Probabilistic Timed Automata with Clock-Dependent Probabilities

Probabilistic timed automata are classical timed automata extended with discrete probability distributions over edges. We introduce clock-dependent probabilistic timed automata, a variant of probabilistic timed automata in which transition probabilities can depend linearly on clock values. Clock-dependent probabilistic timed automata allow the modelling of a continuous relationship between time passage and the likelihood of system events. We show that the problem of deciding whether the maximum probability of reaching a certain location is above a threshold is undecidable for clock-dependent probabilistic timed automata. On the other hand, we show that the maximum and minimum probability of reaching a certain location in clock-dependent probabilistic timed automata can be approximated using a region-graph-based approach.Comment: Full version of a paper published at RP 201

Heat-killed probiotic bacteria differentially regulate colonic epithelial cell production of human β-defensin-2: dependence on inflammatory cytokines.

The inducible antimicrobial peptide human β-defensin-2 (hBD-2) stimulated by pro-inflammatory cytokines and bacterial products is essential to antipathogen responses of gut epithelial cells. Commensal and probiotic bacteria can augment such mucosal defences. Probiotic use in the treatment of inflammatory bowel disease, however, may have adverse effects, boosting inflammatory responses. The aim of this investigation was to determine the effect of selected probiotic strains on hBD-2 production by epithelial cells induced by pathologically relevant pro-inflammatory cytokines and the role of cytokine modulators in controlling hBD-2. Caco-2 colonic intestinal epithelial cells were pre-incubated with heat-killed probiotics, i.e. Lactobacillus casei strain Shirota (LcS) or Lactobacillus fermentum strain MS15 (LF), followed by stimulation of hBD-2 by interleukin (IL)-1β and tumour necrosis factor alpha (TNF-α) in the absence or presence of exogenous IL-10 or anti-IL-10 neutralising antibody. Cytokines and hBD-2 mRNA and protein were analysed by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. LcS augmented IL-1β-induced hBD-2, whereas LF enhanced TNF-α- and suppressed IL-1β-induced hBD-2. LF enhanced TNF-α-induced TNF-α and suppressed IL-10, whereas augmented IL-1β-induced IL-10. LcS upregulated IL-1β-induced TNF-α mRNA and suppressed IL-10. Endogenous IL-10 differentially regulated hBD-2; neutralisation of IL-10 augmented TNF-α- and suppressed IL-1β-induced hBD-2. Exogenous IL-10, however, suppressed both TNF-α- and IL-1β-induced hBD-2; LcS partially rescued suppression in TNF-α- and IL-1β-stimulation, whereas LF further suppressed IL-1β-induced hBD-2. It can be concluded that probiotic strains differentially regulate hBD-2 mRNA expression and protein secretion, modulation being dictated by inflammatory stimulus and resulting cytokine environment

Distribution-based bisimulation for labelled Markov processes

In this paper we propose a (sub)distribution-based bisimulation for labelled Markov processes and compare it with earlier definitions of state and event bisimulation, which both only compare states. In contrast to those state-based bisimulations, our distribution bisimulation is weaker, but corresponds more closely to linear properties. We construct a logic and a metric to describe our distribution bisimulation and discuss linearity, continuity and compositional properties.Comment: Accepted by FORMATS 201

Short-Cut Method to Assess a Gross Available Energy in a Medium-Load Screw Friction Press

The present study proposed a rapid method, based on a previous universal compression tests, to estimate the required load capacity to cold forge different specimen quantity in a screw press. Accordingly, experimental and theoretical approach are performed to check new adjustable drive motor of the modified forging machine to achieve a gross available energy to deform the specimens preventing damage of the forging machine. During the forging experiments, two screw friction presses (as-received and modified) are used to validate the theoretical approach. The modified press exhibits an increase of 51% of gross energy and 11% of maximum load capacity compare to the as-received press. This method is used to improve the effective of the forging process avoiding excessive loads that could promote machine failure. Therefore, a low-cost and easy to implement methodology is proposed to determine the energy and load capacity of a screw friction press to forge different specimen quantities with symmetry pattern configurations.This work is supported by the Ministry of Economy and Competitiveness of Spain (reference project: FJCI-2016-29297), Instituto Nacional de Tecnologia Industrial (INTI) of Argentina and the Aeronautics Advanced Manufacturing Center (CFAA) of Bilbao

Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.

