Verifying That a Compiler Preserves Concurrent Value-Dependent Information-Flow Security

It is common to prove by reasoning over source code that programs do not leak sensitive data. But doing so leaves a gap between reasoning and reality that can only be filled by accounting for the behaviour of the compiler. This task is complicated when programs enforce value-dependent information-flow security properties (in which classification of locations can vary depending on values in other locations) and complicated further when programs exploit shared-variable concurrency. Prior work has formally defined a notion of concurrency-aware refinement for preserving value-dependent security properties. However, that notion is considerably more complex than standard refinement definitions typically applied in the verification of semantics preservation by compilers. To date it remains unclear whether it can be applied to a realistic compiler, because there exist no general decomposition principles for separating it into smaller, more familiar, proof obligations. In this work, we provide such a decomposition principle, which we show can almost halve the complexity of proving secure refinement. Further, we demonstrate its applicability to secure compilation, by proving in Isabelle/HOL the preservation of value-dependent security by a proof-of-concept compiler from an imperative While language to a generic RISC-style assembly language, for programs with shared-memory concurrency mediated by locking primitives. Finally, we execute our compiler in Isabelle on a While language model of the Cross Domain Desktop Compositor, demonstrating to our knowledge the first use of a compiler verification result to carry an information-flow security property down to the assembly-level model of a non-trivial concurrent program

Proving the Absence of Microarchitectural Timing Channels

Microarchitectural timing channels are a major threat to computer security. A set of OS mechanisms called time protection was recently proposed as a principled way of preventing information leakage through such channels and prototyped in the seL4 microkernel. We formalise time protection and the underlying hardware mechanisms in a way that allows linking them to the information-flow proofs that showed the absence of storage channels in seL4.Comment: Scott Buckley and Robert Sison were joint lead author

The Effects of Small Farm Mechanization on Employment and Output in Selected Rice-Growing Areas in Nueva Ecija, Philippines

This article is part of the seminar-workshop on the "Consequences of Small Farm Mechanization on Production, Employment and Incomes in the Philippines” sponsored jointly by the Ministry of Agriculture, the National Economic and Development Authority, the Philippine Institute for Development Studies and the International Rice Research Institute held on December 1-2, 1983 at Tagaytay City. It develops a working definition of a mechanized rice farm, determines the existence of mechanized and nonmechanized rice farms and looks into various factors that affect labor employment and output of small rice farms in Nueva Ecija.labor force, agriculture sector, rice commodities, rice farm, farm lands, impact analysis, mechanization

The Effects of Small Farm Mechanization on Employment and Output in Selected Rice-Growing Areas in Nueva Ecija, Philippines

This article is part of the seminar-workshop on the "Consequences of Small Farm Mechanization on Production, Employment and Incomes in the Philippines” sponsored jointly by the Ministry of Agriculture, the National Economic and Development Authority, the Philippine Institute for Development Studies and the International Rice Research Institute held on December 1-2, 1983 at Tagaytay City. It develops a working definition of a mechanized rice farm, determines the existence of mechanized and nonmechanized rice farms and looks into various factors that affect labor employment and output of small rice farms in Nueva Ecija.labor force, agriculture sector, rice commodities, rice farm, farm lands, impact analysis, mechanization

Detection of Hepatic Drug Metabolite-Specific T-Cell Responses Using a Human Hepatocyte, Immune Cell Coculture System

Drug-responsive T-cells are activated with the parent compound or metabolites, often via different pathways (pharmacological interaction and hapten). An obstacle to the investigation of drug hypersensitivity is the scarcity of reactive metabolites for functional studies and the absence of coculture systems to generate metabolites in situ. Thus, the aim of this study was to utilize dapsone metabolite-responsive T-cells from hypersensitive patients, alongside primary human hepatocytes to drive metabolite formation, and subsequent drug-specific T-cell responses. Nitroso dapsone-responsive T-cell clones were generated from hypersensitive patients and characterized in terms of cross-reactivity and pathways of T-cell activation. Primary human hepatocytes, antigen-presenting cells, and T-cell cocultures were established in various formats with the liver and immune cells separated to avoid cell contact. Cultures were exposed to dapsone, and metabolite formation and T-cell activation were measured by LC-MS and proliferation assessment, respectively. Nitroso dapsone-responsive CD4+ T-cell clones from hypersensitive patients were found to proliferate and secrete cytokines in a dose-dependent manner when exposed to the drug metabolite. Clones were activated with nitroso dapsone-pulsed antigen-presenting cells, while fixation of antigen-presenting cells or omission of antigen-presenting cells from the assay abrogated the nitroso dapsone-specific T-cell response. Importantly, clones displayed no cross-reactivity with the parent drug. Nitroso dapsone glutathione conjugates were detected in the supernatant of hepatocyte immune cell cocultures, indicating that hepatocyte-derived metabolites are formed and transferred to the immune cell compartment. Similarly, nitroso dapsone-responsive clones were stimulated to proliferate with dapsone, when hepatocytes were added to the coculture system. Collectively, our study demonstrates the use of hepatocyte immune cell coculture systems to detect in situ metabolite formation and metabolite-specific T-cell responses. Similar systems should be used in future diagnostic and predictive assays to detect metabolite-specific T-cell responses when synthetic metabolites are not available

