A theoretical basis for the analysis of redundant software subject to coincident errors

Fundamental to the development of redundant software techniques fault-tolerant software, is an understanding of the impact of multiple-joint occurrences of coincident errors. A theoretical basis for the study of redundant software is developed which provides a probabilistic framework for empirically evaluating the effectiveness of the general (N-Version) strategy when component versions are subject to coincident errors, and permits an analytical study of the effects of these errors. The basic assumptions of the model are: (1) independently designed software components are chosen in a random sample; and (2) in the user environment, the system is required to execute on a stationary input series. The intensity of coincident errors, has a central role in the model. This function describes the propensity to introduce design faults in such a way that software components fail together when executing in the user environment. The model is used to give conditions under which an N-Version system is a better strategy for reducing system failure probability than relying on a single version of software. A condition which limits the effectiveness of a fault-tolerant strategy is studied, and it is posted whether system failure probability varies monotonically with increasing N or whether an optimal choice of N exists

Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel

In human cardiac ventricular myocytes, caveolin-3 functions as a scaffolding and regulatory protein for signaling molecules and compartmentalizes ion channels. Our lab has recently explored this sub-cellular microdomain and found that potassium inward rectifier Kir2.x is found in association with caveolin-3. The three cardiac Kir2.x isoforms (Kir2.1, Kir2.2, and Kir2.3) are the molecular correlates of IK1 in the heart, of which Kir2.1 is the dominant isoform in the ventricle. Kir2.1 channels assemble with Kir2.2 and Kir2.3 forming hetero-tetramers that modulate IK1. IK1 sets the resting membrane potential and assists with terminal phase 3 ventricular repolarization. In our studies using native human ventricular tissue, Kir2.x co-localizes with caveolin-3 and significance of the association between Kir2.x and caveolin-3 is emphasized in relation to mutations in the gene which encodes caveolin-3, CAV3, associated with Long QT Syndrome 9 (LQT9). LQT9-associated CAV3 mutations cause decreased current density in Kir2.1 and Kir2.2 as homomeric and heteromeric channels, which affects repolarization and membrane potential stability. A portion of Kir2.1 cardiac localization parallels that of the cardiac sodium channel (Nav1.5). This may have implications for Long QT9 in which CAV3 mutations cause an increase in the late current of Nav1.5 (INa−L) via nNOS mediated nitrosylation of Nav1.5. In iPS-CMs, expression of LQT9 CAV3 mutations resulted in action potential duration (APD) prolongation and early-after depolarizations (EADs), supporting the arrhythmogenicity of LQT9. To evaluate the combined effect of the CAV3 mutants on INa−L and IK1, we studied both ventricular and Purkinje myocyte mathematical modeling. Interestingly, mathematical ventricular myocytes, similar to iPS-CMs, demonstrated EADs but no sustained arrhythmia. In contrast, Purkinje modeling demonstrated delayed-after depolarizations (DADs) driven mechanism for sustained arrhythmia, dependent on the combined loss of IK1 and gain of INa−L. This finding changes the overall assumed arrhythmia phenotype for LQT9. In future studies, we are exploring caveolar micro-domain disruption in heart failure and how this effects Kir2.x and Nav1.5. Here we review the caveolae cardiac microdomain of Kir2.x and Nav1.5 and explore some of the downstream effects of caveolin-3 and caveolae disruption in specific clinical scenarios

Ultracold neutrons, quantum effects of gravity and the Weak Equivalence Principle

We consider an extension of the recent experiment with ultracold neutrons and the quantization of its vertical motion in order to test the Weak Equivalence Principle. We show that an improvement on the energy resolution of the experiment may allow to establish a modest limit to the Weak Equivalence Principle and on the gravitational screening constant. We also discuss the influence of a possible new interaction of Nature.Comment: Revtex4, 4 pages. Discussion on the equivalence principle altered. Bound is improve

KT&G : From Korean monopoly to ‘a global name in the tobacco industry’

Until the late 1980s, the former South Korean tobacco monopoly KT&G was focused on the protected domestic market. The opening of the market to foreign competition, under pressure from the U.S. Trade Representative, led to a steady erosion of market share over the next 10 years. Drawing on company documents and industry sources, this paper examines the adaptation of KT&G to the globalization of the South Korean tobacco industry since the 1990s. It is argued that KT&G has shifted from a domestic monopoly to an outward-looking, globally oriented business in response to the influx of transnational tobacco companies. Like other high-income countries, South Korea has also seen a decline in smoking prevalence as stronger tobacco control measures have been adopted. Faced with a shrinking domestic market, KT&G initially focused on exporting Korean-manufactured cigarettes. Since the mid-2000s, a broader global business strategy has been adopted including the building of overseas manufacturing facilities, establishing strategic partnerships and acquiring foreign companies. Trends in KT&G sales suggest an aspiring transnational tobacco company poised to become a major player in the global tobacco market. This article is part of the special issue \u27The emergence of Asian tobacco companies: Implications for global health governance\u27

