Software integration testing based on communication coverage criteria and partial model generation

This paper considers the problem of integration testing the components of a timed distributed software system. We assume that communication between the components is specified using timed interface automata and use computational tree logic (CTL) to define communication-based coverage criteria that refer to send- and receive-statements and communication paths. The proposed method enables testers to focus during component integration on such parts of the specification, e.g. behaviour specifications or Markovian usage models, that are involved in the communication between components to be integrated. A more specific application area of this approach is the integration of test-models, e.g. a transmission gear can be tested based on separated models for the driver behaviour, the engine condition, and the mechanical and hydraulical transmission states. Given such a state-based specification of a distributed system and a concrete coverage goal, a model checker is used in order to determine the coverage or generate test sequences that achieve the goal. Given the generated test sequences we derive a partial test-model of the components from which the test sequences are derived. The partial model can be used to drive further testing and can also be used as the basis for producing additional partial models in incremental integration testing. While the process of deriving the test sequences could suffer from a combinatorial explosion, the effort required to generate the partial model is polynomial in the number of test sequences and their length. Thus, where it is not feasible to produce test sequences that achieve a given type of coverage it is still possible to produce a partial model on the basis of test sequences generated to achieve some other criterion. As a result, the process of generating a partial model has the potential to scale to large industrial software systems. While a particular model checker, UPPAAL, was used, it should be relatively straightforward to adapt the approach for use with other CTL based model checkers. A potential additional benefit of the approach is that it provides a visual description of the state-based testing of distributed systems, which may be beneficial in other contexts such as education and comprehension

IL-1α and TNF-α Down-Regulate CRH Receptor-2 mRNA Expression in the Mouse Heart

Two receptors (CRH receptor type 1 and CRH receptor type 2) have been identified for the stress-induced neuropeptide, CRH and related peptides, urocortin, and urocortin II. We previously found marked down-regulation of cardiac CRH receptor type 2 expression following administration of bacterial endotoxin, lipopolysaccharide, a model of systemic immune activation, and inflammation. We postulated that inflammatory cytokines may regulate CRH receptor type 2. We show that systemic IL-1α administration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFα treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1α. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFα or IL-1α. Thus, cytokine regulation may be indirect. Exogenous administration of corticosterone in vivo or acute restraint stress also reduces cardiac CRH receptor type 2 mRNA expression, but like cytokines, in vitro corticosterone treatment does not modulate expression in cardiomyocytes. Interestingly, treatment with urocortin significantly decreases CRH receptor type 2 mRNA in cultured cardiomyocytes. We speculate that in vivo, inflammatory mediators such as lipopolysaccharide and/or cytokines may increase urocortin, which in turn down-regulates CRH receptor type 2 expression in the heart. Because CRH and urocortin increase cardiac contractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ultimately diminish the adaptive cardiac response to adverse conditions

Adenosine and Stroke: Maximizing the Therapeutic Potential of Adenosine as a Prophylactic and Acute Neuroprotectant

Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant

On Farm Riparian Grazing Demonstration

Two farm demonstrations were designed to show effects of periodic grazing of riparian areas. Sites were monitored for vegetative cover, degree of treading or hoof prints and dung deposition within three m of stream edge following grazing by beef cattle. A fenced enclosure was established along a 350 m stream reach on Farm-1, and eleven permanent stations were monitored following six graze periods over 12-months. Farm-2 involved grazing of two 0.13 ha paddocks, each of which contained a 22 m stream reach. On Farm-1 the cover improved following riparian exclusion, and evidence of treading in the 11 stations declined following each graze period. On Farm-2, vegetation was dense in the beginning, and one day graze periods with high stock density did not result in significant soil exposure, even though hoof prints were evident at more than 30% of the transect points. Having access to a drinking water tank 45 m up slope did not influence cover nor dung deposition in the riparian zone. The number of dung patties found within 3 m of the stream edge ranged from 15 to 28/100 m (Farm-1) and from 41 to 96/100 m (Farm-2). Estimates of potential dung N deposited within three m of the entire reach of the respective streams was 565 g and 83 g. This project showed ways to use riparian areas with minimal impact on its function

LER screening algorithm for identification of potential accident sequence precursor events

A computer algorithm has been developed and implemented to search the Sequence Coding and Search System Licensee Event (LER) database for failures or conditions common to Accident Sequence Precursor (ASP) events. Use of the algorithm has greatly improved the efficiency and timeliness in identifying potential ASP events and, by focusing attention on the most likely precursor events, has reduced the likelihood that these events will be overlooked in manual screening

Long-term solar activity influences on South American rivers

River streamflows are excellent climatic indicators since they integrate precipitation over large areas. Here we follow up on our previous study of the influence of solar activity on the flow of the Parana River, in South America. We find that the unusual minimum of solar activity in recent years have a correlation on very low levels in the Parana's flow, and we report historical evidence of low water levels during the Little Ice Age. We also study data for the streamflow of three other rivers (Colorado, San Juan and Atuel), and snow levels in the Andes. We obtained that, after eliminating the secular trends and smoothing out the solar cycle, there is a strong positive correlation between the residuals of both the Sunspot Number and the streamflows, as we obtained for the Parana. Both results put together imply that higher solar activity corresponds to larger precipitation, both in summer and in wintertime, not only in the large basin of the Parana, but also in the Andean region north of the limit with Patagonia.Comment: Accepted to publication by Journal of Atmospheric and Solar-Terrestrial Physic

