Refinement of higher-order logic programs

A refinement calculus provides a method for transforming specifications to executable code, maintaining the correctness of the code with respect to its specification. In this paper we extend the refinement calculus for logic programs to include higher-order programming capabilities in specifications and programs, such as procedures as terms and lambda abstraction. We use a higher-order type and term system to describe programs, and provide a semantics for the higher-order language and refinement. The calculus is illustrated by refinement examples

Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease

Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention

Lack of a-disintegrin-and-metalloproteinase ADAM10 leads to intracellular accumulation and loss of shedding of the cellular prion protein in vivo

<p>Abstract</p> <p>Background</p> <p>The cellular prion protein (PrP^C) fulfils several yet not completely understood physiological functions. Apart from these functions, it has the ability to misfold into a pathogenic scrapie form (PrP^Sc) leading to fatal transmissible spongiform encephalopathies. Proteolytic processing of PrP^Cgenerates N- and C-terminal fragments which play crucial roles both in the pathophysiology of prion diseases and in transducing physiological functions of PrP^C. A-disintegrin-and-metalloproteinase 10 (ADAM10) has been proposed by cell culture experiments to be responsible for both shedding of PrP^Cand its α-cleavage. Here, we analyzed the role of ADAM10 in the proteolytic processing of PrP^C<it>in vivo</it>.</p> <p>Results</p> <p>Using neuron-specific <it>Adam10 </it>knockout mice, we show that ADAM10 is the sheddase of PrP^Cand that its absence <it>in vivo </it>leads to increased amounts and accumulation of PrP^Cin the early secretory pathway by affecting its posttranslational processing. Elevated PrP^Clevels do not induce apoptotic signalling via p53. Furthermore, we show that ADAM10 is not responsible for the α-cleavage of PrP^C.</p> <p>Conclusion</p> <p>Our study elucidates the proteolytic processing of PrP^Cand proves a role of ADAM10 in shedding of PrP^C<it>in vivo</it>. We suggest that ADAM10 is a mediator of PrP^Chomeostasis at the plasma membrane and, thus, might be a regulator of the multiple functions discussed for PrP^C. Furthermore, identification of ADAM10 as the sheddase of PrP^Copens the avenue to devising novel approaches for therapeutic interventions against prion diseases.</p

Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

The multifunctional signaling protein p75 neurotrophin receptor (p75NTR) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75NTR is required for p75NTR-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75NTR or treatment of animals bearing p75NTR-positive intracranial tumors with clinically applicable γ-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75NTR was observed in p75NTR-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75NTR as a therapeutic target, suggesting that γ-secretase inhibitors may have direct clinical application for the treatment of malignant glioma

Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity

BACKGROUND: Processing by gamma-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes. Because the list of gamma-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimer's disease therapeutic target, the mapping of gamma-secretase activity susceptible gene transcription is important for sharpening our view of specific affected genes, molecular functions and biological pathways. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes and molecular functions transcriptionally affected by gamma-secretase activity, the cellular transcriptomes of Chinese hamster ovary (CHO) cells with enhanced and inhibited gamma-secretase activity were analyzed and compared by cDNA microarray. The functional clustering by FatiGO of the 1,981 identified genes revealed over- and under-represented groups with multiple activities and functions. Single genes with the most pronounced transcriptional susceptibility to gamma-secretase activity were evaluated by real-time PCR. Among the 21 validated genes, the strikingly decreased transcription of PTPRG and AMN1 and increased transcription of UPP1 potentially support data on cell cycle disturbances relevant to cancer, stem cell and neurodegenerative diseases' research. The mapping of interactions of proteins encoded by the validated genes exclusively relied on evidence-based data and revealed broad effects on Wnt pathway members, including WNT3A and DVL3. Intriguingly, the transcription of TERA, a gene of unknown function, is affected by gamma-secretase activity and was significantly altered in the analyzed human Alzheimer's disease brain cortices. CONCLUSIONS/SIGNIFICANCE: Investigating the effects of gamma-secretase activity on gene transcription has revealed several affected clusters of molecular functions and, more specifically, 21 genes that hold significant potential for a better understanding of the biology of gamma-secretase and its roles in cancer and Alzheimer's disease pathology

Integrin affinity modulation and survival signalling.

