Certainty Closure: Reliable Constraint Reasoning with Incomplete or Erroneous Data

Constraint Programming (CP) has proved an effective paradigm to model and solve difficult combinatorial satisfaction and optimisation problems from disparate domains. Many such problems arising from the commercial world are permeated by data uncertainty. Existing CP approaches that accommodate uncertainty are less suited to uncertainty arising due to incomplete and erroneous data, because they do not build reliable models and solutions guaranteed to address the user's genuine problem as she perceives it. Other fields such as reliable computation offer combinations of models and associated methods to handle these types of uncertain data, but lack an expressive framework characterising the resolution methodology independently of the model. We present a unifying framework that extends the CP formalism in both model and solutions, to tackle ill-defined combinatorial problems with incomplete or erroneous data. The certainty closure framework brings together modelling and solving methodologies from different fields into the CP paradigm to provide reliable and efficient approches for uncertain constraint problems. We demonstrate the applicability of the framework on a case study in network diagnosis. We define resolution forms that give generic templates, and their associated operational semantics, to derive practical solution methods for reliable solutions.Comment: Revised versio

Mylonitic deformation at the Kane oceanic core complex : implications for the rheological behavior of oceanic detachment faults

Author Posting. © American Geophysical Union, 2013. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 14 (2013): 3085–3108, doi:10.1002/ggge.20184.The depth extent, strength, and composition of oceanic detachment faults remain poorly understood because the grade of deformation-related fabrics varies widely among sampled oceanic core complexes (OCCs). We address this issue by analyzing fault rocks collected from the Kane oceanic core complex at 23°30′N on the Mid-Atlantic Ridge. A portion of the sample suite was collected from a younger fault scarp that cuts the detachment surface and exposes the interior of the most prominent dome. The style of deformation was assessed as a function of proximity to the detachment surface, revealing a ∼450 m thick zone of high-temperature mylonitization overprinted by a ∼200 m thick zone of brittle deformation. Geothermometry of deformed gabbros demonstrates that crystal-plastic deformation occurred at temperatures >700°C. Analysis of the morphology of the complex in conjunction with recent thermochronology suggests that deformation initiated at depths of ∼7 km. Thus we suggest the detachment system extended into or below the brittle-plastic transition (BPT). Microstructural evidence suggests that gabbros and peridotites with high-temperature fabrics were dominantly deforming by dislocation-accommodated processes and diffusion creep. Recrystallized grain size piezometry yields differential stresses consistent with those predicted by dry-plagioclase flow laws. The temperature and stress at the BPT determined from laboratory-derived constitutive models agree well with the lowest temperatures and highest stresses estimated from gabbro mylonites. We suggest that the variation in abundance of mylonites among oceanic core complexes can be explained by variation in the depth of the BPT, which depends to a first order on the thermal structure and water content of newly forming oceanic lithosphere.Knorr Cruise 180-2 data and sample acquisition was supported by NSF grant 0118445.2014-02-2

Parametric hazard rate models for long-term sickness absence

PURPOSE: In research on the time to onset of sickness absence and the duration of sickness absence episodes, Cox proportional hazard models are in common use. However, parametric models are to be preferred when time in itself is considered as independent variable. This study compares parametric hazard rate models for the onset of long-term sickness absence and return to work. METHOD: Prospective cohort study on sickness absence with four follow-up years of 53,830 employees working in the private sector in the Netherlands. The time to onset of long-term (>6 weeks) sickness absence and return to work were modelled by parametric hazard rate models. RESULTS: The exponential parametric model with a constant hazard rate most accurately described the time to onset of long-term sickness absence. Gompertz-Makeham models with monotonically declining hazard rates best described return to work. CONCLUSIONS: Parametric models offer more possibilities than commonly used models for time-dependent processes as sickness absence and return to work. However, the advantages of parametric models above Cox models apply mainly for return to work and less for onset of long-term sickness absence

