Realism and political normativity

A prevailing understanding of realism, chiefly among its critics, casts realists as those who seek a ‘distinctively political normativity’, where this is interpreted as meaning nonmoral in kind. Moralists, on this account, are those who reject this and believe that political normativity remains moral. Critics have then focused much of their attention on demonstrating that the search for a nonmoral political normativity is doomed to fail which, if right, would then seem to fatally undermine the realist endeavour. This paper makes the case that casting the difference between realism and moralism in these terms is a mistake, one which overlooks the substantial body of realist work which is clear that it has no such aspirations to develop a nonmoral political normativity. The hope is that in drawing attention to this mistake a line can be drawn under these unhelpful debates, and we can move on to more fruitful constructive and critical discussions between realists and their critics

Ethics, morality and the case for realist political theory

A common trait of all realistic political theories is the rejection of a conception of political theory as applied moral philosophy and an attempt to preserve some form of distinctively political thinking. Yet the reasons for favouring such an account of political theory can vary, a point that has often been overlooked in recent discussions by realism’s friends and critics alike. While a picture of realism as first-and-foremost an attempt to develop a more practical political theory which does not reduce morality to politics is often cited, in this paper we present an alternative understanding in which the motivation to embrace realism is grounded in a set of critiques of or attitudes towards moral philosophy which then feed into a series of political positions. Political realism, on this account, is driven by a set of philosophical concerns about the nature of ethics and the place of ethical thinking in our lives. This impulse is precisely what motivated Bernard Williams and Raymond Geuss to their versions of distinctively realist political thought and is important to emphasise because it demonstrates that realism does not set politics against ethics (a misunderstanding typically endorsed by realism’s critics) but is rather an attempt to philosophise about politics without relying on understandings of morality which we have little reason to endorse

A static, transaction based design methodology for hard real-time systems

This thesis is concerned with the design and implementation stages of the development lifecycle of a class of systems known as hard real-time systems. Many of the existing methodologies are appropriate for meeting the functional requirements of this class of systems. However, it is proposed that these methodologies are not entirely appropriate for meeting the non-functional requirement of deadlines for work within these real-time systems. After discussing the concept of real-time systems and their characteristic requirements, this thesis proposes the use of a general transaction model of execution for the implementation of the system. Whereas traditional methodologies consider the system from the flow of data or control in the system, we consider the system from the viewpoint of the role of each shared data entity. A control dependency is implied between otherwise independent processes that make use of a shared data entity; our viewpoint is known as the data dependency viewpoint. This implied control dependency between independent processes, necessary to preserve the consistency of the entity in the face of concurrent access, is ignored during the design stages of other methodologies. In considering the role of each data entity, it is possible to generate other viewpoints, such as the dataflow through the processes, automatically. This however, is not considered in the work. This thesis describes a staged methodology for taking the requirements specification for a system and generating a design and implementation for that system. The methodology is intended to be more than a set of vague guidelines for implementation; a more rigid approach to the design and implementation stages is sought. The methodology begins by decomposing the system into more manageable units of processing. These units are known as tasks with a very low degree of coupling and high degree of cohesion. Following the system decomposition, the data dependency viewpoint is constructed; a descriptive notation and CASE tool support this viewpoint. From this viewpoint, implementation issues such as generating control flow; task and data allocation and hard real-time scheduling concerns, are addressed. A complete runtime environment to support the transaction model is described. This environment is hierarchical and can be adapted to many distributed implementations. Finally, the stages of the methodology are applied to a large example, a Ship Control System. Starting with a specification of the requirements, the methodology is applied to generate a design and implementation of the system

Can Modus Vivendi Save Liberalism from Moralism? A Critical Assessment of John Gray’s Political Realism

This chapter assesses John Gray’s modus vivendi-based justification for liberalism. I argue that his approach is preferable to the more orthodox deontological or teleological justificatory strategies, at least because of the way it can deal with the problem of diversity. But then I show how that is not good news for liberalism, for grounding liberal political authority in a modus vivendi undermines liberalism’s aspiration to occupy a privileged normative position vis-à-vis other kinds of regimes. So modus vivendi can save liberalism from moralism, but at cost many liberals will not be prepared to pay

Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

Rawls and Political Realism: Realistic Utopianism or Judgement in Bad Faith?

