Développement d'une technique d'acquisition de contraintes basée sur le nombre de solutions

Plusieurs paradigmes de programmation existent pour aider à résoudre des problèmes d'optimisation combinatoire, l'un d'entre eux étant la programmation par contraintes. L'idée de ce paradigme consiste à modéliser le problème à résoudre à l'aide de contraintes, c'est-à-dire des déclarations qui forcent les variables du problème à respecter une relation mathématique. Les contraintes des problèmes ont habituellement des paramètres qui permettent de préciser la relation mathématique à respecter et des variables de décision qui représentent les variables pour lesquelles la relation mathématique doit s'appliquer. Bien qu'intéressant en soi, la programmation par contraintes peut également s'étendre sur d'autres concepts, notamment la modélisation automatique. L'acquisition ou apprentissage de contraintes consiste à apprendre les différentes contraintes, incluant les valeurs des paramètres, qui peuvent expliquer un ensemble d'exemples fournis. L'apprentissage de contraintes peut être utile dans plusieurs situations, comme l'apprentissage de structures d'horaires d'hôpitaux à l'aide d'anciens exemples d'horaires. L'apprentissage de contraintes est encore un domaine nouveau pour lequel les stratégies doivent encore être adaptées ou développées. Les techniques d'acquisition existantes varient en genre, incluant des méthodes qui créent des solutions artificielles pour interagir avec un utilisateur ou des approches qui se basent sur des analyses mathématiques rigoureuses de solutions pour faire des choix sans jamais communiquer avec l'utilisateur. Dans ce mémoire, nous explorons une nouvelle méthode pour performer l'acquisition de contraintes. Le critère principal de la méthode développée est basé sur le nombre de solutions du modèle considéré et utilise des outils de dénombrement. Notre technique performe bien sur les problèmes essayés et ouvre la porte à une nouvelle manière d'apprivoiser les problèmes d'acquisition de contraintes.Several programming paradigms exist to help solve combinatorial optimization problems, one of them being constraint programming. The idea of this paradigm is to model the problems to solve using constraints, i.e. statements that force the variables of the problem to respect a mathematical relation. The constraints of a problem usually have parameters that allow to specify the mathematical relationship to be respected and decision variables that represent the variables on which the mathematical relationship must be applied. Although interesting in itself, constraint programming can also expand on other concepts, such as the automatisation of the modeling process. Constraints acquisition consists in learning the different constraints, including parameter values, which can explain a set of examples provided. Constraint acquisition can be useful in multiple situations, such as learning structures in schedules for hospitals using old schedules. Constraint learning is still a new area for which strategies still need to be adapted or developed. The existing techniques of acquisition varies widely in style, including methods that create artificial solutions to interact with a user or approaches which are based on complex mathematical analyzes of real solutions to make choices without ever communicating with the user. In this thesis, we explore a new method to perform the acquisition of constraints. The main criterion of the developed method is based on the number of solutions of the considered model and uses tools of model counting. Our technique works well on proven problems and opens the door to a new way of approaching acquisition constraint problems

Towards a Better Understanding of Rural Homelessness: An Examination of Housing Crisis in a Small, Rural Minnesota Community

This report compiles the work done during the Rural Housing Policy course at the University of Minnesota Morris by the students and their instructor, Professor Greg Thorson. the class reviewed the literature on urban and rural homelessness, interviewed local providers of social service programs, developed a survey to be administered at regional homeless shelters, wrote the Institutional Review Board (IRB) proposal to authorize the administration of the survey, administered the survey, and analyzed the results.https://digitalcommons.morris.umn.edu/cst/1009/thumbnail.jp

Distinct Effects of Two HIV-1 Capsid Assembly Inhibitor Families That Bind the Same Site within the N-Terminal Domain of the Viral CA Protein

The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral capsid (CA) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro, and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology, and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on the association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM), resulted in compounds with potent antiviral activity against wild-type and drug-resistant HIV-1. Nuclear magnetic resonance (NMR) spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors but is expanded significantly by these new, more potent CA inhibitors. Virus release and electron microscopic (EM) studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited the formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action

YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling

Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility

Bottom-Up Organizing with Tools from On High: Understanding the Data Practices of Labor Organizers

This paper provides insight into the use of data tools in the American labor movement by analyzing the practices of staff employed by unions to organize alongside union members. We interviewed 23 field-level staff organizers about how they use data tools to evaluate membership. We find that organizers work around and outside of these tools to develop access to data for union members and calibrate data representations to meet local needs. Organizers mediate between local and central versions of the data, and draw on their contextual knowledge to challenge campaign strategy. We argue that networked data tools can compound field organizers' lack of discretion, making it more difficult for unions to assess and act on the will of union membership. We show how the use of networked data tools can lead to less accurate data, and discuss how bottom-up approaches to data gathering can support more accurate membership assessments

Multiple Promoters and Alternative Splicing: Hoxa5 Transcriptional Complexity in the Mouse Embryo

The genomic organization of Hox clusters is fundamental for the precise spatio-temporal regulation and the function of each Hox gene, and hence for correct embryo patterning. Multiple overlapping transcriptional units exist at the Hoxa5 locus reflecting the complexity of Hox clustering: a major form of 1.8 kb corresponding to the two characterized exons of the gene and polyadenylated RNA species of 5.0, 9.5 and 11.0 kb. This transcriptional intricacy raises the question of the involvement of the larger transcripts in Hox function and regulation.We have undertaken the molecular characterization of the Hoxa5 larger transcripts. They initiate from two highly conserved distal promoters, one corresponding to the putative Hoxa6 promoter, and a second located nearby Hoxa7. Alternative splicing is also involved in the generation of the different transcripts. No functional polyadenylation sequence was found at the Hoxa6 locus and all larger transcripts use the polyadenylation site of the Hoxa5 gene. Some larger transcripts are potential Hoxa6/Hoxa5 bicistronic units. However, even though all transcripts could produce the genuine 270 a.a. HOXA5 protein, only the 1.8 kb form is translated into the protein, indicative of its essential role in Hoxa5 gene function. The Hoxa6 mutation disrupts the larger transcripts without major phenotypic impact on axial specification in their expression domain. However, Hoxa5-like skeletal anomalies are observed in Hoxa6 mutants and these defects can be explained by the loss of expression of the 1.8 kb transcript. Our data raise the possibility that the larger transcripts may be involved in Hoxa5 gene regulation.Our observation that the Hoxa5 larger transcripts possess a developmentally-regulated expression combined to the increasing sum of data on the role of long noncoding RNAs in transcriptional regulation suggest that the Hoxa5 larger transcripts may participate in the control of Hox gene expression

NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNα and IFNβ, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds to bacterial peptidoglycan, and this event requires membrane damage that is actively inflicted by the bacterium. Unexpectedly, this recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depend entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system

Constraint Acquisition Based on Solution Counting

We propose CABSC, a system that performs Constraint Acquisition Based on Solution Counting. In order to learn a Constraint Satisfaction Problem (CSP), the user provides positive examples and a Meta-CSP, i.e. a model of a combinatorial problem whose solution is a CSP. This Meta-CSP allows listing the potential constraints that can be part of the CSP the user wants to learn. It also allows stating the parameters of the constraints, such as the coefficients of a linear equation, and imposing constraints over these parameters. The CABSC reads the Meta-CSP using an augmented version of the language MiniZinc and returns the CSP that accepts the fewest solutions among the CSPs accepting all positive examples. This is done using a branch and bound where the bounding mechanism makes use of a model counter. Experiments show that CABSC is successful at learning constraints and their parameters from positive examples