Using honey to heal diabetic foot ulcers

Diabetic ulcers seem to be arrested in the inflammatory/proliferative stage of the healing process, allowing infection and inflammation to preclude healing. Antibiotic-resistant bacteria have become a major cause of infections, including diabetic foot infections. It is proposed here that the modern developments of an ancient and traditional treatment for wounds, dressing them with honey, provide the solution to the problem of getting diabetic ulcers to move on from the arrested state of healing. Honeys selected to have a high level of antibacterial activity have been shown to be very effective against antibiotic-resistant strains of bacteria in laboratory and clinical studies. The potent anti-inflammatory action of honey is also likely to play an important part in overcoming the impediment to healing that inflammation causes in diabetic ulcers, as is the antioxidant activity of honey. The action of honey in promotion of tissue regeneration through stimulation of angiogenesis and the growth of fibroblasts and epithelial cells, and its insulin-mimetic effect, would also be of benefit in stimulating the healing of diabetic ulcers. The availability of honey-impregnated dressings which conveniently hold honey in place on ulcers has provided a means of rapidly debriding ulcers and removing the bacterial burden so that good healing rates can be achieved with neuropathic ulcers. With ischemic ulcers, where healing cannot occur because of lack of tissue viability, these honey dressings keep the ulcers clean and prevent infection occurring

Inhibition of N1-Src kinase by a specific SH3 peptide ligand reveals a role for N1-Src in neurite elongation by L1-CAM

In the mammalian brain the ubiquitous tyrosine kinase, C-Src, undergoes splicing to insert short sequences in the SH3 domain to yield N1- and N2-Src. We and others have previously shown that the N-Srcs have altered substrate specificity and kinase activity compared to C-Src. However, the exact functions of the N-Srcs are unknown and it is likely that N-Src signalling events have been misattributed to C-Src because they cannot be distinguished by conventional Src inhibitors that target the kinase domain. By screening a peptide phage display library, we discovered a novel ligand (PDN1) that targets the unique SH3 domain of N1-Src and inhibits N1-Src in cells. In cultured neurons, PDN1 fused to a fluorescent protein inhibited neurite outgrowth, an effect that was mimicked by shRNA targeting the N1-Src microexon. PDN1 also inhibited L1-CAM-dependent neurite elongation in cerebellar granule neurons, a pathway previously shown to be disrupted in Src(−/−) mice. PDN1 therefore represents a novel tool for distinguishing the functions of N1-Src and C-Src in neurons and is a starting point for the development of a small molecule inhibitor of N1-Src

Neural processes mediating contextual influences on human choice behaviour

Contextual influences on choice are ubiquitous in ecological settings. Current evidence suggests that subjective values are normalized with respect to the distribution of potentially available rewards. However, how this context-sensitivity is realised in the brain remains unknown. To address this, here we examine functional magnetic resonance imaging (fMRI) data during performance of a gambling task where blocks comprise values drawn from one of two different, but partially overlapping, reward distributions or contexts. At the beginning of each block (when information about context is provided), hippocampus is activated and this response is enhanced when contextual influence on choice increases. In addition, response to value in ventral tegmental area/substantia nigra (VTA/SN) shows context-sensitivity, an effect enhanced with an increased contextual influence on choice. Finally, greater response in hippocampus at block start is associated with enhanced context sensitivity in VTA/SN. These findings suggest that context-sensitive choice is driven by a brain circuit involving hippocampus and dopaminergic midbrain

Poverty and Well-being in Post-Apartheid South Africa: An Overview of Data, Outcomes and Policy

WP 2006-03 January 2006This is an overview of poverty and well-being in the first decade of post-apartheid South Africa. It is an introduction to a volume that brings together some of the most prominent academic research done on this topic for the 10-year review process in South Africa. This overview highlights three key aspects of the picture that the detailed research paints. First, data quality and comparability has been a constant issue in arriving at a consensus among analysts on the outcomes for households and individuals in postapartheid South Africa. Second, while the outcomes on unemployment, poverty and inequality are indeed bad, the outcomes on social indicators and access to public services are much more encouraging. Third, the prospects for rapid and sustained economic growth, without which poverty and well-being cannot be addressed in the long run, are themselves negatively affected by increasing inequality, poverty and unemployment

