FRAMEWORK SYNTHESIS FOR SYMBOLIC EXECUTION OF EVENT-DRIVEN FRAMEWORKS

Symbolic execution is a powerful program analysis technique, but it is very challenging to apply to programs built using event-driven frameworks, such as Android. The main reason is that the framework code itself is too complex to symbolically execute. The standard solution is to manually create a framework model that is simpler and more amenable to symbolic execution. However, developing and maintaining such a model by hand is difficult and error-prone. We claim that we can leverage program synthesis to introduce a high-degree of automation to the process of framework modeling. To support this thesis, we present three pieces of work. First, we introduced SymDroid, a symbolic executor for Android. While Android apps are written in Java, they are compiled to Dalvik bytecode format. Instead of analyzing an app’s Java source, which may not be available, or decompiling from Dalvik back to Java, which requires significant engineering effort and introduces yet another source of potential bugs in an analysis, SymDroid works directly on Dalvik bytecode. Second, we introduced Pasket, a new system that takes a first step toward automatically generating Java framework models to support symbolic execution. Pasket takes as input the framework API and tutorial programs that exercise the framework. From these artifacts and Pasket's internal knowledge of design patterns, Pasket synthesizes an executable framework model by instantiating design patterns, such that the behavior of a synthesized model on the tutorial programs matches that of the original framework. Lastly, in order to scale program synthesis to framework models, we devised adaptive concretization, a novel program synthesis algorithm that combines the best of the two major synthesis strategies: symbolic search, i.e., using SAT or SMT solvers, and explicit search, e.g., stochastic enumeration of possible solutions. Adaptive concretization parallelizes multiple sub-synthesis problems by partially concretizing highly influential unknowns in the original synthesis problem. Thanks to adaptive concretization, Pasket can generate a large-scale model, e.g., thousands lines of code. In addition, we have used an Android model synthesized by Pasket and found that the model is sufficient to allow SymDroid to execute a range of apps.

Non-Symbolic Fragmentation

This paper reports on the use of non-symbolic fragmentation of data for securing communications. Non-symbolic fragmentation, or NSF, relies on breaking up data into non-symbolic fragments, which are (usually irregularly-sized) chunks whose boundaries do not necessarily coincide with the boundaries of the symbols making up the data. For example, ASCII data is broken up into fragments which may include 8-bit fragments but also include many other sized fragments. Fragments are then separated with a form of path diversity. The secrecy of the transmission relies on the secrecy of one or more of a number of things: the ordering of the fragments, the sizes of the fragments, and the use of path diversity. Once NSF is in place, it can help secure many forms of communication, and is useful for exchanging sensitive information, and for commercial transactions. A sample implementation is described with an evaluation of the technology.

Brooke-Spiegler Syndrome - an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation

BACKGROUND: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. MAIN OBSERVATIONS: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. CONCLUSIONS: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor".

The metabolic and epigenetic effects of the isocitrate dehydrogenase-1 mutation in glioma

