Violator Spaces: Structure and Algorithms

Sharir and Welzl introduced an abstract framework for optimization problems, called LP-type problems or also generalized linear programming problems, which proved useful in algorithm design. We define a new, and as we believe, simpler and more natural framework: violator spaces, which constitute a proper generalization of LP-type problems. We show that Clarkson's randomized algorithms for low-dimensional linear programming work in the context of violator spaces. For example, in this way we obtain the fastest known algorithm for the P-matrix generalized linear complementarity problem with a constant number of blocks. We also give two new characterizations of LP-type problems: they are equivalent to acyclic violator spaces, as well as to concrete LP-type problems (informally, the constraints in a concrete LP-type problem are subsets of a linearly ordered ground set, and the value of a set of constraints is the minimum of its intersection).Comment: 28 pages, 5 figures, extended abstract was presented at ESA 2006; author spelling fixe

Generalized Shortest Path Kernel on Graphs

We consider the problem of classifying graphs using graph kernels. We define a new graph kernel, called the generalized shortest path kernel, based on the number and length of shortest paths between nodes. For our example classification problem, we consider the task of classifying random graphs from two well-known families, by the number of clusters they contain. We verify empirically that the generalized shortest path kernel outperforms the original shortest path kernel on a number of datasets. We give a theoretical analysis for explaining our experimental results. In particular, we estimate distributions of the expected feature vectors for the shortest path kernel and the generalized shortest path kernel, and we show some evidence explaining why our graph kernel outperforms the shortest path kernel for our graph classification problem.Comment: Short version presented at Discovery Science 2015 in Banf

A novel string representation and kernel function for the comparison of I/O access patterns

Parallel I/O access patterns act as fingerprints of a parallel program. In order to extract meaningful information from these patterns, they have to be represented appropriately. Due to the fact that string objects can be easily compared using Kernel Methods, a conversion to a weighted string representation is proposed in this paper, together with a novel string kernel function called Kast Spectrum Kernel. The similarity matrices, obtained after applying the mentioned kernel over a set of examples from a real application, were analyzed using Kernel Principal Component Analysis (Kernel PCA) and Hierarchical Clustering. The evaluation showed that 2 out of 4 I/O access pattern groups were completely identified, while the other 2 conformed a single cluster due to the intrinsic similarity of their members. The proposed strategy can be promisingly applied to other similarity problems involving tree-like structured data

New insight into breast cancer cells involving drug combinations for dopamine and serotonin receptors

The breast cancer therapies available are insufficient, especially since first-line treatments, such as paclitaxel, result in drug resistance and their toxicity often limits their concentration. Strategies like drug repurposing are beneficial, and novel treatments can emerge by repurposing drugs that interfere with the dopamine and serotonin receptors, and thus influence tumor growth. In this study, the MTT assay was used to test the efficacy of such repurposed drugs commonly used for neurodegenerative disorders that act on the dopamine and serotonin receptors to reduce the MCF7 cell’s viability, either by their single use or in combination with the reference drug paclitaxel. Furthermore, the expression of vimentin and E-cadherin was assayed by immunofluorescence. The dopamine receptor-altering drugs benztropine and thioridazine resulted in the strongest reduction of cell viability when combined with paclitaxel, which may be connected to the alteration of E-cadherin rather than vimentin expression. More studies are needed to understand the mechanism of action of the combinations tested and the efficacious role of dopamine and serotonin.This work was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) and FEDER (Fundo Europeu de Desenvolvimento Regional) funds through the COMPETE 2020 Operational Programme for Competitiveness and Internationalisation (POCI), Portugal, in the framework of the project IF/00092/2014/CP1255/CT0004. N.V. thanks Fundação para a Ciência e a Tecnologia (FCT, Portugal) for supporting these studies through nationally-funded projects within the CINTESIS R&D unit (reference UIDB/4255/2020). The contents of this report are solely the responsibility of the authors and do not necessarily represent the official view of the FCT

Inhibition of the formation in vitro of putatively carcinogenic metabolites derived from S. Haematobium and O. Viverrini by Combination of Drugs with Antioxidants

Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as carcinogenic. Although carcinogenesis might be a multifactorial process, it has been postulated that these helminth produce/excrete oxysterols and estrogen-like metabolites that might act as initiators of their infection-associated carcinogenesis. Current treatment and control of these infections rely on a single drug, praziquantel, that mainly targets the parasites and not the pathologies related to the infection including cancer. Thus, there is a need to search for novel therapeutic alternatives that might include combinations of drugs and drug repurposing. Based on these concepts, we propose a novel therapeutic strategy that combines drugs with molecule antioxidants. We evaluate the efficacy of a novel therapeutic strategy to prevent the formation of putative carcinogenic metabolites precursors and DNA adducts. Firstly, we used a methodology previously established to synthesize metabolites precursors and DNA adducts in the presence of CYP450. Then, we evaluated the inhibition of their formation induced by drugs and antioxidants alone or in combination. Drugs and resveratrol alone did not show a significant inhibitory effect while N-acetylcysteine inhibited the formation of most metabolite precursors and DNA adducts. Moreover, the combinations of classical drugs with antioxidants were more effective rather than compounds alone. This strategy might be a valuable tool to prevent the initiation of helminth infection-associated carcinogenesis.This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia, in the framework of the projects "Institute for Research and Innovation in Health Sciences" (POCI-01-0145-FEDER-007274). N.V. also acknowledges support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004. FUNDING TEXT 2: Funding: This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia, in the framework of the projects “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). N.V. also acknowledges support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004

On group properties and reality conditions of UOSp(1|2) gauge transformations

For osp(1|2;C) graded Lie algebra, which proper Lie subalgebra is su(2), we consider the Baker-Campbell-Hausdorff formula and formulate a reality condition for the Grassmann-odd transformation parameters that multiply the pair of odd generators of the graded Lie algebra. Utilization of su(2)-spinors clarifies the nature of Grassmann-odd transformation parameters and allow us an investigation of the corresponding infinitesimal gauge transformations. We also explore action of the corresponding group element of UOSp(1|2) on an appropriately graded representation space and find that the graded generalization of hermitian conjugation is compatible with the Dirac adjoint. Consistency of generalized (graded) unitary condition with the proposed reality condition is shown.Comment: 14 page

Micrometer-sized Water Ice Particles for Planetary Science Experiments: Influence of Surface Structure on Collisional Properties

Models and observations suggest that ice-particle aggregation at and beyond the snowline dominates the earliest stages of planet formation, which therefore is subject to many laboratory studies. However, the pressure–temperature gradients in protoplanetary disks mean that the ices are constantly processed, undergoing phase changes between different solid phases and the gas phase. Open questions remain as to whether the properties of the icy particles themselves dictate collision outcomes and therefore how effectively collision experiments reproduce conditions in protoplanetary environments. Previous experiments often yielded apparently contradictory results on collision outcomes, only agreeing in a temperature dependence setting in above ≈210 K. By exploiting the unique capabilities of the NIMROD neutron scattering instrument, we characterized the bulk and surface structure of icy particles used in collision experiments, and studied how these structures alter as a function of temperature at a constant pressure of around 30 mbar. Our icy grains, formed under liquid nitrogen, undergo changes in the crystalline ice-phase, sublimation, sintering and surface pre-melting as they are heated from 103 to 247 K. An increase in the thickness of the diffuse surface layer from ≈10 to ≈30 Å (≈2.5 to 12 bilayers) proves increased molecular mobility at temperatures above ≈210 K. Because none of the other changes tie-in with the temperature trends in collisional outcomes, we conclude that the surface pre-melting phenomenon plays a key role in collision experiments at these temperatures. Consequently, the pressure–temperature environment, may have a larger influence on collision outcomes than previously thought

Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency

Summary: The oral loading test with tetrahydrobiopterin (BH4) is used to discriminate between variants of hyperphenylalaninaemia and to detect BH4-responsive patients. The outcome of the loading test depends on the genotype, dosage of BH4, and BH4 pharmacokinetics. A total of 71 patients with hyperphenylalaninaemia (mild to classic) were challenged with BH4 (20 mg/kg) according to different protocols (1 × 20 mg or 2 × 20 mg) and blood BH4 concentrations were measured in dried blood spots at different time points (T0, T2, T4, T8, T12, T24, T32 and T48 h). Maximal BH4 concentrations (median 22.69 nmol/g Hb) were measured 4 h after BH4 administration in 63 out of 71 patients. Eight patients presented with maximal BH4 concentrations ∼44% higher at 8 h than at 4 h. After 24 h, BH4 blood concentrations dropped to 11% of maximal values. This profile was similar using different protocols. The following pharmacokinetic parameters were calculated for BH4 in blood: t max = 4 h, AUC (T0−32) = 370 nmol × h/g Hb, and t 1/2 for absorption (1.1 h), distribution (2.5 h), and elimination (46.0 h) phases. Maximal BH4 blood concentrations were not significantly lower in non-responders and there was no correlation between blood concentrations and responsiveness. Of mild PKU patients, 97% responded to BH4 administration, while one was found to be a non-responder. Only 10/19 patients (53%) with Phe concentrations of 600-1200 μmol/L responded to BH4 administration, and of the patients with the severe classical phenotype (blood Phe > 1200 μmol/L) only 4 out of 17 patient responded. An additional 36 patients with mild hyperphenylalaninaemia (HPA) who underwent the combined loading test with Phe+BH4 were all responders. Slow responders and non-responders were found in all groups of HP