TLR2 and TLR4 as Potential Biomarkers of Environmental Particulate Matter Exposed Human Myeloid Dendritic Cells

In many subjects who are genetically susceptible to asthma, exposure to environmental stimuli may exacerbate their condition. However, it is unknown how the expression and function of a family of pattern-recognition receptors called toll-like receptors (TLR) are affected by exposure to particulate pollution. TLRs serve a critical function in alerting the immune system of tissue damage or infection—the so-called “danger signals”. We are interested in the role that TLRs play in directing appropriate responses by innate immunity, particularly dendritic cells (DC), after exposing them to particulate pollution. Dendritic cells serve a pivotal role in directing host immunity. Thus, we hypothesized that alterations in TLR expression could be further explored as potential biomarkers of effect related to DC exposure to particulate pollution. We show some preliminary data that indicates that inhaled particulate pollution acts directly on DC by down-regulating TLR expression and altering the activation state of DC. While further studies are warranted, we suggest that alterations in TLR2 and TLR4 expression should be explored as potential biomarkers of DC exposure to environmental particulate pollution

Differential impact of LPG-and PG-deficient Leishmania major mutants on the immune response of human dendritic cells

<div><p>Background</p><p><i>Leishmania major</i> infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of <i>Leishmania</i> parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.</p><p>Methodology/Principal Findings</p><p>Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating <i>L</i>. <i>major</i> Friedlin V1 mutants defective in LPG alone, (FV1 <i>lpg1-</i>), or generally deficient for all PGs, (FV1 <i>lpg2-</i>). Infection with metacyclic, infective stage, <i>L</i>. <i>major</i> or purified LPG induced high levels of <i>IL12B</i> subunit gene transcripts in hDCs, which was abrogated with FV1 <i>lpg1-</i> infections. In contrast, hDC infections with FV1 <i>lpg2-</i> displayed increased <i>IL12B</i> expression, suggesting other PG-related/<i>LPG2</i> dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 <i>lpg1-</i>, FV1 <i>lpg2-</i> infections revealed that FV1 <i>lpg1-</i> mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription.</p><p>Conclusions/Significance</p><p>These data suggest that <i>L</i>. <i>major</i> LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring <i>Leishmania</i> surface glycoconjugates that result in modulation of host cellular IL12.</p></div

Regulatory subunits of PKA define an axis of cellular proliferation/differentiation in ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>The regulatory subunit of cAMP-dependent protein kinase (PKA) exists in two isoforms, RI and RII, which distinguish the PKA isozymes, type I (PKA-I) and type II (PKA-II). Evidence obtained from a variety of different experimental approaches has shown that the relative levels of type I and type II PKA in cells can play a major role in determining the balance between cell growth and differentiation. In order to characterize the effect of PKA type I and type II regulatory subunits on gene transcription at a global level, the PKA regulatory subunit genes for RIα and RIIβ were stably transfected into cells of the ovarian cancer cell line (OVCAR8).</p> <p>Results</p> <p>RIα transfected cells exhibit hyper-proliferative growth and RIIβ transfected cells revert to a relatively quiescent state. Profiling by microarray revealed equally profound changes in gene expression between RIα, RIIβ, and parental OVCAR cells. Genes specifically up-regulated in RIα cells were highly enriched for pathways involved in cell growth while genes up-regulated in RIIβ cells were enriched for pathways involved in differentiation. A large group of genes (~3600) was regulated along an axis of proliferation/differentiation between RIα, parental, and RIIβ cells. RIα/wt and RIIβ/wt gene regulation was shown by two separate and distinct gene set analytical methods to be strongly cross-correlated with a generic model of cellular differentiation.</p> <p>Conclusion</p> <p>Overexpression of PKA regulatory subunits in an ovarian cancer cell line dramatically influences the cell phenotype. The proliferation phenotype is strongly correlated with recently identified clinical biomarkers predictive of poor prognosis in ovarian cancer suggesting a possible pivotal role for PKA regulation in disease progression.</p