The Importance of Learning History and Philosophy of Computing

Computers have invaded our offices, our homes, cars and coffee-pots; they have become ubiquitous. However, the advance of computing technologies is associated with an increasing lack of “visibility” of the underlying software and hardware technologies. While we use and accept the computer, we neither know its history nor functionality. In this paper, we argue that this is not a healthy situation. Also, recruitment onto UK Computing degree courses is steadily falling; these courses are appearing less attractive to school-leavers. This may be associated with the increasing ubiquity. In this paper we reflect on an MSc. module of instruction, Concepts and Philosophy of Computing, and a BSc. module Computer Games Development developed at the University of Worcester which address these issues. We propose that the elements of these modules form a necessary part of the education of all citizens, and we suggest how this may be realized. We also suggest how to re-enthuse our youth about computing as a discipline and halt the drop in recruitment.

Concise Encyclopaedia of Philosophy of Language, ed. P.V. Lamarque, Pergamon 1997, ISBN: 978-0080429915 and, Readings in the Philosophy of Language, ed. P. Ludlow, The MIT Press, 1997, ISBN: 978-0262621144 [Book review]

Abstract not available

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.

Philosophy of Computer Science and its Effect on Education: Towards the Construction of an Interdisciplinary Group

This article presents an interdisciplinary experience that brings together two areas of computer science; didactics and philosophy. As such, the article introduces a relatively unexplored area of research, not only in Uruguay but in the whole Latin American region. The reflection on the ontological status of computer science, its epistemic and educational problems, as well as their relationship with technology, allows us to elaborate a critical analysis of the discipline and a social perception of it as a basic science.

'Yes, the century is an ashen sun': poem and subject in the philosophy of Alain Badiou

This thesis examines the relation between philosophy, the poem and the subject in the mature philosophy of Alain Badiou. It investigates Badiou’s decisive contribution to these questions primarily by means of comparison, especially to Martin Heidegger, Philippe Lacoue-Labarthe and Theodor Adorno, as well as by analysing Badiou’s readings of poems and prose by Paul Celan and Samuel Beckett respectively as sites of potential dialogue with his immediate predecessors. The thesis stresses the importance of French philosophy’s German heritage, emphasising not only Badiou’s radical departure from Heidegger and his legacy, but also the former’s wholesale rejection of philosophies that would, in the wake of twentieth-century violence and beyond, proclaim their own end or completion. The thesis argues Badiou’s innovative readings of Celan and Beckett to be crucial to understanding this endeavour: for Badiou, both writers use the poem to affirm novel conceptions of subjectivity capable of transcending the historical conditions of their presentation. The title quotation from Badiou’s The Century, ‘Yes, the century is an ashen sun’, anticipates both the affirmative nature of these subjective figures, and their presience, beyond the bounds of a twentieth-century ‘ashen sun’ pervaded by melancholy, for the ‘new suns’ of the twenty-first. The thesis is in four chapters. The first chapter unfolds the central concepts of Badiou’s departure from Heidegger using Paul Celan’s poems to focus the enquiry. It is guided by two of Badiou’s most condensed declarations about the poem, that, firstly, ‘the modern poem harbours a central silence’, and secondly, that ‘Celan completes Heidegger’. The second chapter exposes the political implications of Heidegger’s writings on Friedrich Hölderlin and the role of the subject therein, offering at its close some thoughts about what Badiou calls, following Philippe Lacoue-Labarthe, the poem’s ‘becoming-prose’. It concludes by drawing the poem and politics into relation by way of the philosophical category of the subject. The third chapter reads Badiou’s concept of ‘anabasis’ against Heidegger’s ‘homecoming’ in order to think the possibility of a collective political subject’s formation in the wake of Auschwitz. The final chapter examines the imbrication of the Two of love and the ‘latent poem’ in Badiou’s reading of Samuel Beckett’s late prose, contrasting this ‘affirmative’ reading of Beckett to Theodor Adorno’s earlier emphases on negation. Following its investigations of subjectivity, poem and prose throughout, the thesis concludes by returning to the title quotation in order to unfold the particular relations between subject, affirmation and negation Badiou’s philosophy enacts, and to offer further routes forward for research regarding Badiou’s philosophy and aesthetic figuration.

