that can benefit space agriculture

Discovery of small molecule modulators for Eps15 homology domain containing proteins

Eps15 (epidermal growth factor receptor pathway substrate 15) homology domain containing proteins (EHDs) comprise a family of dynamin-related ATPases. The four mammalian members of this family (EHD1-4) are involved in various endocytic and membrane trafficking pathways. Structural studies revealed that EHDs assemble at the surface of membranes to form ring-like filaments. Assembly on membranes was shown to stimulate the ATPase activity. In case of EHD2, ring-like oligomers were proposed to stabilize the neck of caveolae, which in turn regulates cellular fatty acid uptake. The aim of this thesis was the identification of small molecule inhibitors that modulate EHD2 function and therefore cellular fatty acid uptake. Until now, there are no known inhibitors for EHD proteins. To this end, I optimized a malachite green-based ATPase assay to be robust and reproducible for a high-throughput setup. Drug screening was then employed to identify small molecules that inhibit the liposome-stimulated ATP hydrolysis of EHDs. Since EHD2 showed only a low ATPase activity, I initially screened for inhibitors against the closely related homologue EHD4. Validated hits were subsequently evaluated for inhibition against EHD2 in an HPLC-based setup. In this way, I identified chemical compounds that inhibited the ATPase activity of EHD4 and EHD2, and validated them in different biochemical assays. Interestingly, two of these small molecules were found to increase and decrease lipid droplet size in a cell-based assay. I also identified three inhibitors that were specific to EHD4 and did not interfere with the ATPase of EHD2 and the GTPase activity of Drp1, which was used as a control. Another exciting finding in this project were discovery of two compounds that accelerated the liposome-stimulated GTPase activity of Drp1. The identified inhibitors may have future applications to explore the function of EHDand Drp1-dependent cellular signaling pathways. Furthermore, they may be developed as therapeutic agents. Finally, my assay optimizations can be used to systematically and efficiently identify inhibitors for other dynamin superfamily membersEps15 (epidermal growth factor receptor pathway substrate 15) homology domain containing proteins (EHDs) umfassen eine Familie von Dynamin-verwandten ATPasen. Die vier Säugetiermitglieder dieser Familie (EHD1-4) sind in verschiedenen endozytischen- und Membran-Transportwegen beteiligt. Strukturelle Studien zeigten, dass sich EHDs an der Oberfläche von Membranen zu ringförmigen Filamenten zusammenlagern, wobei die Anordnung an Membranen die ATPase-Aktivität stimuliert. Im Fall von EHD2 wurden ringförmige Oligomere vorgeschlagen, die den Hals von Caveolae stabilisieren, was wiederum die zelluläre Fettsäureaufnahme reguliert. Das Ziel dieser Arbeit war die Identifizierung niedermolekularer Inhibitoren, die die EHD2-Funktion und damit die zelluläre Fettsäureaufnahme modulieren. Bisher sind keine Inhibitoren für EHD-Proteine bekannt. Zu diesem Zweck optimierte ich einen auf Malachitgrün-basierenden ATPase-Assay, um ihn robust und reproduzierbar für einen Hochdurchsatz-Screen zu machen. Anschließend wurde ein Inhibitorscreening durchgeführt, um kleine Moleküle zu identifizieren, die die Liposomen-stimulierte ATP-Hydrolyse von EHDs hemmen. Da EHD2 nur eine geringe ATPase-Aktivität zeigte, suchte ich zunächst nach Inhibitoren gegen das engverwandte Homolog EHD4. Validierte Hits wurden anschließend in einem HPLC-basierten Setup auf Hemmung gegen EHD2 ausgewertet. Auf diese Weise habe ich chemische Verbindungen identifiziert, die die ATPase-Aktivität von EHD4 und EHD2 hemmen, die ich in verschiedenen biochemischen Assays validiert habe. Interessanterweise wurde festgestellt, dass zwei dieser kleinen Moleküle in einem zellbasierten Assay Einfluss auf die Lipidtröpfchengröße haben, d.h. diese vergrößern oder verringern. Ich identifizierte auch drei Inhibitoren, die spezifisch für EHD4 waren und nicht die ATPase von EHD2 und die GTPase-Aktivität von Drp1 stören, welche als Kontrolle verwendet wurden. Eine aufregende Entdeckung in diesem Projekt waren zwei Verbindungen, die die Liposomen-stimulierte GTPase-Aktivität von Drp1 beschleunigten. Die identifizierten Inhibitoren können in zukünftigen Studien zur detaillierten Untersuchung der zellulären Funktion von EHD- und Drp1-abhängigen Signalwegen genutzt werden. Darüber hinaus können sie als Therapeutika weiter entwickelt werden. Letztendlich können meine Assay-Optimierungen auch verwendet werden, um Inhibitoren für andere Mitglieder der Dynamin-Superfamilie systematisch und effizient zu identifizieren

