91 research outputs found
Hybrid - a definitional two-level approach to reasoning with higher-order abstract syntax
Combining higher-order abstract syntax and (co)-induction in a logical
framework is well known to be problematic.We describe the theory and the practice
of a tool called Hybrid, within Isabelle/HOL and Coq, which aims to address many
of these difficulties. It allows object logics to be represented using higher-order
abstract syntax, and reasoned about using tactical theorem proving and principles
of (co)induction. Moreover, it is definitional, which guarantees consistency within
a classical type theory. The idea is to have a de Bruijn representation of \u3bb-terms
providing a definitional layer that allows the user to represent object languages using
higher-order abstract syntax, while offering tools for reasoning about them at the
higher level. In this paper we describe how to use Hybrid in a multi-level reasoning
fashion, similar in spirit to other systems such as Twelf and Abella. By explicitly
referencing provability in a middle layer called a specification logic, we solve the
problem of reasoning by (co)induction in the presence of non-stratifiable hypothetical
judgments, which allow very elegant and succinct specifications of object logic
inference rules. We first demonstrate the method on a simple example, formally
proving type soundness (subject reduction) for a fragment of a pure functional
language, using a minimal intuitionistic logic as the specification logic. We then
prove an analogous result for a continuation-machine presentation of the operational semantics of the same language, encoded this time in an ordered linear logic that
serves as the specification layer. This example demonstrates the ease with which
we can incorporate new specification logics, and also illustrates a significantly more
complex object logic whose encoding is elegantly expressed using features of the new
specification logic
Recommended from our members
DOE reactor-pumped laser program
FALCON is a high-power, steady-state, nuclear reactor-pumped laser (RPL) concept that is being developed by the Department of Energy. The FALCON program has experimentally demonstrated reactor-pumped lasing in various mixtures of xenon, argon, neon, and helium at at wavelengths of 585, 703, 725, 1271, 1733, 1792, 2032, 2630, 2650, and 3370 nm with intrinsic efficiency as high as 2.5%. The major strengths of a reactor-pumped laser are continuous high-power operation, modular construction, self-contained power, compact size, and a variety of wavelengths (from visible to infrared). These characteristics suggest numerous applications not easily accessible to other laser types. A ground-based RPL could beam its power to space for such activities as illuminating geosynchronous communication satellites in the earth`s shadow to extend their lives, beaming power to orbital transfer vehicles, removing space debris, and providing power (from earth) to a lunar base during the long lunar night. The compact size and self-contained power also makes an RPL very suitable for ship basing so that power-beaming activities could be situated around the globe. The continuous high power of an RPL opens many potential manufacturing applications such as deep-penetration welding and cutting of thick structures, wide-area hardening of metal surfaces by heat treatment or cladding application, wide-area vapor deposition of ceramics onto metal surfaces, production of sub-micron sized particles for manufacturing of ceramics, wide-area deposition of diamond-like coatings, and 3-D ceramic lithography
Redox signalling to nuclear regulatory proteins by reactive oxygen species contributes to oestrogen-induced growth of breast cancer cells
Background:
17β-Oestradiol (E2)-induced reactive oxygen species (ROS) have been implicated in regulating the growth of breast cancer cells. However, the underlying mechanism of this is not clear. Here we show how ROS through a novel redox signalling pathway involving nuclear respiratory factor-1 (NRF-1) and p27 contribute to E2-induced growth of MCF-7 breast cancer cells. Methods:
Chromatin immunoprecipitation, qPCR, mass spectrometry, redox western blot, colony formation, cell proliferation, ROS assay, and immunofluorescence microscopy were used to study the role of NRF-1. Results:
The major novel finding of this study is the demonstration of oxidative modification of phosphatases PTEN and CDC25A by E2-generated ROS along with the subsequent activation of AKT and ERK pathways that culminated in the activation of NRF-1 leading to the upregulation of cell cycle genes. 17β-Oestradiol-induced ROS by influencing nuclear proteins p27 and Jab1 also contributed to the growth of MCF-7 cells. Conclusions:
Taken together, our results present evidence in the support of E2-induced ROS-mediated AKT signalling leading to the activation of NRF-1-regulated cell cycle genes as well as the impairment of p27 activity, which is presumably necessary for the growth of MCF-7 cells. These observations are important because they provide a new paradigm by which oestrogen may contribute to the growth of breast cancer
A formalized general theory of syntax with bindings
We present the formalization of a theory of syntax with bindings that has been developed and refined over the last decade to support several large formalization efforts. Terms are defined for an arbitrary number of constructors of varying numbers of inputs, quotiented to alpha-equivalence and sorted according to a binding signature. The theory includes a rich collection of properties of the standard operators on terms, such as substitution and freshness. It also includes induction and recursion principles and support for semantic interpretation, all tailored for smooth interaction with the bindings and the standard operators