An ethical philosophy of life presented in its main outlines,

Autobiographical introduction.--Philosophical theory.--Applications: the three shadows, sickness, sorrow and sin, and the right to life, property and reputation.--Applications: the ethics of the family, the state, the international relations, etc.

Comparison of the modes of action of Apremilast and Roflumilast

The phosphodiesterase 4 (PDE4) family are cAMP specific phosphodiesterases that play an important role in the inflammatory response and is the major PDE type found in inflammatory cells. A significant number of PDE4 specific inhibitors have been developed and are currently being investigated for use as therapeutic agents. Apremilast, a small molecule inhibitor of PDE 4 is in development for chronic inflammatory disorders and has shown promise for the treatment of psoriasis, psoriatic arthritis as well as other inflammatory diseases. It has been found to be safe and well tolerated in humans and in March 2014 it was approved by the US food and drug administration for the treatment of adult patients with active psoriatic arthritis. The only other PDE4 inhibitor on the market is Roflumilast and it is used for treatment of respiratory disease. Roflumilast is approved in the EU for the treatment of COPD and was recently approved in the US for treatment to reduce the risk of COPD exacerbations. Roflumilast is also a selective PDE4 inhibitor, administered as an oral tablet once daily, and is thought to act by increasing cAMP within lung cells. As both (Apremilast and Roflumilast) compounds selectively inhibit PDE4 but are targeted at different diseases, there is a need for a clear understanding of their mechanism of action (MOA). Differences and similarity of MOA should be defined for the purposes of labelling, for communication to the scientific community, physicians, and patients, and for an extension of utility to other diseases and therapeutic areas. In order to obtain a complete comparative picture of the MOA of both inhibitors, additional molecular and cellular biology studies are required to more fully elucidate the signalling mediators downstream of PDE4 inhibition which result in alterations in pro- and anti-inflammatory gene expression. My studies were conducted to directly compare Apremilast with Roflumilast, in order to substantiate the differences observed in the molecular and cellular effects of these compounds, and to search for other possible differentiating effects. Therefore the main aim of this thesis was to utilise cutting-edge biochemical techniques to discover whether Apremilast and Roflumilast work with different modes of action. In the first part of my thesis I used novel genetically encoded FRET based cAMP sensors targeted to different intracellular compartments, in order to monitor cAMP levels within specific microdomains of cells as a consequence of challenge with Apremilast and Roflumilast, which revealed that Apremilast and Roflumilast do regulate different pools of cAMP in cells. In the second part of my thesis I focussed on assessing whether Apremilast and Roflumilast cause differential effects on the PKA phosphorylation state of proteins in cells. I used various biochemical techniques (Western blotting, Substrate kinase arrays and Reverse Phase Protein array and found that Apremilast and Roflumilast do lead to differential PKA substrate phosphorylation. For example I found that Apremilast increases the phosphorylation of Ribosomal Protein S6 at Ser240/244 and Fyn Y530 in the S6 Ribosomal pathway of Rheumatoid Arthritis Synovial fibroblast and HEK293 cells, whereas Roflumilast does not. This data suggests that Apremilast has distinct biological effects from that of Roflumilast and could represent a new therapeutic role for Apremilast in other diseases. In the final part of my thesis, Phage display technology was employed in order to identify any novel binding motifs that associate with PDE4 and to identify sequences that were differentially regulated by the inhibitors in an attempt to find binding motifs that may exist in previously characterised signalling proteins. Petide array technology was then used to confirm binding of specific peptide sequences or motifs. Results showed that Apremilast and Roflumilast can either enhance or decrease the binding of PDE4A4 to specific peptide sequences or motifs that are found in a variety of proteins in the human proteome, most interestingly Ubiquitin-related proteins. The data from this chapter is preliminary but may be used in the discovery of novel binding partners for PDE4 or to provide a new role for PDE inhibition in disease. Therefore the work in this thesis provides a unique snapshot of the complexity of the cAMP signalling system and is the first to directly compare action of the two approved PDE4 inhibitors in a detailed way.