Reactor Technology Options Study for Near-Term Deployment of GNEP Grid-Appropriate Reactors

World energy demand is projected to significantly increase over the coming decades. The International Energy Agency projects that electricity demand will increase 50% by 2015 and double by 2030, with most of the increase coming in developing countries as they experience double-digit rates of economic growth and seek to improve their standards of living. Energy is the necessary driver for human development, and the demand for energy in these countries will be met using whatever production technologies are available. Recognizing this inevitable energy demand and its implications for the United States, the U.S. National Security Strategy has proposed the Global Nuclear Energy Partnership (GNEP) to work with other nations to develop and deploy advanced nuclear recycling and reactor technologies. This initiative will help provide reliable, emission-free energy with less of the waste burden of older technologies and without making available separated plutonium that could be used by rogue states or terrorists for nuclear weapons. These new technologies will make possible a dramatic expansion of safe, clean nuclear energy to help meet the growing global energy demand. In other words, GNEP seeks to create an international regime to support large-scale growth in the worldwide use of nuclear energy without increasing the risk of nuclear weapon proliferation. This global expansion of nuclear power is strategically important to the United States for several reasons, including the following: (1) National security, by reducing the competition and potential for conflict over increasingly scarce fossil energy resources; (2) Economic security, by helping maintain stable prices for nonrenewable resources such as oil, gas, and coal; (3) Environmental security, by replacing or off-setting large-scale burning of greenhouse gas-emitting fuels for electricity production; and (4) Regaining technical leadership, through deployment of innovative U.S. technology-based reactors. Fully meeting the GNEP vision may require the deployment of thousands of reactors during the next century in dozens of countries, many of which are in the developing world where nuclear energy is not used currently. Such a large-scale deployment will have significant implications related to both fuel supply and spent fuel/waste management, both domestically and worldwide. Consequently, GNEP must address the development and demonstration of proliferation-resistant technologies to ensure both a safe and sustainable nuclear fuel cycle, and reactor designs that are appropriate for the range of needs across the global community. The focus of this report is the latter need, that is, the development and demonstration of proliferation-resistant reactors that are well matched to the needs and capabilities of developing countries

CRF Receptor Antagonist Astressin-B Reverses and Prevents Alopecia in CRF Over-Expressing Mice

Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4–9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF2 receptor antagonist, astressin2-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress

Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck

The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes

LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 4 (TLR4) is activated in response to cerebral ischemia leading to substantial brain damage. In contrast, mild activation of TLR4 by preconditioning with low dose exposure to lipopolysaccharide (LPS) prior to cerebral ischemia dramatically improves outcome by reprogramming the signaling response to injury. This suggests that TLR4 signaling can be altered to induce an endogenously neuroprotective phenotype. However, the TLR4 signaling events involved in this neuroprotective response are poorly understood. Here we define several molecular mediators of the primary signaling cascades induced by LPS preconditioning that give rise to the reprogrammed response to cerebral ischemia and confer the neuroprotective phenotype.</p> <p>Methods</p> <p>C57BL6 mice were preconditioned with low dose LPS prior to transient middle cerebral artery occlusion (MCAO). Cortical tissue and blood were collected following MCAO. Microarray and qtPCR were performed to analyze gene expression associated with TLR4 signaling. EMSA and DNA binding ELISA were used to evaluate NFκB and IRF3 activity. Protein expression was determined using Western blot or ELISA. MyD88-/- and TRIF-/- mice were utilized to evaluate signaling in LPS preconditioning-induced neuroprotection.</p> <p>Results</p> <p>Gene expression analyses revealed that LPS preconditioning resulted in a marked upregulation of anti-inflammatory/type I IFN-associated genes following ischemia while pro-inflammatory genes induced following ischemia were present but not differentially modulated by LPS. Interestingly, although expression of pro-inflammatory genes was observed, there was decreased activity of NFκB p65 and increased presence of NFκB inhibitors, including Ship1, Tollip, and p105, in LPS-preconditioned mice following stroke. In contrast, IRF3 activity was enhanced in LPS-preconditioned mice following stroke. TRIF and MyD88 deficient mice revealed that neuroprotection induced by LPS depends on TLR4 signaling via TRIF, which activates IRF3, but does not depend on MyD88 signaling.</p> <p>Conclusion</p> <p>Our results characterize several critical mediators of the TLR4 signaling events associated with neuroprotection. LPS preconditioning redirects TLR4 signaling in response to stroke through suppression of NFκB activity, enhanced IRF3 activity, and increased anti-inflammatory/type I IFN gene expression. Interestingly, this protective phenotype does not require the suppression of pro-inflammatory mediators. Furthermore, our results highlight a critical role for TRIF-IRF3 signaling as the governing mechanism in the neuroprotective response to stroke.</p