MethyCancer: the database of human DNA methylation and cancer

Cancer is ranked as one of the top killers in all human diseases and continues to have a devastating effect on the population around the globe. Current research efforts are aiming to accelerate our understanding of the molecular basis of cancer and develop effective means for cancer diagnostics, treatment and prognosis. An altered pattern of epigenetic modifications, most importantly DNA methylation events, plays a critical role in tumorigenesis through regulating oncogene activation, tumor suppressor gene silencing and chromosomal instability. To study interplay of DNA methylation, gene expression and cancer, we developed a publicly accessible database for human DNA Methylation and Cancer (MethyCancer, http://methycancer.genomics.org.cn). MethyCancer hosts both highly integrated data of DNA methylation, cancer-related gene, mutation and cancer information from public resources, and the CpG Island (CGI) clones derived from our large-scale sequencing. Interconnections between different data types were analyzed and presented. Furthermore, a powerful search tool is developed to provide user-friendly access to all the data and data connections. A graphical MethyView shows DNA methylation in context of genomics and genetics data facilitating the research in cancer to understand genetic and epigenetic mechanisms that make dramatic changes in gene expression of tumor cells

Baryon Stopping and Charged Particle Distributions in Central Pb+Pb Collisions at 158 GeV per Nucleon

Net proton and negative hadron spectra for central \PbPb collisions at 158 GeV per nucleon at the CERN SPS were measured and compared to spectra from lighter systems. Net baryon distributions were derived from those of net protons, utilizing model calculations of isospin contributions as well as data and model calculations of strange baryon distributions. Stopping (rapidity shift with respect to the beam) and mean transverse momentum \meanpt of net baryons increase with system size. The rapidity density of negative hadrons scales with the number of participant nucleons for nuclear collisions, whereas their \meanpt is independent of system size. The \meanpt dependence upon particle mass and system size is consistent with larger transverse flow velocity at midrapidity for \PbPb compared to \SS central collisions.Comment: This version accepted for publication in PRL. 4 pages, 3 figures. Typos corrected, some paragraphs expanded in response to referee comments, to better explain details of analysi

Ancestry reported by white adults with cutaneous melanoma and control subjects in central Alabama

BACKGROUND: We sought to evaluate the hypothesis that the high incidence of cutaneous melanoma in white persons in central Alabama is associated with a predominance of Irish and Scots descent. METHODS: Frequencies of country of ancestry reports were tabulated. The reports were also converted to scores that reflect proportional countries of ancestry in individuals. Using the scores, we computed aggregate country of ancestry indices as estimates of group ancestry composition. HLA-DRB1*04 allele frequencies and relationships to countries of ancestry were compared in probands and controls. Results were compared to those of European populations with HLA-DRB1*04 frequencies. RESULTS: Ninety evaluable adult white cutaneous melanoma probands and 324 adult white controls reported countries of ancestry of their grandparents. The respective frequencies of Ireland, and Scotland and "British Isles" reported countries of ancestry were significantly greater in probands than in controls. The respective frequencies of Wales, France, Italy and Poland were significantly greater in controls. 16.7% of melanoma probands and 23.8% of controls reported "Native American" ancestry; the corresponding "Native American" country of ancestry index was not significantly different in probands and controls. The frequency of HLA-DRB1*04 was significantly greater in probands, but was not significantly associated with individual or aggregate countries of ancestry. The frequency of DRB1*04 observed in Alabama was compared to DRB1*04 frequencies reported from England, Wales, Ireland, Orkney Island, France, Germany, and Australia. CONCLUSION: White adults with cutaneous melanoma in central Alabama have a predominance of Irish, Scots, and "British Isles" ancestry and HLA-DRB1*04 that likely contributes to their high incidence of cutaneous melanoma

Sensory Experience Differentially Modulates the mRNA Expression of the Polysialyltransferases ST8SiaII and ST8SiaIV in Postnatal Mouse Visual Cortex

Polysialic acid (PSA) is a unique carbohydrate composed of a linear homopolymer of α-2,8 linked sialic acid, and is mainly attached to the fifth immunoglobulin-like domain of the neural cell adhesion molecule (NCAM) in vertebrate neural system. In the brain, PSA is exclusively synthesized by the two polysialyltransferases ST8SiaII (also known as STX) and ST8SiaIV (also known as PST). By modulating adhesive property of NCAM, PSA plays a critical role in several neural development processes such as cell migration, neurite outgrowth, axon pathfinding, synaptogenesis and activity-dependent plasticity. The expression of PSA is temporally and spatially regulated during neural development and a tight regulation of PSA expression is essential to its biological function. In mouse visual cortex, PSA is downregulated following eye opening and its decrease allows the maturation of GABAergic synapses and the opening of the critical period for ocular dominance plasticity. Relatively little is known about how PSA levels are regulated by sensory experience and neuronal activity. Here, we demonstrate that while both ST8SiaII and ST8SiaIV mRNA levels decrease around the time of eye opening in mouse visual cortex, only ST8SiaII mRNA level reduction is regulated by sensory experience. Using an organotypic culture system from mouse visual cortex, we further show that ST8SiaII gene expression is regulated by spiking activity and NMDA-mediated excitation. Further, we show that both ST8SiaII and ST8SiaIV mRNA levels are positively regulated by PKC-mediated signaling. Therefore, sensory experience-dependent ST8SiaII gene expression regulates PSA levels in postnatal visual cortex, thus acting as molecular link between visual activity and PSA expression