Approximate probabilistic verification of hybrid systems

Hybrid systems whose mode dynamics are governed by non-linear ordinary differential equations (ODEs) are often a natural model for biological processes. However such models are difficult to analyze. To address this, we develop a probabilistic analysis method by approximating the mode transitions as stochastic events. We assume that the probability of making a mode transition is proportional to the measure of the set of pairs of time points and value states at which the mode transition is enabled. To ensure a sound mathematical basis, we impose a natural continuity property on the non-linear ODEs. We also assume that the states of the system are observed at discrete time points but that the mode transitions may take place at any time between two successive discrete time points. This leads to a discrete time Markov chain as a probabilistic approximation of the hybrid system. We then show that for BLTL (bounded linear time temporal logic) specifications the hybrid system meets a specification iff its Markov chain approximation meets the same specification with probability $1$. Based on this, we formulate a sequential hypothesis testing procedure for verifying -approximately- that the Markov chain meets a BLTL specification with high probability. Our case studies on cardiac cell dynamics and the circadian rhythm indicate that our scheme can be applied in a number of realistic settings

Evaluation of the Predictive Ability, Environmental Regulation and Pharmacogenetics Utility of a BMI-Predisposing Genetic Risk Score during Childhood and Puberty

The authors would like to thank the Spanish children and parents who participated in the study.Polygenetic risk scores (pGRSs) consisting of adult body mass index (BMI) genetic variants have been widely associated with obesity in children populations. The implication of such obesity pGRSs in the development of cardio-metabolic alterations during childhood as well as their utility for the clinical prediction of pubertal obesity outcomes has been barely investigated otherwise. In the present study, we evaluated the utility of an adult BMI predisposing pGRS for the prediction and pharmacological management of obesity in Spanish children, further investigating its implication in the appearance of cardio-metabolic alterations. For that purpose, we counted on genetics data from three well-characterized children populations (composed of 574, 96 and 124 individuals), following both cross-sectional and longitudinal designs, expanding childhood and puberty. As a result, we demonstrated that the pGRS is strongly associated with childhood BMI Z-Score (B = 1.56, SE = 0.27 and p-value = 1.90 × 10−8 ), and that could be used as a good predictor of obesity longitudinal trajectories during puberty. On the other hand, we showed that the pGRS is not associated with cardio-metabolic comorbidities in children and that certain environmental factors interact with the genetic predisposition to the disease. Finally, according to the results derived from a weight-reduction metformin intervention in children with obesity, we discarded the utility of the pGRS as a pharmacogenetics marker of metformin response.Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI1102042 PI1102059 PI1601301 PI1600871Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products EC10-243 EC10-056 EC10-281 EC10-227Regional Government of Andalusia ("Plan Andaluz de investigacion, desarrollo e innovacion (2018)") P18-RT-2248Mapfre Foundation ("Research grants by Ignacio H. de Larramendi 2017")Instituto de Salud Carlos III IFI17/0004

Corner contributions to holographic entanglement entropy

The entanglement entropy of three-dimensional conformal field theories contains a universal contribution coming from corners in the entangling surface. We study these contributions in a holographic framework and, in particular, we consider the effects of higher curvature interactions in the bulk gravity theory. We find that for all of our holographic models, the corner contribution is only modified by an overall factor but the functional dependence on the opening angle is not modified by the new gravitational interactions. We also compare the dependence of the corner term on the new gravitational couplings to that for a number of other physical quantities, and we show that the ratio of the corner contribution over the central charge appearing in the two-point function of the stress tensor is a universal function for all of the holographic theories studied here. Comparing this holographic result to the analogous functions for free CFT's, we find fairly good agreement across the full range of the opening angle. However, there is a precise match in the limit where the entangling surface becomes smooth, i.e., the angle approaches $\pi$, and we conjecture the corresponding ratio is a universal constant for all three-dimensional conformal field theories. In this paper, we expand on the holographic calculations in our previous letter arXiv:1505.04804, where this conjecture was first introduced.Comment: 62 pages, 6 figures, 1 table; v2: minor modifications to match published version, typos fixe

Residual Expression of the Reprogramming Factors Prevents Differentiation of iPSC Generated from Human Fibroblasts and Cord Blood CD34+ Progenitors

Human induced pluripotent stem cells (hiPSC) have been generated from different tissues, with the age of the donor, tissue source and specific cell type influencing the reprogramming process. Reprogramming hematopoietic progenitors to hiPSC may provide a very useful cellular system for modelling blood diseases. We report the generation and complete characterization of hiPSCs from human neonatal fibroblasts and cord blood (CB)-derived CD34+ hematopoietic progenitors using a single polycistronic lentiviral vector containing an excisable cassette encoding the four reprogramming factors Oct4, Klf4, Sox2 and c-myc (OKSM). The ectopic expression of OKSM was fully silenced upon reprogramming in some hiPSC clones and was not reactivated upon differentiation, whereas other hiPSC clones failed to silence the transgene expression, independently of the cell type/tissue origin. When hiPSC were induced to differentiate towards hematopoietic and neural lineages those hiPSC which had silenced OKSM ectopic expression displayed good hematopoietic and early neuroectoderm differentiation potential. In contrast, those hiPSC which failed to switch off OKSM expression were unable to differentiate towards either lineage, suggesting that the residual expression of the reprogramming factors functions as a developmental brake impairing hiPSC differentiation. Successful adenovirus-based Cre-mediated excision of the provirus OKSM cassette in CB-derived CD34+ hiPSC with residual transgene expression resulted in transgene-free hiPSC clones with significantly improved differentiation capacity. Overall, our findings confirm that residual expression of reprogramming factors impairs hiPSC differentiation

