Efficient Parallel Statistical Model Checking of Biochemical Networks

We consider the problem of verifying stochastic models of biochemical networks against behavioral properties expressed in temporal logic terms. Exact probabilistic verification approaches such as, for example, CSL/PCTL model checking, are undermined by a huge computational demand which rule them out for most real case studies. Less demanding approaches, such as statistical model checking, estimate the likelihood that a property is satisfied by sampling executions out of the stochastic model. We propose a methodology for efficiently estimating the likelihood that a LTL property P holds of a stochastic model of a biochemical network. As with other statistical verification techniques, the methodology we propose uses a stochastic simulation algorithm for generating execution samples, however there are three key aspects that improve the efficiency: first, the sample generation is driven by on-the-fly verification of P which results in optimal overall simulation time. Second, the confidence interval estimation for the probability of P to hold is based on an efficient variant of the Wilson method which ensures a faster convergence. Third, the whole methodology is designed according to a parallel fashion and a prototype software tool has been implemented that performs the sampling/verification process in parallel over an HPC architecture

Physical properties of z>4 submillimeter galaxies in the COSMOS field

We study the physical properties of a sample of 6 SMGs in the COSMOS field, spectroscopically confirmed to lie at z>4. We use new GMRT 325 MHz and 3 GHz JVLA data to probe the rest-frame 1.4 GHz emission at z=4, and to estimate the sizes of the star-forming (SF) regions of these sources, resp. Combining our size estimates with those available in the literature for AzTEC1 and AzTEC3 we infer a median radio-emitting size for our z>4 SMGs of (0.63"+/-0.12")x(0.35"+/-0.05") or 4.1x2.3 kpc^2 (major times minor axis; assuming z=4.5) or lower if we take the two marginally resolved SMGs as unresolved. This is consistent with the sizes of SF regions in lower-redshift SMGs, and local normal galaxies, yet higher than the sizes of SF regions of local ULIRGs. Our SMG sample consists of a fair mix of compact and more clumpy systems with multiple, perhaps merging, components. With an average formation time of ~280 Myr, derived through modeling of the UV-IR SEDs, the studied SMGs are young systems. The average stellar mass, dust temperature, and IR luminosity we derive are M*~1.4x10^11 M_sun, T_dust~43 K, and L_IR~1.3x10^13L_sun, resp. The average L_IR is up to an order of magnitude higher than for SMGs at lower redshifts. Our SMGs follow the correlation between dust temperature and IR luminosity as derived for Herschel-selected 0.1=1.95+/-0.26 for our sample, compared to q~2.6 for IR luminous galaxies at z4 SMGs put them at the high end of the L_IR-T_dust distribution of SMGs, and that our SMGs form a morphologically heterogeneous sample. Thus, further in-depth analyses of large, statistical samples of high-redshift SMGs are needed to fully understand their role in galaxy formation and evolution

On the cosmic evolution of the scaling relations between black holes and their host galaxies: Broad Line AGN in the zCOSMOS survey

(Abriged) We report on the measurement of the rest frame K-band luminosity and total stellar mass of the hosts of 89 broad line Active Galactic Nuclei detected in the zCOSMOS survey in the redshift range 1<z<2.2. The unprecedented multiwavelength coverage of the survey field allows us to disentangle the emission of the host galaxy from that of the nuclear black hole in their Spectral Energy Distributions. We derive an estimate of black hole masses through the analysis of the broad Mg II emission lines observed in the medium-resolution spectra taken with VIMOS/VLT as part of the zCOSMOS project. We found that, as compared to the local value, the average black hole to host galaxy mass ratio appears to evolve positively with redshift, with a best fit evolution of the form (1+z)^{0.68 \pm0.12 +0.6 -0.3}, where the large asymmetric systematic errors stem from the uncertainties in the choice of IMF, in the calibration of the virial relation used to estimate BH masses and in the mean QSO SED adopted. A thorough analysis of observational biases induced by intrinsic scatter in the scaling relations reinforces the conclusion that an evolution of the MBH-M* relation must ensue for actively growing black holes at early times: either its overall normalization, or its intrinsic scatter (or both) appear to increase with redshift. This can be interpreted as signature of either a more rapid growth of supermassive black holes at high redshift, a change of structural properties of AGN hosts at earlier times, or a significant mismatch between the typical growth times of nuclear black holes and host galaxies.Comment: 47 pages, 8 figures. Accepted for publication in Ap

