ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.     

Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis

We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.     

Evolution of neoplastic cell lineages in Barrett oesophagus.

It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models.     

A partial robust optimization approach to inventory management for the offline-to-online problem under different selling prices

This study examines an optimal inventory strategy when a retailer markets a product at different selling prices through a dual-channel supply chain, comprising an online channel and an offline channel. Using the operating pattern of the offline-to-online (O2O) business model, we develop a partial robust optimization (PRO) model. Then, we provide a closed-form solution when only the mean and standard deviation of the online channel demand distribution is known and the offline channel demand follows a uniform distribution (partial robust). Specifically, owing to the good structural properties of the solution, we obtain a heuristic ordering formula for the general distribution case (i.e., the offline channel demand follows a general distribution). In addition, a series of numerical experiments prove the rationality of our conjecture. Moreover, after comparing our solution with other possible policies, we conclude that the PRO approach improves the performance of incorporating the internet into an existing supply chain and, thus, is able to adjust the level of conservativeness of the solution. Finally, in a degenerated situation, we compare our PRO approach with a combination of information approach. The results show that the PRO approach has more “robust” performance. As a result, a reasonable trade-off between robustness and performance is achieved.     

Operationalising “Double-Loop” Learning in Service Organisations: A Systems Approach for Creating Knowledge

Learning organisation literature has widely discussed the connections between “double-loop” learning and its significance to organisational performance, but paying little attention to tools and systems that can operationalise “double-loop” learning in organisations. This paper investigates the impact of applying a systems approach for service operations design, expressed as the Vanguard Method (Seddon, Freedom from command and control: a better way to make the work work, 2003), in order to activate “double-loop” learning in service organisations. Two case studies were conducted in the banking mortgage operations and adults’ social care services in the UK, using the dimensions of the learning organisation questionnaire (DLOQ), semi-structured interviews, observations, and documents. The findings of the cross-case analysis support the link of applying the Vanguard Method with operationalising “double-loop” learning through three main factors, namely systematic-operations improvement, organisational capacity development, and outside-in mode of work; that are all embedded into the seven dimensions of the DLOQ. The value of this paper is the introduction of a service operations design tool that can activate “double-loop” learning performance in the fast changing knowledge era. It also provides an impetus for service organisations to creatively influence employees’ competencies to effectively improve internal systems.     

Generating semi-algebraic invariants for non-autonomous polynomial hybrid systems

Hybrid systems are dynamical systems with interacting discrete computation and continuous physical processes, which have become more common, more indispensable, and more complicated in our modern life. Particularly, many of them are safety-critical, and therefore are required to meet a critical safety standard. Invariant generation plays a central role in the verification and synthesis of hybrid systems. In the previous work, the fourth author and his coauthors gave a necessary and sufficient condition for a semi-algebraic set being an invariant of a polynomial autonomous dynamical system, which gave a confirmative answer to the open problem. In addition, based on which a complete algorithm for generating all semi-algebraic invariants of a given polynomial autonomous hybrid system with the given shape was proposed. This paper considers how to extend their work to non-autonomous dynamical and hybrid systems. Non-autonomous dynamical and hybrid systems are with inputs, which are very common in practice; in contrast, autonomous ones are without inputs. Furthermore, the authors present a sound and complete algorithm to verify semi-algebraic invariants for non-autonomous polynomial hybrid systems. Based on which, the authors propose a sound and complete algorithm to generate all invariants with a pre-defined template.     

The generalized Serre problem over <Emphasis Type="Italic">K</Emphasis>-Hermite rings

This paper investigates the completion and the zero prime factorization for matrices over a K-Hermite ring. The authors have generalized Kaplansky’s related results, solved similar Lin-Bose problem and generalized Serre problem over a K-Hermite ring.     

Greenhouse Effects in Global Warming based on Analogical Reasoning

Using an analogy in science and everyday life is a double-edged sword because they are accompanied by alternative ideas, in addition to scientific concepts. Schools and public education explain global warming by making a common analogy between this phenomenon and greenhouse effects (Chen in Philos Cogn Sci 105–114, 2012). Unfortunately, this analogy sometimes produces various incorrect explanatory mental models. To construct a correct understanding of global warming, it is necessary: first, to investigate the attributes of analogical reasoning; second, to understand these features by restructuring the greenhouse analogy; and third, to explore the problems and benefits of the greenhouse analogy. The characteristics of relations, rather than objects, must be mapped according to the principle of systematicity, but the public tends to preserve the attributes of the base domain, which is mapped relatively easily. In conclusion, certain facets of the prevailing greenhouse analogy cause a distorted public view of climate change. We must use the greenhouse analogy and yet simultaneously emphasize the relations and attributes highlighted and hidden in the analogy during evaluation.     

Love and Realism

In this reply I try to show that, contrary to Milberry’s apparent assertion, the general intellect of the multitude does not have the explanatory robustness she accredits to it (following both Virno and the Hardt and Negri of the Empire trilogy). Digital network technologies are currently overwhelmingly effective in proletarianizing and disempowering the cognitariat and only an active technopolitics of deproletarianization could reverse this hegemonic situation. In my response to Verbeek, I attempt to correct his misinterpretation (shared by Milberry) of the Stieglerian approach as being dialectical in nature and show that, far from reinstating the humanist dichotomy between human beings and technologies, my analysis assumes their original, albeit fundamentally ambiguous and even ‘uncanny’ [unheimlich] interconnection. I conclude with pointing out some implications of this view for a ‘really realistic’ political theory of technology.     

The Struggle for Technology: Towards a Realistic Political Theory of Technology

Pieter Lemmens’ neo-Marxist approach to technology urges us to rethink how to do political philosophy of technology. First, Lemmens’ high level of abstraction raises the question of how empirically informed a political theory of technology needs to be. Second, his dialectical focus on a “struggle” between humans and technologies reveals the limits of neo-Marxism. Political philosophy of technology needs to return “to the things themselves”. The political significance of technologies cannot be reduced to its origins in systems of production or social organization, but requires study at the micro-level, where technologies help to shape engagement, interaction, power, and social awareness.