WAP four-disulfide core domain protein 2 gene(WFDC2) is a target of estrogen in ovarian cancer cells
BACKGROUND: WAP four-disulfide core domain protein 2 (WFDC2) shows a tumor-restricted upregulated pattern of expression in ovarian cancer. METHODS: We investigated the role of estradiol (E2) on cell growth in estrogen-sensitive or estrogen-insensitive ovarian cancer cell lines. Real-time (RT)-PCR and western blotting were used to examine the expression of WFDC2 at RNA and protein levels. Growth traits of cells transfected with WFDC2-shRNA or blank control were assessed using MMT arrays. Cell apoptosis was analyzed using annexin V-FITC/PI and flow cytometry. Estrogen receptor expression was evaluated using RT-PCR and flow cytometry. Apoptosis-related proteins induced by E2 directly and indirectly were determined using an antibody array comparing cells transfected with WFDC2- shRNA or a blank control. RESULTS: High-dose (625 ng/ml) E2 increased the expression of WFDC2 in HO8910 cells at both the mRNA and protein levels. However, E2 had no effect on WFDC2 expression in estrogen-insensitive SKOV3 cells. Of interest, knockdown of WFDC2 enabled a considerable estrogen response in SKOV3 cells in terms of proliferation, similar to estrogen-responsive HO8910 cells. This transformation of SKOV3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor beta (ERß) and an effect on cell apoptosis under E2 treatment by regulating genes related to cell proliferation and apoptosis. CONCLUSIONS: We postulate that increased WFDC2 expression plays an important role in altering the estrogen pathway in ovarian cancer, and the identification of WFDC2 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13048-015-0210-y) contains supplementary material, which is available to authorized users
Hypoxia-inducible Factor-1 Activation in Nonhypoxic Conditions: The Essential Role of Mitochondrial-derived Reactive Oxygen Species
Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Here we report that the generation of mitochondrial reactive oxygen species are essential for regulating HIF-1 in normal oxygen conditions in the vasculature
Polyphenols Sensitization Potentiates Susceptibility of MCF-7 and MDA MB-231 Cells to Centchroman
Polyphenols as “sensitizers” together with cytotoxic drugs as “inducers” cooperate to trigger apoptosis in various cancer cells. Hence, their combination having similar mode of mechanism may be a novel approach to enhance the efficacy of inducers. Additionally, this will also enable to achieve the physiological concentrations facilitating significant increase in the activity at concentrations which the compound can individually provide. Here we propose that polyphenols (Resveratrol (RES) and Curcumin (CUR)) pre-treatment may sensitize MCF-7/MDA MB-231 (Human Breast Cancer Cells, HBCCs) to Centchroman (CC, antineoplastic agent). 6 h pre-treated cells with 10 µM RES/CUR and 100 µM RES/30 µM CUR doses, followed by 10 µM CC for 18 h were investigated for Ser-167 ER-phosphorylation, cell cycle arrest, redox homeostasis, stress activated protein kinase (SAPKs: JNK and p38 MAPK) pathways and downstream apoptosis effectors. Low dose RES/CUR enhances the CC action through ROS mediated JNK/p38 as well as mitochondrial pathway in MCF-7 cells. However, RES/CUR sensitization enhanced apoptosis in p53 mutant MDA MB-231 cells without/with involvement of ROS mediated JNK/p38 adjunct to Caspase-9. Contrarily, through high dose sensitization in CC treated cells, the parameters remained unaltered as in polyphenols alone. We conclude that differential sensitization of HBCCs with low dose polyphenol augments apoptotic efficacy of CC. This may offer a novel approach to achieve enhanced action of CC with concomitant reduction of side effects enabling improved management of hormone-dependent breast cancer
Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation
Background: Estrogen receptors alpha (ERa) and beta (ERb) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERb being able to modulate the effects of ERa on gene transcription and cell proliferation. ERb is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERb in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology.
Results: Expression of full-length ERb in hormone-responsive, ERa-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERb and 6024 ERa binding sites in estrogen-stimulated cells, comprising sites occupied by either ERb, ERa or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERb+ vs ERb- cells, 424 showed one or more ERb site within 10 kb. These putative primary ERb target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERb binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions.
Conclusions: Results indicate that the vast majority of the genomic targets of ERb can bind also ERa, suggesting that the overall action of ERb on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell
Bindings as bounded natural functors
We present a general framework for specifying and reasoning about syntax with bindings. Abstract binder types are modeled using a universe of functors on sets, subject to a number of operations that can be used to construct complex binding patterns and binding-aware datatypes, including non-well-founded and infinitely branching types, in a modular fashion. Despite not committing to any syntactic format, the framework is “concrete” enough to provide definitions of the fundamental operators on terms (free variables, alpha-equivalence, and capture-avoiding substitution) and reasoning and definition principles. This work is compatible with classical higher-order logic and has been formalized in the proof assistant Isabelle/HOL
- …