Formal Availability Analysis using Theorem Proving

Availability analysis is used to assess the possible failures and their restoration process for a given system. This analysis involves the calculation of instantaneous and steady-state availabilities of the individual system components and the usage of this information along with the commonly used availability modeling techniques, such as Availability Block Diagrams (ABD) and Fault Trees (FTs) to determine the system-level availability. Traditionally, availability analyses are conducted using paper-and-pencil methods and simulation tools but they cannot ascertain absolute correctness due to their inaccuracy limitations. As a complementary approach, we propose to use the higher-order-logic theorem prover HOL4 to conduct the availability analysis of safety-critical systems. For this purpose, we present a higher-order-logic formalization of instantaneous and steady-state availability, ABD configurations and generic unavailability FT gates. For illustration purposes, these formalizations are utilized to conduct formal availability analysis of a satellite solar array, which is used as the main source of power for the Dong Fang Hong-3 (DFH-3) satellite.Comment: 16 pages. arXiv admin note: text overlap with arXiv:1505.0264

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators

The Value of Suction Drainage Fluid Culture during Aseptic and Septic Orthopedic Surgery: A Prospective Study of 901 Patients

There are no guidelines on the value of suction drainage fluid culture (SDC), and it is difficult to determine whether the organisms cultured from suction drainage fluid samples are pathogenic or simply contaminants. We performed 2989 cultures of suction drainage fluid samples obtained, during a 1-year period, from 901 patients who underwent aseptic or septic orthopedic surgery (946 operations). The culture results were analyzed to evaluate their ability to detect postoperative infection after aseptic operations or to detect either a persistent or new episode of sepsis in patients known to have infection. For aseptic operations, the sensitivity of SDC was 25%, the specificity was 99%, the positive predictive value was 25%, and the negative predictive value was 99%. For septic operations, the sensitivity of SDC was 81%, the specificity was 96%, the positive predictive value was 87%, and the negative predictive value was 94%. We conclude that, for aseptic orthopedic surgery, SDC is not useful in detecting postoperative infection. However, for septic orthopedic surgery, it is of clinical importanc

Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC

The "ram effect": new insights into neural modulation of the gonadotropic axis by male odors and socio-sexual interactions

Reproduction in mammals is controlled by the hypothalamo-pituitary-gonadal (HPG) axis under the influence of external and internal factors such as photoperiod, stress, nutrition, and social interactions. Sheep are seasonal breeders and stop mating when day length is increasing (anestrus). However, interactions with a sexually active ram during this period can override the steroid negative feedback responsible for the anoestrus state, stimulate LH secretion and eventually reinstate cyclicity. This is known as the ram effect and research into the mechanisms underlying it is shedding new light on HPG axis regulation. The first step in the ram effect is increased LH pulsatile secretion in anestrus ewes exposed to a sexually active male or only to its fleece, the latter finding indicating a pheromone-like effect. Estradiol secretion increases in all ewes and this eventually induces a LH surge and ovulation, just as during the breeding season. An exception is a minority of ewes that exhibit a precocious LH surge (within 4h) with no prior increase in estradiol. The main olfactory system and the cortical nucleus of the amygdala are critical brain structures in mediating the ram effect since it is blocked by their inactivation. Sexual experience is also important since activation (increased c-fos expression) in these and other regions is greatly reduced in sexually naïve ewes. In adult ewes kisspeptin neurons in both arcuate and preoptic regions and some preoptic GnRH neurons are activated 2h after exposure to a ram. Exposure to rams also activates noradrenergic neurons in the locus coeruleus and A1 nucleus and increased noradrenalin release occurs in the posterior preoptic area. Pharmacological modulation of this system modifies LH secretion in response to the male or his odor. Together these results show that the ram effect can be a fruitful model to promote both a better understanding of the neural and hormonal regulation of the HPG axis in general and also the spe

Let's Make Love: Whiteness, Cleanliness and Sexuality in the French Reception of Marilyn Monroe

Copyright © by SAGE PublicationsRichard Dyer’s seminal work on whiteness in film considers Marilyn Monroe as the epitome of an institutionally racist Hollywood system that imagines the most desirable woman to be blonde, given that blondeness is understood as a guarantee of whiteness. This article adds to other recent scholarship on Monroe that has sought to complicate this reading by examining other meanings that can be attributed to her bleached blonde hair. By closely analyzing media texts that discussed Monroe in 1950s France, this article demonstrates the way in which her performance of ideal American female sexuality was read through the prism of Monroe as icon of cleanliness and (linked) modernity. It examines the way in which Monroe’s modernity allowed her to partially escape the traditional feminine private sphere and it concludes that Monroe’s bleached blonde hair can be seen in this context as having liberatory potential

Single-molecule and super-resolved imaging deciphers membrane behavior of onco-immunogenic CCR5

The ability of tumors to establish a pro-tumorigenic microenvironment is an important point of investigation in the search for new therapeutics. Tumors form microenvironments in part by the “education” of immune cells attracted via chemotactic axes such as that of CCR5-CCL5. Further, CCR5 upregulation by cancer cells, coupled with its association with pro-tumorigenic features such as drug resistance and metastasis, has suggested CCR5 as a therapeutic target. However, with several conformational “pools” being reported, phenotypic investigations must be capable of unveiling conformational heterogeneity. Addressing this challenge, we performed super-resolution structured illumination microscopy (SIM) and single molecule partially TIRF-coupled HILO (PaTCH) microscopy of CCR5 in fixed cells. SIM data revealed a non-random spatial distribution of CCR5 assemblies, while Intensity-tracking of CCR5 assemblies from PaTCH images indicated dimeric sub-units independent of CCL5 perturbation. These biophysical methods can provide important insights into the structure and function of onco-immunogenic receptors and many other biomolecules

