Papillomavirus E5: the smallest oncoprotein with many functions

Papillomaviruses (PVs) are established agents of human and animal cancers. They infect cutaneous and mucous epithelia. High Risk (HR) Human PVs (HPVs) are consistently associated with cancer of the uterine cervix, but are also involved in the etiopathogenesis of other cancer types. The early oncoproteins of PVs: E5, E6 and E7 are known to contribute to tumour progression. While the oncogenic activities of E6 and E7 are well characterised, the role of E5 is still rather nebulous. The widespread causal association of PVs with cancer makes their study worthwhile not only in humans but also in animal model systems. The Bovine PV (BPV) system has been the most useful animal model in understanding the oncogenic potential of PVs due to the pivotal role of its E5 oncoprotein in cell transformation. This review will highlight the differences between HPV-16 E5 (16E5) and E5 from other PVs, primarily from BPV. It will discuss the targeting of E5 as a possible therapeutic agent

Formalising Confluence in PVS

Confluence is a critical property of computational systems which is related with determinism and non ambiguity and thus with other relevant computational attributes of functional specifications and rewriting system as termination and completion. Several criteria have been explored that guarantee confluence and their formalisations provide further interesting information. This work discusses topics and presents personal positions and views related with the formalisation of confluence properties in the Prototype Verification System PVS developed at our research group.Comment: In Proceedings DCM 2015, arXiv:1603.0053

The persistent vegetative state: legal and ethical issues

Recent advances in technology and medical expertise have enabled doctors to prolong the lives of many severely injured patients who only a few years ago would have died from their injuries. The prolongation of life by such measures has raised many legal, ethical and social issues. When in 1992 the House of Lords determined in Airdale NHS Trust V Bland that life-supporting measures, including artificial nutrition and hydration (ANH) might lawfully be withdrawn from Anthony Bland, a patient in a persistent vegetative state (PVS), attention was focused on these issues particularly as they apply to the patient in PVS. Since the PVS patient is neither competent to refuse treatment, nor is he dying or suffering, the reasons normally advanced for withdrawing life-supporting measures do not apply. In Bland, their Lordships relied on the best interests test laid down in Re F (mental patient: sterilisation) [1989] 2 All ER 545, and, with the exception of Lord Mustill, on the Bolam test (Bolam v Friern Barnet Hospital Management Committee) [1957] 1 WLR 582. This thesis examines the decision mBland and addresses some of the issues raised. The appropriateness of the best interests test as applied to the patient in PVS is explored and compared with the approach of substituted judgement employed in some other common law jurisdictions. The relevance of the Bolam test to decisions regarding the withdrawal of life-supporting measures is considered. The legal requirements for the withdrawal of ANH are discussed, together with the ethical debate and the moral dilemmas posed by its withdrawal. Finally, the question as to whether the decision in Bland is good law is addressed, and it will be argued that whilst it may be morally acceptable to withdraw ANH from some patients, as regards a patient in PVS, the moral imperative is that we should not

Lyophilisation of influenza, rabies and Marburg lentiviral pseudotype viruses for the development and distribution of a neutralisation-assay based diagnostic kit

Pseudotype viruses (PVs) are chimeric, replication-deficient virions that mimic wild-type virus entry mechanisms and can be safely employed in neutralisation assays, bypassing the need for high biosafety requirements and performing comparably to established serological assays. However, PV supernatant necessitates -80°C long-term storage and cold-chain maintenance during transport, which limits the scope of dissemination and application throughout resource-limited laboratories. We therefore investigated the effects of lyophilisation on influenza, rabies and Marburg PV stability, with a view to developing a pseudotype virus neutralisation assay (PVNA) based kit suitable for affordable global distribution. Infectivity of each PV was calculated after lyophilisation and immediate reconstitution, as well as subsequent to incubation of freeze-dried pellets at varying temperatures, humidities and timepoints. Integrity of glycoprotein structure following treatment was also assessed by employing lyophilised PVs in downstream PVNAs. In the presence of 0.5M sucrose-PBS cryoprotectant, each freeze-dried pseudotype was stably stored for 4 weeks at up to 37°C and could be neutralised to the same potency as unlyophilised PVs when employed in PVNAs. These results confirm the viability of a freeze-dried PVNA-based kit, which could significantly facilitate low-cost serology for a wide portfolio of emerging infectious viruses