Cancer cells have been noted to have an altered metabolic phenotype for over ninety years. In the presence of oxygen, differentiated cells predominately utilise the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to efficiently produce energy and the metabolites necessary for protein and lipid synthesis. However, in hypoxia, this process is altered and cells switch to a higher rate of glycolysis and lactate production to maintain their energy and metabolic needs. In cancer cells, glycolysis is maintained at a high rate, even in the presence of oxygen; a term described as “aerobic glycolysis”. Tumour cells are rapidly dividing and have a much greater need for anabolism compared to normal differentiated cells. Rapid glucose metabolism enables faster ATP production as well as a greater redistribution of carbons to nucleotide, protein, and fatty acid synthesis, thus maximising cell growth. Recently, other metabolic changes, driven by mutations in genes related to the TCA cycle, indicate an alternative role for metabolism in cancer, the “oncometabolite”. This is where a particular metabolite builds up within the cell and contributes to the tumorigenic process. One of these genes is isocitrate dehydrogenase (IDH) IDH is an enzyme that forms part of the tricarboxylic acid (TCA) cycle and converts isocitrate to α-ketoglutarate (α-KG). It exists in three isoforms; IDH1, IDH2 and IDH3 with the former present in the cytoplasm and the latter two in the mitochondria. Point mutations have been identified in the IDH1 and IDH2 genes in glioma which result in a gain of function by converting α-KG to 2-hydroxyglutarate (2HG), an oncometabolite. 2HG acts as a competitive inhibitor of the α-KG dependent dioxygenases, a superfamily of enzymes that are involved in numerous cellular processes such as DNA and histone demethylation. It was hypothesised that the IDH1 mutation would result in other metabolic changes in the cell other than 2HG production, and could potentially identify pathways which could be targeted for therapeutic treatment. In addition, 2HG can act as a potential competitive inhibitor of α-KG dependent dioxygenases, so it was hypothesised that there would be an effect on histone methylation. This may alter gene expression and provide a mechanism for tumourogenesis and potentially identify further therapeutic targets. Metabolic analysis of clinical tumour samples identified changes associated with the IDH1 mutation, which included a reduction in α-KG and an increase in GABA, in addition to the increase in 2HG. This was replicated in several cell models, where 13C labelled metabolomics was also used to identify a possible increase in metabolic flux from glutamate to GABA, as well as from α-KG to 2HG. This may provide a mechanism whereby the cell can bypass the IDH1 mutation as GABA can be metabolised to succinate in the mitochondria by GABA transaminase via the GABA shunt. JMJ histone demethylases are a subset of the α-KG dependent dioxygenases, and are involved in removing methyl groups from histone tails. Changes in histone methylation are associated with changes in gene expression depending on the site and extent of chemical modification. To identify whether the increase in 2HG and fall in α-KG was associated with inhibition of histone demethylases a histone methylation screen was used. The IDH1 mutation was associated with an increase in methylation of H3K4, which is associated with gene activation. ChiP and RNA sequencing identified an increase in H3K4me3 at the transcription start site of the GABRB3 subunit, resulting in an increase in gene expression. The GABRB3 subunit forms part of the GABA-A receptor, a chloride channel, which on activation can reduce cell proliferation. The IDH1 mutation was associated with an increase in GABA and GABRB3 subunit of the GABA-A receptor. This raises the possibility of GABA transaminase as a potential therapeutic target. Inhibition of this enzyme could reduce GABA metabolism, potentially reducing any beneficial effect of the GABA shunt in IDH1 mutant tumours, and increasing activation of the GABA-A receptor by increasing the concentration of GABA in the brain. This in turn may reduce cell proliferation, and could be achieved by using Vigabatrin, a GABA transaminase inhibitor licensed for use in epilepsy.

Original sin: divine and symbolic violence in the turn to the Apostle Paul

When we take a step back from the imposing figure of physical violence, it becomes possible to examine other structurally violent forces that constantly shape our cultural and political landscapes. One of the driving interests in the “turn to Paul” in recent continental philosophy stems from wrestling with questions about the real nature of contemporary violence. Paul is positioned as a thinker whose messianic experience began to cut through the violent masquerade of the existing order. The crucifixion and resurrection of the Messiah (a slave and a God co-existing in one body) exposed the empty grounding upon which power resided. The Christ-event signifies a moment of violent interruption in the existing order which Paul enjoins the Gentiles to participate in through a dedication of love for the neighbour. This divine violence aims to reveal and subvert the “powers,” epitomised in the Roman Empire, in order to fulfil the labour of the Messianic now-time which had arrived. The impetus behind this research comes from a typically enigmatic and provocative section of text by the Slovene philosopher, cultural critic, and Christian atheist Slavoj Žižek. He claims that 'the notion of love should be given here all its Paulinian weight: the domain of pure violence… is the domain of love' (2008a, 173). In this move he links Paul’s idea of love to that of Walter Benjamin’s divine violence; the sublime and the cataclysmic come together in this seemingly perverse notion. At stake here is the way in which uncovering violent forces in the “zero-level” of our narrative worldviews aids the diagnosis of contemporary political and ethical issues. It is not enough to imagine Paul’s encounter with the Christ-event as non-violent. This Jewish apocalyptic movement was engaged in a violent struggle within an existing order that God’s wrath will soon dismantle. Paul’s weak violence, inspired by his fidelity to the Christ-event, places all responsibility over creation in the role of the individual within the collective body. The centre piece of this re-imagined construction of the Pauline narrative comes in Romans 13: the violent dedication to love understood in the radical nature of the now-time. 3 This research examines the role that narratives play in the creation and diagnosis of these violent forces. In order to construct a new genealogy of violence in Christianity it is crucial to understand the role of the slave of Christ (the revolutionary messianic subject). This turn in the Symbolic is examined through creating a literary structure in which we can approach a radical Nietzschean shift in Pauline thought. The claim here, a claim which is also central to Paul’s letters, is that when the symbolic violence which manipulates our worldviews is undone by a divine violence, if even for a moment, new possibilities are created in the opening for a transvaluation of values. Through this we uncover the nature of original sin: the consequences of the interconnected reality of our actions. The role of literature is vital in the construction of this narrative; starting with Cormac McCarthy’s No Country for Old Men, and continuing through works such as Melville’s Bartleby the Scrivener, this thesis draws upon the power of literature in the shaping of our narrative worlds. Typical of the continental philosophy at the heart of this work, a diverse range of illustrations and inspirations from fiction is pulled into its narrative to reflect the symbolic universe that this work was forged through. What this work attempts to do is give this theory a greater grounding in Paul’s letters by demonstrating this radical kenotic power at the heart of the Christ-event. Romans 13 reveals, in a way that has not yet been picked up by Critchley, Žižek, and others, that Paul opposed the biopolitical power of the Roman Empire through the weak violence of love that is the labour of the slaves of Christ on the “now-time” that had arrived.