Recent EUROfusion Achievements in Support of Computationally Demanding Multiscale Fusion Physics Simulations and Integrated Modeling

Integrated modeling (IM) of present experiments and future tokamak reactors requires the provision of computational resources and numerical tools capable of simulating multiscale spatial phenomena as well as fast transient events and relatively slow plasma evolution within a reasonably short computational time. Recent progress in the implementation of the new computational resources for fusion applications in Europe based on modern supercomputer technologies (supercomputer MARCONI-FUSION), in the optimization and speedup of the EU fusion-related first-principle codes, and in the development of a basis for physics codes/modules integration into a centrally maintained suite of IM tools achieved within the EUROfusion Consortium is presented. Physics phenomena that can now be reasonably modelled in various areas (core turbulence and magnetic reconnection, edge and scrape-off layer physics, radio-frequency heating and current drive, magnetohydrodynamic model, reflectometry simulations) following successful code optimizations and parallelization are briefly described. Development activities in support to IM are summarized. They include support to (1) the local deployment of the IM infrastructure and access to experimental data at various host sites, (2) the management of releases for sophisticated IM workflows involving a large number of components, and (3) the performance optimization of complex IM workflows.This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014 to 2018 under grant agreement 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission or ITER.Peer ReviewedPostprint (published version

Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver

Leukocyte adhesion and transmigration are central features governing immune surveillance and inflammatory reactions in body tissues. Within the liver sinusoids, chemokines initiate the first crucial step of T-cell migration into the hepatic tissue. We studied molecular mechanisms involved in endothelial chemokine supply during hepatic immune surveillance and liver inflammation and their impact on the recruitment of CD4+ T cells into the liver. In the murine model of Concanavalin A-induced T cell-mediated hepatitis, we showed that hepatic expression of the inflammatory CXC chemokine ligands (CXCL)9 and CXCL10 strongly increased whereas homeostatic CXCL12 significantly decreased. Consistently, CD4+ T cells expressing the CXC chemokine receptor (CXCR)3 accumulated within the inflamed liver tissue. In histology, CXCL9 was associated with liver sinusoidal endothelial cells (LSEC) which represent the first contact site for T-cell immigration into the liver. LSEC actively transferred basolaterally internalized CXCL12, CXCL9 and CXCL10 via clathrin- coated vesicles to CD4+ T cells leading to enhanced transmigration of CXCR4+ total CD4+ T cells and CXCR3+ effector/memory CD4+ T cells, respectively in vitro. LSEC-expressed CXCR4 mediated CXCL12 transport and blockage of endothelial CXCR4 inhibited CXCL12-dependent CD4+ T-cell transmigration. In contrast, CXCR3 was not involved in the endothelial transport of its ligands CXCL9 and CXCL10. The clathrin-specific inhibitor chlorpromazine blocked endothelial chemokine internalization and CD4+ T-cell transmigration in vitro as well as migration of CD4+ T cells into the inflamed liver in vivo. Moreover, hepatic accumulation of CXCR3+ CD4+ T cells during T cell-mediated hepatitis was strongly reduced after administration of chlorpromazine. These data demonstrate that LSEC actively provide perivascularly expressed homeostatic and inflammatory chemokines by CXCR4- and clathrin-dependent intracellular transport mechanisms thereby contributing to the hepatic recruitment of CD4+ T-cell populations during immune surveillance and liver inflammation

Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis

Acidic tissue microenvironment commonly exists in inflammatory diseases, tumors, ischemic organs, sickle cell disease, and many other pathological conditions due to hypoxia, glycolytic cell metabolism and deficient blood perfusion. However, the molecular mechanisms by which cells sense and respond to the acidic microenvironment are not well understood. GPR4 is a proton-sensing receptor expressed in endothelial cells and other cell types. The receptor is fully activated by acidic extracellular pH but exhibits lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To delineate the function and signaling pathways of GPR4 activation by acidosis in endothelial cells, we compared the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. The results demonstrated that acidosis activation of GPR4 in HUVEC substantially increased the expression of a number of inflammatory genes such as chemokines, cytokines, adhesion molecules, NF-κB pathway genes, and prostaglandin-endoperoxidase synthase 2 (PTGS2 or COX-2) and stress response genes such as ATF3 and DDIT3 (CHOP). Similar GPR4-mediated acidosis induction of the inflammatory genes was also noted in other types of endothelial cells including human lung microvascular endothelial cells and pulmonary artery endothelial cells. Further analyses indicated that the NF-κB pathway was important for the acidosis/GPR4-induced inflammatory gene expression. Moreover, acidosis activation of GPR4 increased the adhesion of HUVEC to U937 monocytic cells under a flow condition. Importantly, treatment with a recently identified GPR4 antagonist significantly reduced the acidosis/GPR4-mediated endothelial cell inflammatory response. Taken together, these results show that activation of GPR4 by acidosis stimulates the expression of a wide range of inflammatory genes in endothelial cells. Such inflammatory response can be suppressed by GPR4 small molecule inhibitors and hold potential therapeutic value