Iroquois Complex Genes Induce Co-Expression of rhodopsins in Drosophila

The Drosophila eye is a mosaic that results from the stochastic distribution of two ommatidial subtypes. Pale and yellow ommatidia can be distinguished by the expression of distinct rhodopsins and other pigments in their inner photoreceptors (R7 and R8), which are implicated in color vision. The pale subtype contains ultraviolet (UV)-absorbing Rh3 in R7 and blue-absorbing Rh5 in R8. The yellow subtype contains UV-absorbing Rh4 in R7 and green-absorbing Rh6 in R8. The exclusive expression of one rhodopsin per photoreceptor is a widespread phenomenon, although exceptions exist. The mechanisms leading to the exclusive expression or to co-expression of sensory receptors are currently not known. We describe a new class of ommatidia that co-express rh3 and rh4 in R7, but maintain normal exclusion between rh5 and rh6 in R8. These ommatidia, which are localized in the dorsal eye, result from the expansion of rh3 into the yellow-R7 subtype. Genes from the Iroquois Complex (Iro-C) are necessary and sufficient to induce co-expression in yR7. Iro-C genes allow photoreceptors to break the “one receptor–one neuron” rule, leading to a novel subtype of broad-spectrum UV- and green-sensitive ommatidia

VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis

Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b+ microglia-like cells and GFAP+ astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation. Using pharmacological interventions targeting VEGFR2 in arthritic rats, to inhibit endothelial cell activation, the number of dorsal horn ICAM-1+ blood vessels, CD11b+ microglia and the development of secondary mechanical allodynia, an indicator of central sensitization, were all prevented. Targeting endothelial VEGFR2 by inducible Tie2-specific VEGFR2 knock-out also prevented secondary allodynia in mice and glio-vascular activation in the dorsal horn in response to inflammatory arthritis. Inhibition of VEGFR2 in vitro significantly blocked ICAM-1-dependent monocyte adhesion to brain microvascular endothelial cells, when stimulated with inflammatory mediators TNFa and VEGF-A165a. Taken together our findings suggest that a novel VEGFR2-mediated spinal cord gliovascular mechanism may promote peripheral CD11b+ circulating cell transmigration into the CNS parenchyma and contribute to the development of chronic pain in inflammatory arthritis. We hypothesise that preventing this glio-vascular activation and circulating cell translocation into the spinal cord could be a new therapeutic strategy for pain caused by rheumatoid arthritis

Model-based identification of TNF alpha-induced IKK beta-mediated and I kappa B alpha-mediated regulation of NF kappa B signal transduction as a tool to quantify the impact of drug-induced liver injury compounds

Drug-induced liver injury: mathematical model quantifies impact of liver-damaging drugs Drug-induced liver injury (DILI) is one of the most important obstacles during drug development. More than 1000 drugs have been identified to damage the liver, but the current test systems are poor in predicting DILI. A team of cell biologists, theoretical physicists, and clinical pharmacologists combined experimental data generated in cultured liver cells with mathematical modeling to quantify the impact of the anti-inflammatory drug diclofenac. The analysis demonstrated that diclofenac induces multiple changes in the signal transduction network activated by the tumor necrosis factor alpha (TNFα), one of the known factors to amplify liver toxicity. Data of other liver injury-causing compounds were integrated into the mathematical model and their impact was quantified, thereby demonstrating the potential use of the mathematical model for the further analysis of other compounds in order to improve DILI test systems

Stem cell-derived models to improve mechanistic understanding and prediction of human drug induced liver injury

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135984/1/hep28886.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135984/2/hep28886_am.pd

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data