Colour differentiation of high-lycopene tomato fruit through the addition of the colourless-epidermis (y) mutation

High-lycopene tomatoes (Solanum lycopersicum) are characterised by an intense red flesh-colour, due to an elevated concentration of the carotenoid, lycopene. However, this characteristic is only visible once fruit are cut open, making it impossible to differentiate intact high-lycopene fruit from standard tomato fruit, a clear market disadvantage. The reason that fruit colour of both high-lycopene and standard fruit looks almost identical from the outside is because tomato fruit normally contain the yellow flavonoid 'naringenin chalcone' in a thin layer of epidermal cells. It is this combination of naringenin chalcone and the underlying lycopene in the flesh that gives tomatoes their characteristic orange-red colour. By incorporation of the recessive colourless epidermis mutant allele 'y' (which prevents naringenin chalcone accumulation) into high-lycopene fruit, we have been able to create high-lycopene tomatoes (hp1.ogc.y) exhibiting a deep-pink colour visible from the outside. Hue angle of the skin of the high-lycopene 'y' mutant and a regular highlycopene tomato (hp1.ogc.Y) was 30 and 38°, respectively, while flesh values were similar at 31 and 32°, respectively. Removal of naringenin chalcone from the epidermis appeared to improve the visibility of underlying lycopene, such that fruit outer colour became a subsequent indicator of underlying flesh colour. The removal of epidermal pigmentation means that high-lycopene fruit can now be differentiated from standard tomato fruit in the market place without the need to cut fruit open.

Targeting the serrated pathway of colorectal cancer with mutation in BRAF

A recently acknowledged morphological pathway to colorectal cancer originates from precursor polyps with a serrated appearance due to branching and folding of the colon epithelium. This serrated origin accounts for up to 30% of all colorectal tumors but these are heterogeneous regarding molecular characteristics and patient outcome. Here we review the current knowledge about the classification of this tumor subtype and its association with five key features: mutation status of the BRAF or KRAS genes, the CpG island methylation phenotype, microsatellite instability, immune cell infiltration, and overexpression of GTPase RAC1b. Subsequently, available therapeutic approaches for targeting these molecular characteristics are presented and critically discussed.

A Novel Noonan Syndrome RAF1 Mutation: Lethal Course in a Preterm Infant

Noonan syndrome is a relatively common and heterogeneous genetic disorder, associated with congenital heart defect in about 50% of the cases. If the defect is not severe, life expectancy is normal. We report a case of Noonan syndrome in a preterm infant with hypertrophic cardiomyopathy and lethal outcome associated to acute respiratory distress syndrome caused by Adenovirus pneumonia. A novel mutation in the RAF1 gene was identified: c.782C>G (p.Pro261Arg) in heterozygosity, not described previously in the literature. Consequently, the common clinical course in this mutation and its respective contribution to the early fatal outcome is unknown. No conclusion can be established regarding genotype/phenotype correlation.