Differential activation of inflammatory pathways in A549 type II pneumocytes by Streptococcus pneumoniae strains with different adherence properties

BACKGROUND: Adherence of Streptococcus pneumoniae bacteria to lung cells is a first step in the progression from asymptomatic carriage to pneumonia. Adherence abilities vary widely among S. pneumoniae patient isolates. In this study, the binding properties of S. pneumoniae isolates and the effects of binding on activation of the Nuclear Factor-Kappa-B (NFκB) pathway and cytokine secretion by type II pneumocytes were measured. METHODS: Mechanisms of high- and low-binding S. pneumoniae adherence to A549 cells were investigated by blocking putative receptors on bacteria and host cells with antibody and by eluting choline-binding proteins off of bacterial surfaces. NFκB activation was measured by western blot and immunocytochemistry and cytokine secretion was detected by a protein array. RESULTS: This study shows that S. pneumoniae isolates from pneumonia patients (n = 298) can vary by as much as 1000-fold in their ability to bind to human lung epithelial cells. This difference resulted in differential activation of the NFκB pathway. High-, but not low-binding S. pneumoniae used Choline-binding protein A (CbpA) to bind to complement component C3 on epithelial cell surfaces. Interleukin-8 (IL-8) was the only cytokine secreted by cells treated with either low- or high-binding S. pneumoniae. CONCLUSION: These results indicate that S. pneumoniae clinical isolates are not homogeneous in their interaction with host epithelial cells. The differential activation of host cells by high- and low-binding S. pneumoniae strains could have implications for the treatment of pneumococcal pneumonia and for vaccine development

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a ‘protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens

Engineered Picornavirus VPg-RNA Substrates: Analysis of a Tyrosyl-RNA Phosphodiesterase Activity

Using poliovirus, the prototypic member of Picornaviridae, we have further characterized a host cell enzymatic activity found in uninfected cells, termed “unlinkase,” that recognizes and cleaves the unique 5′ tyrosyl-RNA phosphodiester bond found at the 5′ end of picornavirus virion RNAs. This bond connects VPg, a viral-encoded protein primer essential for RNA replication, to the viral RNA; it is cleaved from virion RNA prior to its engaging in protein synthesis as mRNA. Due to VPg retention on nascent RNA strands and replication templates, but not on viral mRNA, we hypothesize that picornaviruses utilize unlinkase activity as a means of controlling the ratio of viral RNAs that are translated versus those that either serve as RNA replication templates or are encapsidated. To test our hypothesis and further characterize this enzyme, we have developed a novel assay to detect unlinkase activity. We demonstrate that unlinkase activity can be detected using this assay, that this unique activity remains unchanged over the course of a poliovirus infection in HeLa cells, and that unlinkase activity is unaffected by the presence of exogenous VPg or anti-VPg antibodies. Furthermore, we have determined that unlinkase recognizes and cleaves a human rhinovirus-poliovirus chimeric substrate with the same efficiency as the poliovirus substrate

CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line. Corresponding mutant forms of murine Csf1r were expressed on the cell surface at normal levels, and bound CSF1, but were not able to sustain cell proliferation. Since Csf1r signaling requires receptor dimerization initiated by CSF1 binding, the data suggest a mechanism for phenotypic dominance of the mutant allele in HDLS

The evolution of the cosmic molecular gas density

Large scale structure and cosmolog