Political realism criticises the putative abstraction, foundationalism and neglect of the agonistic dimension of political practice in the work of John Rawls. This paper argues that had Rawls not fully specified the implementation of his theory of justice in one particular form of political economy then he would be vulnerable to a realist critique. But he did present such an implementation: a property-owning democracy. An appreciation of Rawls s specificationist method undercuts the realist critique of his conception of justice as fairness

Loss of Niemann-Pick C1 or C2 Protein Results in Similar Biochemical Changes Suggesting That These Proteins Function in a Common Lysosomal Pathway

Niemann-Pick Type C (NPC) disease is a lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids in the endolysosomal system. NPC disease results from a defect in either of two distinct cholesterol-binding proteins: a transmembrane protein, NPC1, and a small soluble protein, NPC2. NPC1 and NPC2 are thought to function closely in the export of lysosomal cholesterol with both proteins binding cholesterol in vitro but they may have unrelated lysosomal roles. To investigate this possibility, we compared biochemical consequences of the loss of either protein. Analyses of lysosome-enriched subcellular fractions from brain and liver revealed similar decreases in buoyant densities of lysosomes from NPC1 or NPC2 deficient mice compared to controls. The subcellular distribution of both proteins was similar and paralleled a lysosomal marker. In liver, absence of either NPC1 or NPC2 resulted in similar alterations in the carbohydrate processing of the lysosomal protease, tripeptidyl peptidase I. These results highlight biochemical alterations in the lysosomal system of the NPC-mutant mice that appear secondary to lipid storage. In addition, the similarity in biochemical phenotypes resulting from either NPC1 or NPC2 deficiency supports models in which the function of these two proteins within lysosomes are linked closely

Viral Small Interfering RNAs Target Host Genes to Mediate Disease Symptoms in Plants

The Cucumber mosaic virus (CMV) Y-satellite RNA (Y-Sat) has a small non-protein-coding RNA genome that induces yellowing symptoms in infected Nicotiana tabacum (tobacco). How this RNA pathogen induces such symptoms has been a longstanding question. We show that the yellowing symptoms are a result of small interfering RNA (siRNA)-directed RNA silencing of the chlorophyll biosynthetic gene, CHLI. The CHLI mRNA contains a 22-nucleotide (nt) complementary sequence to the Y-Sat genome, and in Y-Sat-infected plants, CHLI expression is dramatically down-regulated. Small RNA sequencing and 5′ RACE analyses confirmed that this 22-nt sequence was targeted for mRNA cleavage by Y-Sat-derived siRNAs. Transformation of tobacco with a RNA interference (RNAi) vector targeting CHLI induced Y-Sat-like symptoms. In addition, the symptoms of Y-Sat infection can be completely prevented by transforming tobacco with a silencing-resistant variant of the CHLI gene. These results suggest that siRNA-directed silencing of CHLI is solely responsible for the Y-Sat-induced symptoms. Furthermore, we demonstrate that two Nicotiana species, which do not develop yellowing symptoms upon Y-Sat infection, contain a single nucleotide polymorphism within the siRNA-targeted CHLI sequence. This suggests that the previously observed species specificity of Y-Sat-induced symptoms is due to natural sequence variation in the CHLI gene, preventing CHLI silencing in species with a mismatch to the Y-Sat siRNA. Taken together, these findings provide the first demonstration of small RNA-mediated viral disease symptom production and offer an explanation of the species specificity of the viral disease

Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)

The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery

A Critical Tryptophan and Ca2+ in Activation and Catalysis of TPPI, the Enzyme Deficient in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis

Tripeptidyl aminopeptidase I (TPPI) is a crucial lysosomal enzyme that is deficient in the fatal neurodegenerative disorder called classic late-infantile neuronal ceroid lipofuscinosis (LINCL). It is involved in the catabolism of proteins in the lysosomes. Recent X-ray crystallographic studies have provided insights into the structural/functional aspects of TPPI catalysis, and indicated presence of an octahedrally coordinated Ca(2+).Purified precursor and mature TPPI were used to study inhibition by NBS and EDTA using biochemical and immunological approaches. Site-directed mutagenesis with confocal imaging technique identified a critical W residue in TPPI activity, and the processing of precursor into mature enzyme.NBS is a potent inhibitor of the purified TPPI. In mammalian TPPI, W542 is critical for tripeptidyl peptidase activity as well as autocatalysis. Transfection studies have indicated that mutants of the TPPI that harbor residues other than W at position 542 have delayed processing, and are retained in the ER rather than transported to lysosomes. EDTA inhibits the autocatalytic processing of the precursor TPPI.We propose that W542 and Ca(2+) are critical for maintaining the proper tertiary structure of the precursor proprotein as well as the mature TPPI. Additionally, Ca(2+) is necessary for the autocatalytic processing of the precursor protein into the mature TPPI. We have identified NBS as a potent TPPI inhibitor, which led in delineating a critical role for W542 residue. Studies with such compounds will prove valuable in identifying the critical residues in the TPPI catalysis and its structure-function analysis