Homozygosity for the E526V Mutation in Fibrinogen A Alpha-Chain Amyloidosis: The First Report

Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated by Clostridium difficile colitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis.

The symbolic, socio-economic and exchange value of Imperial German and National Socialist medals and badges, 1701 to the present

This thesis examines the manufacture, use, exchange (including gift exchange), collecting and commodification of German medals and badges from the early 18th century until the present-day, with particular attention being given to the symbols that were deployed by the National Socialist German Workers’ Party (NSDAP) between 1919 and 1945. It does so by focusing in particular on the construction of value through insignia, and how such badges and their symbolic and monetary value changed over time. In order to achieve this, the thesis adopts a chronological structure, which encompasses the creation of Prussia in 1701, the Napoleonic wars and the increased democratisation of military awards such as the Iron Cross during the Great War. The collapse of the Kaiserreich in 1918 was the major factor that led to the creation of the NSDAP under the eventual strangle-hold of Hitler, a fundamentally racist and anti-Semitic movement that continued the German tradition of awarding and wearing badges. The traditional symbols of Imperial Germany, such as the eagle, were then infused with the swastika, an emblem that was meant to signify anti-Semitism, thus creating a hybrid identity. This combination was then replicated en-masse, and eventually eclipsed all the symbols that had possessed symbolic significance in Germany’s past. After Hitler was appointed Chancellor in 1933, millions of medals and badges were produced in an effort to create a racially based “People’s Community”, but the steel and iron that were required for munitions eventually led to substitute materials being utilised and developed in order to manufacture millions of politically oriented badges. The Second World War unleashed Nazi terror across Europe, and the conscripts and volunteers who took part in this fight for living-space were rewarded with medals that were modelled on those that had been instituted during Imperial times. The colonial conquest and occupation of the East by the Wehrmacht, the Order Police and the Waffen-SS surpassed the brutality of former wars that finally culminated in the Holocaust, and some of these horrific crimes and the perpetrators of them were perversely rewarded with medals and badges. Despite Nazism being thoroughly discredited, many of the Allied soldiers who occupied Germany took part in the age-old practice of obtaining trophies of war, which reconfigured the meaning of Nazi badges as souvenirs, and began the process of their increased commodification on an emerging secondary collectors’ market. In order to analyse the dynamics of this market, a “basket” of badges is examined that enables a discussion of the role that aesthetics, scarcity and authenticity have in determining the price of the artefacts. In summary, this thesis demonstrates how the symbolic, socio-economic and exchange value of German military and political medals and badges has changed substantially over time, provides a stimulus for scholars to conduct research in this under-developed area, and encourages collectors to investigate the artefacts that they collect in a more historically contextualised manner.

Towards a Bourdieusian analysis of the disabled body and practice: embodying negative symbolic capitals and the uneasy experience of hysteresis

Within the last few years, disabled people have become the target of government austerity measures through drastic cuts to welfare justified through the portrayal of benefit claimants as inactive, problem citizens who are wilfully unemployed. For all that is wrong with these cuts, they are one of many aspects of exclusion that disabled people face. Attitudes towards disability are deteriorating (Scope, 2011) and disabled people are devalued and negatively positioned in a myriad of ways, meaning that an understanding of the perceptions and positioning of disability and the power of disabling practices is critical. This thesis will examine how Bourdieu’s theoretical repertoire may be applied to the area of Disability Studies in order to discern how society produces oppressive and exclusionary systems of classification which structures the social position and perceptions of disability. The composite nature of disability and multiple forms of exclusion and inequality associated with it benefits from a multipronged approach which acknowledges personal, embodied and psychological aspects of disability alongside socio-political and cultural conceptualisations. Bourdieu’s approach is one in which the micro and macro aspects of social life are brought together through their meso interplay and provides a thorough analysis of the many aspects of disability.

A novel mutation in the TMC1 gene causes non-syndromic hearing loss in a Moroccan family

International audience

Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability

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A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability

International audience