Abeta42 oligomers trigger synaptic loss through AMPK-dependent activation of mitochondrial fission and mitophagy

The following dissertation discusses the role of Aβ42 dependent hyperactivation of AMPK mediating synaptic loss through coordinated Mff-dependent mitochondrial fission and Ulk2-dpendent mitophagy in dendrites of PNs. In Chapter 1, I provide a brief background on Alzheimer’s disease and the cellular and molecular mechanisms that have been relevant to the pathogenesis of the disease including disruption on mitochondrial homeostasis and autophagy. In Chapter 2, I discuss the findings of my main project describing the role of Aβ42 induced mitochondrial remodeling leading to synapse loss in vitro and in vivo in part by hyperactivation of CAMKKII-AMPK. Chapter 3 covers a review article that I participated in in examining the role of mitochondria in various ND. In Chapter 4, I discuss about a project I was involved in in examining the mechanism behind maintaining mitochondrial morphology in axon versus dendrite and its functional consequence. In Chapter 5, I end the dissertation by highlighting key findings, potential future studies, and concluding remarks

Optimization with interval data: new problems, algorithms, and applications.

The parameters of real-world optimization problems are often uncertain due to the failure of exact estimation of data entries. Throughout the years, several approaches have been developed to cope with uncertainty in the input parameters of optimization problems, such as robust optimization, stochastic optimization, fuzzy programming, parametric programming, and interval optimization. Each of these approaches tackles the uncertainty in the input data with different assumptions on the source of uncertainty and imposes different requirements on the returned solutions. In this dissertation, the approach we take is that of interval optimization, and more specifically, interval linear programming. The two main problems we consider in this context are, considering all realizations of the interval data, the problems of finding the range of the optimal values and determining the set of all possible optimal solutions. While the theoretical aspects of these problems are well-studied, the algorithmic aspects and the engineering implications have not been explored. In this dissertation, we partially fill these voids. In the first part of the dissertation, we present and test three heuristics to find bounds on the worst optimal value of the equality-constrained interval linear program, which is known to be an intractable problem. In the second part of the dissertation, motivated by a real-case problem in the healthcare context, we define and analyze a new problem, the outcome range problem, in interval linear programming. The solution to the problem would help decision-makers quantify unintended/further consequences of optimal decisions made under uncertainty. Basically, the problem finds the range of an extra function of interest (different from the objective function) over all possible optimal solutions of an interval linear program. We analyze the problem from the theoretical and algorithmic perspectives. We evaluate the performance of our algorithms on simulated problem instances and on a real-world healthcare application. In the third part of the dissertation, we extend our analysis of the outcome range problem, exploring different theoretical properties and designing several new solution algorithms. We also test our solution approaches on different datasets, highlighting the strengths and weaknesses of each approach. Finally, in the last part of the dissertation, we discuss an application of interval optimization in the sensor location problem in the traffic management context. Particularly, we propose an optimization approach to handle the measurement errors in the full link flow observability problem. We show the applicability of our approach on several real-world traffic networks