Integrins are heterodimeric transmembrane proteins that provide a bi-directional link between the cell’s internal biological mechanisms and the extracellular environment. During inside-out signalling, intracellular messages converge on the integrin cytoplasmic domain to induce a conformational change. This is transmitted to the extracellular domain where it results in an alteration in affinity for integrin ligands such as fibronectin and laminin. In this way the cell has developed the ability to modulate the critical functions of adhesion and cell movement. In outside-in signalling, the integrin performs a more complex function than simple adhesion; upon binding to ligand, the integrin extracellular domain undergoes a conformational change which is transmitted to the cytoplasmic domain. This alters the integrin’s cytoplasmic domain affinity for intracellular signalling proteins and results in the activation of intracellular second messenger pathways. In this way, the extracellular milieu is able to influence intracellular signalling including those involved in apoptosis. This thesis demonstrates data which provide original insights into bi-directional integrin signalling: Inside-out signalling: Constitutively active Notch1 increases β3-integrin affinity and abrogates Hras-mediated integrin suppression without increasing expression of β3- integrin. Dominant-Negative Rras blocks Notch-mediated integrin activation and Notch1-mediated reversal of Hras and Raf-mediated integrin suppression and this is independent of erk phosphorylation. Notch1 induces Rras activation. Functional adhesion assays confirm that Notch1IC increases K562 adhesion in a β1-integrin dependent manner and this is abrogated by Dominant-Negative Rras. This data supports a mechanism in which Notch1 increases integrin affinity via activation of Rras. Outside-in signalling: Evidence is presented demonstrating that extracellular matrix proteins, laminin and fibronectin, activate β1-integrins to protect SCLC cells against the apoptotic effects of etoposide and ionizing radiation via PI3Kinase activation. This occurs in two ways: 1) PI3Kinase-dependent β1-integrin signalling resulting in phosphorylation of Bad and reduced caspase-9 cleavage and 2) a β1-integrinmediated over-riding of etoposide and radiotherapy-induced cell cycle S phase delay and G2/M arrest. β1-integrin-mediated outside-in survival signalling was investigated further in the in vivo setting; MatrigelTM, a basement membrane product rich in extracellular matrix proteins, promoted SCLC xenograft survival and growth in a β1-integrin and tyrosine kinase-dependent manner. This data provides novel insights into the critical functions that integrins play in adhesion and survival signalling

Maximising the information gained from an experimental analysis of code inspection and static analysis for concurrent Java components

The results of empirical studies are limited to particular contexts, difficult to generalise and the studies themselves are expensive to perform. Despite these problems, empirical studies in software engineering can be made effective and they are important to both researchers and practitioners. The key to their effectiveness lies in the maximisation of the information that can be gained by examining existing studies, conducting power analyses for an accurate minimum sample size and benefiting from previous studies through replication. This approach was applied in a controlled experiment examining the combination of automated static analysis tools and code inspection in the context of verification and validation (V&V) of concurrent Java components. The combination of these V&V technologies was shown to be cost-effective despite the size of the study, which thus contributes to research in V&V technology evaluation

Agent-based distributed software verification

Despite decades of research, the takeup of formal methods for developing provably correct software in industry remains slow. One reason for this is the high cost of proof construction, an activity that, due to the complexity of the required proofs, is typically carried out using interactive theorem provers. In this paper we propose an agent-oriented architecture for interactive theorem proving with the aim of reducing the user interactions (and thus the cost) of constructing software verification proofs. We describe a prototype implementation of our architecture and discuss its application to a small, but non-trivial case study

Calculating modules in contextual logic program refinement

The refinement calculus for logic programs is a framework for deriving logic programs from specifications. It is based on a wide-spectrum language that can express both specifications and code, and a refinement relation that models the notion of correct implementation. In this paper we extend and generalise earlier work on contextual refinement. Contextual refinement simplifies the refinement process by abstractly capturing the context of a subcomponent of a program, which typically includes information about the values of the free variables. This paper also extends and generalises module refinement. A module is a collection of procedures that operate on a common data type; module refinement between a specification module A and an implementation module C allows calls to the procedures of A to be systematically replaced with calls to the corresponding procedures of C. Based on the conditions for module refinement, we present a method for calculating an implementation module from a specification module. Both contextual and module refinement within the refinement calculus have been generalised from earlier work and the results are presented in a unified framework

A process framework for characterising security properties of component-based software systems

This paper presents a security characterisation process framework for software components and their compositions in order to address the issue of trust in component based software. The process is based on the idea of publishing trust related properties of software components in machine readable as well as understandable form at the component level and incorporating such properties with runtime composition of the application system. We explore the actual process involved in specifying publishable security properties of atomic components, component certification, reasoning about compositional security contracts, and characterising ultimate systems-level security properties to inspire trust in software components