Understanding resistance vs. susceptibility in visceral leishmaniasis using mouse models of Leishmania infantum Infection

Every year, up to 90,000 new cases of Visceral Leishmaniasis and 30,000 resultant deaths are estimated to occur worldwide. Such numbers give relevance to the continuous study of this complex form of the disease: a zoonosis and an anthroponosis; two known etiological agents (Leishmania infantum and L. donovani, respectively); with an estimated average ratio of 1 symptomatic per 10 asymptomatic individuals; and sometimes associated with atypical clinical presentations. This complexity, which results from a long co-evolutionary process involving vector-host, host-pathogen, and pathogen-vector interactions, is still not completely understood. The determinants of visceralization are not fully defined and the dichotomy resistance vs. susceptibility remains unsolved, translating into obstacles that delay the progress of global disease control. Inbred mouse models, with different susceptibility patterns to Leishmania infection, have been very useful in exploring this dichotomy. BALB/c and C57BL/6 mice were described as susceptible strains to L. donovani visceral infection, while SV/129 was considered resistant. Here, we used these three mouse models, but in the context of L. infantum infection, the other Leishmania species that cause visceral disease in humans, and dynamically compared their local and systemic infection-induced immune responses in order to establish a parallel and to ultimately better understand susceptibility vs. resistance in visceral leishmaniasis. Overall, our results suggest that C57BL/6 mice develop an intermediate "infection-phenotype" in comparison to BALB/c and SV/129 mouse strains, considering both the splenic parasite burden and the determined target organs weights. However, the immune mechanisms associated with the control of infection seem to be different in each mouse strain. We observed that both BALB/c and SV/129, but not C57BL/6 mice, show an infection-induced increase of splenic T follicular helper cells. On the other hand, differences detected in terms of CD21 expression by B cells early after infection, together with the quantified anti-Leishmania specific antibodies, suggest that SV/129 are faster than BALB/c and C57BL/6 mice in the assembly of an efficient B-cell response. Additionally, we observed an infection-induced increase in polyfunctional CD4+ T cells in the resistant SV/129 model, opposing an infection-induced increase in CD4+IL-10+ cells in susceptible BALB/c mice. Our data aligns with the observations reported for L. donovani infection and suggest that not only a single mechanism, but an interaction of several could be necessary for the control of this parasitic disease.The research leading to these results has received funding from the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). PC was supported by Foundation for Science and Technology (FCT), Portugal, through the individual grant SFRH/BD/121252/2016

Temperature and Tree Size Explain the Mean Time to Fall of Dead Standing Trees across Large Scales

Dead standing trees (DSTs) generally decompose slower than wood in contact with the forest floor. In many regions, DSTs are being created at an increasing rate due to accelerating tree mortality caused by climate change. Therefore, factors determining DST fall are crucial for predicting dead wood turnover time but remain poorly constrained. Here, we conduct a re-analysis of published DST fall data to provide standardized information on the mean time to fall (MTF) of DSTs across biomes. We used multiple linear regression to test covariates considered important for DST fall, while controlling for mortality and management effects. DSTs of species killed by fire, insects and other causes stood on average for 48, 13 and 19 years, but MTF calculations were sensitive to how tree size was accounted for. Species’ MTFs differed significantly between DSTs killed by fire and other causes, between coniferous and broadleaved plant functional types (PFTs) and between managed and unmanaged sites, but management did not explain MTFs when we distinguished by mortality cause. Mean annual temperature (MAT) negatively affected MTFs, whereas larger tree size or being coniferous caused DSTs to stand longer. The most important explanatory variables were MAT and tree size, with minor contributions of management and plant functional type depending on mortality cause. Our results provide a basis to improve the representation of dead wood decomposition in carbon cycle assessments