Molecular identification of papillomavirus in ducks

Papillomaviruses infect many vertebrates, including birds. Persistent infections by some strains can cause malignant proliferation of cells (i.e. cancer), though more typically infections cause benign tumours, or may be completely subclinical. Sometimes extensive, persistent tumours are recorded– notably in chaffinches and humans. In 2016, a novel papillomavirus genotype was characterized from a duck faecal microbiome, in Bhopal, India; the sixth papillomavirus genotype from birds. Prompted by this finding, we screened 160 cloacal swabs and 968 faecal samples collected from 299 ducks sampled at Ottenby Bird Observatory, Sweden in 2015, using a newly designed real-time PCR. Twenty one samples (1.9%) from six individuals (2%) were positive. Eighteen sequences were identical to the published genotype, duck papillomavirus 1. One additional novel genotype was recovered from three samples. Both genotypes were recovered from a wild strain domestic mallard that was infected for more than 60 days with each genotype. All positive individuals were adult (P = 0.004). Significantly more positive samples were detected from swabs than faecal samples (P < 0.0001). Sample type data suggests transmission may be via direct contact, and only infrequently, via the oral-faecal route. Infection in only adult birds supports the hypothesis that this virus is sexually transmitted, though more work is required to verify this.Thanks to duck trappers at Ottenby Bird Observatory for support and sample collection, and to Abbtesaim Jawad for DNA extraction. This work was supported by the Crafoord Foundation Sweden (grants number 20160971 and 20170671). This is contribution no. 306 from Ottenby Bird Observatory

Early Stage Biomineralization in the Periostracum of the ‘Living Fossil’ Bivalve Neotrigonia

A detailed investigation of the shell formation of the palaeoheterodont ‘living fossil’ Neotrigonia concentrated on the timing and manufacture of the calcified ‘bosses’ which stud the outside of all trigonioid bivalves (extant and fossil) has been conducted. Electron microscopy and optical microscopy revealed that Neotrigonia spp. have a spiral-shaped periostracal groove. The periostracum itself is secreted by the basal cell, as a thin dark pellicle, becoming progressively transformed into a thin dark layer by additions of secretions from the internal outer mantle fold. Later, intense secretion of the internal surface of the outer mantle fold forms a translucent layer, which becomes transformed by tanning into a dark layer. The initiation of calcified bosses occurred at a very early stage of periostracum formation, deep within the periostracal groove immediately below the initialmost dark layer. At this stage, they consist of a series of polycyclically twinned crystals. The bosses grow as the periostracum traverse through the periostracal groove, in coordination with the thickening of the dark periostracal layer and until, upon reaching the mantle edge, they impinge upon each other and become transformed into large prisms separated by dark periostracal walls. In conclusion, the initial bosses and the external part of the prismatic layer are fully intraperiostracal. With later growth, the prisms transform into fibrous aggregates, although the details of the process are unknown. This reinforces the relationships with other groups that have the ability to form intraperiostracal calcifications, for example the unionoids with which the trigonioids form the clade Paleoheterodonta. The presence of similar structures in anomalodesmatans and other euheterodonts raises the question of whether this indicates a relationship or represents a convergence. The identification of very early calcification within an organic sheet has interesting implications for our understanding of how shells may have evolved.Coordinated Research Projects CGL2010-20748-C02-01 (AGC, EMH) and 02 (CS) (DGI, Spanish MICINN); the Research Group RNM363 (Consejería de Economía, Investigación, Ciencia y Empleo, Junta de Andalucía); and the FP7 COST Action TD0903 of the European Community

Regulatory T Cell Induction during Plasmodium chabaudi Infection Modifies the Clinical Course of Experimental Autoimmune Encephalomyelitis

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is used as an animal model for human multiple sclerosis (MS), which is an inflammatory demyelinating autoimmune disease of the central nervous system characterized by activation of Th1 and/or Th17 cells. Human autoimmune diseases can be either exacerbated or suppressed by infectious agents. Recent studies have shown that regulatory T cells play a crucial role in the escape mechanism of Plasmodium spp. both in humans and in experimental models. These cells suppress the Th1 response against the parasite and prevent its elimination. Regulatory T cells have been largely associated with protection or amelioration in several autoimmune diseases, mainly by their capacity to suppress proinflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we verified that CD4(+)CD25(+) regulatory T cells (T regs) generated during malaria infection (6 days after EAE induction) interfere with the evolution of EAE. We observed a positive correlation between the reduction of EAE clinical symptoms and an increase of parasitemia levels. Suppression of the disease was also accompanied by a decrease in the expression of IL-17 and IFN-γ and increases in the expression of IL-10 and TGF-β1 relative to EAE control mice. The adoptive transfer of CD4(+)CD25(+) cells from P. chabaudi-infected mice reduced the clinical evolution of EAE, confirming the role of these T regs. CONCLUSIONS/SIGNIFICANCE: These data corroborate previous findings showing that infections interfere with the prevalence and evolution of autoimmune diseases by inducing regulatory T cells, which regulate EAE in an apparently non-specific manner