Investigating the mode of action of AN5568, a novel therapeutic against African trypanosomiasis

No abstract available.

The military in the Chamber of Deputies 1851-1870 – corporative lines of action in defense of the army

Based on our reading of the minutes of the parliamentary sessions, we shall attempt in this study to analyze the performance of army officers in the Chamber of Deputies, which, from 1851 to 1870, represented one of the most important settings for the military’s participation in politics

Biosynthesis and mode of action of ribosomally synthesized and post-translationally modified antimicrobial peptides

One of the greatest sources of biologically active compounds is natural products. Often these compounds serve as platforms for the design and development of novel drugs and therapeutics. The overwhelming amount of genomic information acquired in recent years has revealed that ribosomally synthesized and post-translationally modified natural products are much more widespread than originally anticipated. Identified in nearly all forms of life, these natural products display incredible structural diversity and possess a wide range of biological functions that include antimicrobial, antiviral, anti-inflammatory, antitumor, and antiallodynic activities. The unique pathways taken to biosynthesize these compounds offer exciting opportunities for the bioengineering of these complex molecules. The studies described herein focus on both the mode of action and biosynthesis of antimicrobial peptides. In Chapter 2, it is demonstrated that haloduracin, a recently discovered two-peptide lantibiotic, possesses nanomolar antimicrobial activity against a panel of bacteria strains. The potency of haloduracin rivals that of nisin, an economically and therapeutically relevant lantibiotic, which can be attributed to a similar dual mode of action. Moreover, it was demonstrated that this lantibiotic of alkaliphile origin has better stability at physiological pH than nisin. The molecular target of haloduracin was identified as the cell wall peptidoglycan precursor lipid II. Through the in vitro biosynthesis of haloduracin, several analogues of Halα were prepared and evaluated for their ability to inhibit peptidoglycan biosynthesis as well as bacterial cell growth. In an effort to overcome the limitations of in vitro biosynthesis strategies, a novel strategy was developed resulting in a constitutively active lantibiotic synthetase enzyme. This methodology, described in Chapter 3, enabled the production of fully-modified lacticin 481 products with proteinogenic and non-proteinogenic amino acid substitutions. A number of lacticin 481 analogues were prepared and their antimicrobial activity and ability to bind lipid II was assessed. Moreover, site-directed mutagenesis of the constitutively active synthetase resulted in a kinase-like enzyme with the ability to phosphorylate a number of peptide substrates. The hunt for a lantibiotic synthetase enzyme responsible for installing the presumed dehydro amino acids and a thioether ring in the natural product sublancin, led to the identification and characterization of a unique post-translational modification. The studies described in Chapter 4, demonstrate that sublancin is not a lantibiotic, but rather an unusual S-linked glycopeptide. Its structure was revised based on extensive chemical, biochemical, and spectroscopic characterization. In addition to structural investigation, bioinformatic analysis of the sublancin gene cluster led to the identification of an S-glycosyltransferase predicted to be responsible for the post-translational modification of the sublancin precursor peptide. The unprecedented glycosyltransferase was reconstituted in vitro and demonstrated remarkable substrate promiscuity for both the NDP-sugar co-substrate as well as the precursor peptide itself. An in vitro method was developed for the production of sublancin and analogues which were subsequently evaluated in bioactivity assays. Finally, a number of putative biosynthetic gene clusters were identified that appear to harbor the necessary genes for production of an S-glycopeptide. An additional S-glycosyltransferase with more favorable intrinsic properties including better expression, stability, and solubility was reconstituted in vitro and demonstrated robust catalytic abilities.