The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Förster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials

Area metric gravity and accelerating cosmology

Area metric manifolds emerge as effective classical backgrounds in quantum string theory and quantum gauge theory, and present a true generalization of metric geometry. Here, we consider area metric manifolds in their own right, and develop in detail the foundations of area metric differential geometry. Based on the construction of an area metric curvature scalar, which reduces in the metric-induced case to the Ricci scalar, we re-interpret the Einstein-Hilbert action as dynamics for an area metric spacetime. In contrast to modifications of general relativity based on metric geometry, no continuous deformation scale needs to be introduced; the extension to area geometry is purely structural and thus rigid. We present an intriguing prediction of area metric gravity: without dark energy or fine-tuning, the late universe exhibits a small acceleration.Comment: 52 pages, 1 figure, companion paper to hep-th/061213

In vivo triglyceride synthesis in subcutaneous adipose tissue of humans correlates with plasma HDL parameters

Backgrounds and aims: Low concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans. Methods: The fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after 2H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured. Results: Linear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p < 0.001), I-HDL (r = -0.765,p < 0.001) and S-HDL (r = -0.629, p = 0.009). When analyses were performed by gender, the associations remained significant in women (HDL-C: r = 0.822,p = 0.023; L-HDL: r = 0.892,p = 0.007; I-HDL: r = -0.927,p = 0.003) but not men. Conclusions: Our study demonstrated an in vivo association between subcutaneous abdominal adipose tissue lipid dynamics and HDL parameters in humans, but this was true for women not men. Positive association with L-HDL and negative with I-HDL suggest that subcutaneous abdominal adipose tissue lipid dynamics may play an important role in production of mature functional HDL particles. Further studies evaluating the mechanism responsible for these associations and the observed gender differences are important and warranted to identify potential novel targets of intervention to increase the production of atheroprotective subclasses of HDL-Cs and thus decreasing the risks of development of atherosclerotic conditions

Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective B therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P&lt;0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo

Factors that transformed maize productivity in Ethiopia

Published online: 26 July 2015Maize became increasingly important in the food security of Ethiopia following the major drought and famine that occurred in 1984. More than 9 million smallholder house- holds, more than for any other crop in the country, grow maize in Ethiopia at present. Ethiopia has doubled its maize produc- tivity and production in less than two decades. The yield, currently estimated at >3 metric tons/ha, is the second highest in Sub-Saharan Africa, after South Africa; yield gains for Ethiopia grew at an annual rate of 68 kg/ha between 1990 and 2013, only second to South Africa and greater than Mexico, China, or India. The maize area covered by improved varieties in Ethiopia grew from 14 % in 2004 to 40 % in 2013, and the application rate of mineral fertilizers from 16 to 34 kg/ ha during the same period. Ethiopia ’ s extension worker to farmer ratio is 1:476, compared to 1:1000 for Kenya, 1:1603 for Malawi and 1:2500 for Tanzania. Increased use of im- proved maize varieties and mineral fertilizers, coupled with increased extension services and the absence of devastating droughts are the key factors promoting the accelerated growth in maize productivity in Ethiopia. Ethiopia took a homegrown solutions approach to the research and development of its maize and other commodities. The lesson from Ethiopia ’ s experience with maize is that sustained investment in agricul- tural research and development and policy support by the national government are crucial for continued growth of agricultur

Missing Dark Matter in the Local Universe

A sample of 11 thousand galaxies with radial velocities V_ LG < 3500 km/s is used to study the features of the local distribution of luminous (stellar) and dark matter within a sphere of radius of around 50 Mpc around us. The average density of matter in this volume, Omega_m,loc=0.08+-0.02, turns out to be much lower than the global cosmic density Omega_m,glob=0.28+-0.03. We discuss three possible explanations of this paradox: 1) galaxy groups and clusters are surrounded by extended dark halos, the major part of the mass of which is located outside their virial radii; 2) the considered local volume of the Universe is not representative, being situated inside a giant void; and 3) the bulk of matter in the Universe is not related to clusters and groups, but is rather distributed between them in the form of massive dark clumps. Some arguments in favor of the latter assumption are presented. Besides the two well-known inconsistencies of modern cosmological models with the observational data: the problem of missing satellites of normal galaxies and the problem of missing baryons, there arises another one - the issue of missing dark matter.Comment: 19 pages, 7 figures, 1 table (accepted