Using the bootstrap for improved ARIMA model identification

This paper presents a new method of identifying ARIMA time-series models. We use the bootstrap technique in estimating the distribution of sample autocorrelations both separately and in a simultaneous inference setting. The bootstrap has the advantage of being nonparametric and thus free of reliance on asymptotic normality, which may not hold for short or medium-size series. The simultaneous procedure is unique, as it has no feasible parametric alternatives. An application to exchange rates illustrates our methodology. In the example chosen, we are able to produce better forecasts using the model identified via the bootstrap technique.     

Genetic variation in selenoprotein S influences inflammatory response

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --> A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --> A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.     

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.     

All together now: The circular organization in a university Hospital. Part II. Implementation

The first part of this two-part series described the initial impetus driving a university hospital's planned change project, the planning process itself, and the interventions that were identified to meet our goals. This article describes and discusses the interventions—the implementation of our version of Ackoff's circular organization and issues related to barriers, selected outcomes, the change process, evaluation, and the project's significance to nursing.     

The epidermis both drives and restricts plant shoot growth

The size of an organism is genetically determined, yet how a plant or animal achieves its final size is largely unknown. The shoot of higher plants has a simple conserved body plan based on three major tissue systems: the epidermal (L1), sub-epidermal (L2) and inner ground and vascular (L3) tissues. Which tissue system drives or restricts growth has been a subject of debate for over a century. Here, we use dwarf, brassinosteroid biosynthesis and brassinosteroid response mutants in conjunction with tissue-specific expression of these components as tools to examine the role of the epidermis in shoot growth. We show that expression of the brassinosteroid receptor or a brassinosteroid biosynthetic enzyme in the epidermis, but not in the vasculature, of null mutants is sufficient to rescue their dwarf phenotypes. Brassinosteroid signalling from the epidermis is not sufficient to establish normal vascular organization. Moreover, shoot growth is restricted when brassinosteroids are depleted from the epidermis and brassinosteroids act locally within a leaf. We conclude that the epidermis both promotes and restricts shoot growth by providing a non-autonomous signal to the ground tissues.     

The Vanguard Method as Applied to the Design and Management of English and Welsh Children’s Services Departments

This paper follows several case studies where the children’s services departments of English and Welsh local authorities have fundamentally redesigned the way they worked following the application of the Vanguard Method (Seddon, Systems thinking in the public sector, 2008), a particular form of systems thinking. After first studying the way the children’s social care service worked as a system, the social workers in these authorities were able to demonstrate the way that government-prescribed IT and performance measures were restricting the way they could do what was shown to matter to the children in their care. The paper will document how, after being granted ministerial permission to suspend the use of their old performance measures and IT, a new set of operating principles was developed and employed. The redesigned system has shown encouraging early results. Evidence from these case studies (following Yin 2009) is presented in the form of recorded operational improvements and statements from participants. The paper will be of topical relevance to all involved in social care in the light of the government-commissioned Munro Review (Munro, The Munro Review of child protection: final report, 2011). The issues discussed will also be germane to the many other public sector partner agencies involved in the delivery of social care services (e.g. police, health, housing associations).     

Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia

Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.     

The first axenic cultivation of a rotifer species

Résumé Le Rotifère monogononteLecane inermis, a été mis par les auteurs en cultures axéniques capables de souscultivation indéfinie. C'est le premier Rotifère soumis à cette expérience.

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The early part of this work was done at the Laboratory of Comparative Biology, Kaiser Foundation Research Institute, Richmond (California) and was supported, in part, by Grants G-6018 and G-13138 from the National Science Foundation.