Candidacidal potential of licorice phenolic extract: emphasis on its mode of action

Medicinal plants bave gained a special attention in the last years, due to its renowned health benefits, such as antimicrobial effects [I]. In fact, several natural matrices bave been increasingly studied, namely for its antifungal activity against opportunistic fungi [2,3]. Candida species, although commensa! microorganisms, have caused severe organic dysfunctions to the host, once current antifungal agents have lost their recognized efficiency [2]. So, numerous studies have been carried out focusing the mechanisms of acquired drug-resistance by Candida species [of an efficient multi-drug therapy (i.e. chemical drugs and also natural extracts combination), the discovery of the involved mechanisms of actions, morphological changes and related kinetic parameters are of major importance. Glycyrrhiza glabra L. (licorice) hydromethanolic extract have evidenced promissory candidacidal effects, and therefore, the involved mechanisms of action need to be clarified. Thus, in the present study these modes of action were assessed, by using flow cytometry.Overall, the licorice extract induced significant and irreversible primary damages on Candida cells, being membrane disruption and consequent unviability one of the main targets. In fact, after membrane destabilization, cells lost their proper homeostasis, their metabolic functions were blocked and, consequently cells lost functionality. The relevance and interest of the achieved results open new insights towards the upcorning use of the present phenolic matrix, being important to evaluate its in viva efficacy. Therefore, further studies are necessary to deepen knowledge on this field, aiming not only to establish therapeutic and prophylactic doses, but also to improve the clinical intervention in Candida infections.

Fish Reproduction Is Disrupted upon Lifelong Exposure to Environmental PAHs Fractions Revealing Different Modes of Action

Polycyclic aromatic hydrocarbons (PAHs) constitute a large family of organic pollutants emitted in the environment as complex mixtures, the compositions of which depend on origin. Among a wide range of physiological defects, PAHs are suspected to be involved in disruption of reproduction. In an aquatic environment, the trophic route is an important source of chronic exposure to PAHs. Here, we performed trophic exposure of zebrafish to three fractions of different origin, one pyrolytic and two petrogenic. Produced diets contained PAHs at environmental concentrations. Reproductive traits were analyzed at individual, tissue and molecular levels. Reproductive success and cumulative eggs number were disrupted after exposure to all three fractions, albeit to various extents depending on the fraction and concentrations. Histological analyses revealed ovary maturation defects after exposure to all three fractions as well as degeneration after exposure to a pyrolytic fraction. In testis, hypoplasia was observed after exposure to petrogenic fractions. Genes expression analysis in gonads has allowed us to establish common pathways such as endocrine disruption or differentiation/maturation defects. Taken altogether, these results indicate that PAHs can indeed disrupt fish reproduction and that different fractions trigger different pathways resulting in different effects.

What can the philosophy of science contribute to the ethics of science and technology?

Nascida para permitir que seus criadores possam atender suas próprias necessidades, a técnica científica sempre desempenhou papel significativo na civilização humana. Este é o contexto em que podemos vislumbrar o advento da tecnociência moderna, que tem contribuído significativamente para o incremento do controle humano sobre a natureza. Este estudo tem por objetivo analisar, sob o enfoque da bioética, reflexões sobre como a filosofia da ciência entende a neutralidade da ciência e sua convergência com a racionalidade epistêmica, bem como relacionar essas reflexões ao processo de tomada de decisões na administração da tecnociência. O estudo levantou dúvidas sobre a capacidade do conhecimento tecnocientífico para legitimar e justificar as decisões no âmbito dos sistemas de ciência e tecnologia nacionais, sinalizando assim a necessidade de promover ligação entre a auto-regulação tecnocientífico e hetero-regulação bioética. ______________________________________________________________________________ ABSTRACT