Principal component analysis of atrial fibrillation: Inclusion of posterior ECG leads does not improve correlation with left atrial activity

Background Lead V? is routinely analysed due to its large amplitude AF waveform. V? correlates strongly with right atrial activity but only moderately with left atrial activity. Posterior lead V? correlates strongest with left atrial activity. Aims (1) To establish whether surface dominant AF frequency (DAF) calculated using principal component analysis (PCA) of a modified 12-lead ECG (including posterior leads) has a stronger correlation with left atrial activity compared to the standard ECG. (2) To assess the contribution of individual ECG leads to the AF principal component in both ECG configurations. Methods Patients were assigned to modified or standard ECG groups. In the modified ECG, posterior leads V? and V? replaced V? and V?. AF waveform was extracted from one-minute surface ECG recordings using PCA. Surface DAF was correlated with intracardiac DAF from the high right atrium (HRA), coronary sinus (CS) and pulmonary veins (PVs). Results 96 patients were studied. Surface DAF from the modified ECG did not have a stronger correlation with left atrial activity compared to the standard ECG. Both ECG configurations correlated strongly with HRA, CS and right PVs but only moderately with left PVs. V? contributed most to the AF principal component in both ECG configurations

On the definition of a moist-air potential vorticity

A new potential vorticity is derived by using a specific entropy formulation expressed in terms of a moist-air entropy potential temperature. The new formulation is compared with Ertel's version and with others based on virtual and equivalent potential temperatures. The new potential vorticity is subject to conservative properties ensured by the Second Law applied to the moist-air material derivatives. It is shown that the upper tropospheric and stratospheric (dry) structures are nearly the same as those obtained with Ertel's component. Moreover, new structures are observed in the low troposphere, with negative values associated with moist frontal regions. The negative values are observed in the frontal regions where slantwise convection instabilities may take place, but they are smaller than those observed with the equivalent potential vorticity. The main purpose of the article is to diagnose the behaviour of the new potential vorticity from numerical output generated by the ARPEGE NWP model, with the help of isobaric charts and vertical cross-sections. Two inversion methods are suggested. The first method could be based on the invertibility principle verified by the virtual potential vorticity, with a possibility to control and modify separately potential vorticity components in the (dry) upper and (moist) lower atmospheric levels. The other method may consist of an inversion process directly applied to the new moist-air entropy potential vorticity, because the negative values and the solenoidal term are smaller than those observed with equivalent potential vorticity, as shown by numerical evaluations.Comment: Submitted to the Q. J. R. Meteorol. Soc. in August 2012. Accepted in April 2013. Early view on the QJRMS site http://onlinelibrary.wiley.com/doi/10.1002/qj.2182/abstract. 24 pages, 10 color figures. V2: add the arXiv links of Marquet (2011), Geleyn and Marquet (2012) and Marquet and Geleyn (2013

A library of Taylor models for PVS automatic proof checker

We present in this paper a library to compute with Taylor models, a technique extending interval arithmetic to reduce decorrelation and to solve differential equations. Numerical software usually produces only numerical results. Our library can be used to produce both results and proofs. As seen during the development of Fermat's last theorem reported by Aczel 1996, providing a proof is not sufficient. Our library provides a proof that has been thoroughly scrutinized by a trustworthy and tireless assistant. PVS is an automatic proof assistant that has been fairly developed and used and that has no internal connection with interval arithmetic or Taylor models. We built our library so that PVS validates each result as it is produced. As producing and validating a proof, is and will certainly remain a bigger task than just producing a numerical result our library will never be a replacement to imperative implementations of Taylor models such as Cosy Infinity. Our library should mainly be used to validate small to medium size results that are involved in safety or life critical applications

Metamodel-based model conformance and multiview consistency checking

Model-driven development, using languages such as UML and BON, often makes use of multiple diagrams (e.g., class and sequence diagrams) when modeling systems. These diagrams, presenting different views of a system of interest, may be inconsistent. A metamodel provides a unifying framework in which to ensure and check consistency, while at the same time providing the means to distinguish between valid and invalid models, that is, conformance. Two formal specifications of the metamodel for an object-oriented modeling language are presented, and it is shown how to use these specifications for model conformance and multiview consistency checking. Comparisons are made in terms of completeness and the level of automation each provide for checking multiview consistency and model conformance. The lessons learned from applying formal techniques to the problems of metamodeling, model conformance, and multiview consistency checking are summarized