Inexact inverse iteration for symmetric matrices

AbstractIn this paper we analyse inexact inverse iteration for the real symmetric eigenvalue problem Av=λv. Our analysis is designed to apply to the case when A is large and sparse and where iterative methods are used to solve the shifted linear systems (A−σI)y=x which arise. We present a convergence theory that is independent of the nature of the inexact solver used, and, though the use of the Rayleigh quotient is emphasised, our analysis also extends to quite general choices for shift and inexact solver strategies. Additionally, the convergence framework allows us to treat both standard preconditioning and to present a new analysis of the variation introduced by Simoncini and Eldén (BIT, vol. 42, pp.159–182, 2002). Also, we provide an analysis of the performance of inner iteration solves when preconditioned MINRES is used as the inexact solver. This analysis provides descriptive bounds which are shown to predict well the actual behaviour observed in practice. Also, it explains the improvement in performance of the modification introduced by Simoncini and Eldén over the standard preconditioned form. Importantly, our analysis shows that letting the shift tend to the eigenvalue, as is the case if the Rayleigh quotient is used, does not harm significantly the performance of the iterative method for the shifted systems. Throughout the paper numerical results are given to illustrate the theory

The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver

Secreted frizzled-related protein (sFRP) 4 is an adipokine with increased expression in white adipose tissue from obese subjects with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Yet, it is unknown whether sFRP4 action contributes to the development of these pathologies. Here, we determined whether sFRP4 expression in visceral fat associates with NAFLD and whether it directly interferes with insulin action and lipid and glucose metabolism in primary hepatocytes and myotubes. The association of sFRP4 with clinical measures was investigated in obese men with or without type 2 diabetes and with or without biopsy-proven NAFLD. To determine the impact of sFRP4 on metabolic parameters, primary human myotubes (hSkMC), or primary hepatocytes from metabolic healthy C57B16 and from systemic insulin-resistant mice, i.e. aP2-SREBP-1c, were used. Gene expression of sFRP4 in visceral fat from obese men associated with insulin sensitivity, triglycerides and NAFLD. In C57B16 hepatocytes, sFRP4 disturbed insulin action. Specifically, sFRP4 decreased the abundance of IRS1 and FoxO1 together with impaired insulin-mediated activation of Akt-signalling and glycogen synthesis and a reduced suppression of gluconeogenesis by insulin. Moreover, sFRP4 enhanced insulin-stimulated hepatic de novo lipogenesis (DNL). In hSkMC, sFRP4 induced glycolysis rather than inhibiting insulin signalling. Finally, in hepatocytes from aP2-SREBP-1c mice, sFRP4 potentiates existing insulin resistance. Collectively, we show that sFRP4 interferes with hepatocyte insulin action. Physiologically, sFRP4 promotes DNL in hepatocytes and glycolysis in myotubes. These sFRP4-mediated responses may result in a vicious cycle, in which enhanced rates of DNL and glycolysis aggravate hepatic lipid accumulation and insulin resistance

Towards a tidal loading model for the Argentine-German Geodetic Observatory (La Plata)

We present a regionalized model of ocean tidal loading effects for the Argentine-German Geodetic Observatory in La Plata. It provides the amplitudes and phases of gravity variations and vertical deformation for nine tidal constituents to be applied as corrections to the observatory’s future geodetic observation data. This model combines a global ocean tide model with a model of the tides in the Río de la Plata estuary. A comparison with conventional predictions based only on the global ocean tide model reveals the importance of the incorporation of the regional tide model. Tidal loading at the observatory is dominated by the tides in the Atlantic Ocean. An additional contribution of local tidal loading in channels and groundwater is examined. The magnitude of the tidal loading is also reviewed in the context of the effects of solid earth tides, atmospheric loading and non-tidal loadsFacultad de Ciencias Naturales y Muse

Towards a tidal loading model for the Argentine-German Geodetic Observatory (La Plata)

We present a regionalized model of ocean tidal loading effects for the Argentine-German Geodetic Observatory in La Plata. It provides the amplitudes and phases of gravity variations and vertical deformation for nine tidal constituents to be applied as corrections to the observatory’s future geodetic observation data. This model combines a global ocean tide model with a model of the tides in the Río de la Plata estuary. A comparison with conventional predictions based only on the global ocean tide model reveals the importance of the incorporation of the regional tide model. Tidal loading at the observatory is dominated by the tides in the Atlantic Ocean. An additional contribution of local tidal loading in channels and groundwater is examined. The magnitude of the tidal loading is also reviewed in the context of the effects of solid earth tides, atmospheric loading and non-tidal loadsFacultad de Ciencias Naturales y Muse

Commissioning of Ramp and Squeeze at the LHC

The energy ramp and the betatron squeeze at the CERN Large Hadron Collider (LHC) are particularly critical oper- ational phases that involve the manipulation of beams well above the safe limit for damage of accelerator components. In particular, the squeeze is carried out at top energy with reduced quench limit of superconducting magnets and re- duced aperture in the triplet quadrupoles. In 2010, the commissioning of the ramp from 450 GeV to 3.5 TeV and the squeeze to 2 m in all the LHC experiments have been achieved and smoothly became operational. In this paper, the operational challenges associated to these phases are discussed, the commissioning experience with single- and multi-bunch operation is reviewed and the overall perfor- mance is discusse

Towards a tidal loading model for the Argentine-German Geodetic Observatory (La Plata)

We present a regionalized model of ocean tidal loading effects for the Argentine-German Geodetic Observatory in La Plata. It provides the amplitudes and phases of gravity variations and vertical deformation for nine tidal constituents to be applied as corrections to the observatory’s future geodetic observation data. This model combines a global ocean tide model with a model of the tides in the Río de la Plata estuary. A comparison with conventional predictions based only on the global ocean tide model reveals the importance of the incorporation of the regional tide model. Tidal loading at the observatory is dominated by the tides in the Atlantic Ocean. An additional contribution of local tidal loading in channels and groundwater is examined. The magnitude of the tidal loading is also reviewed in the context of the effects of solid earth tides, atmospheric loading and non-tidal loadsFacultad de Ciencias Naturales y Muse

Genome-Wide Scan Identifies TNIP1, PSORS1C1, and RHOB as Novel Risk Loci for Systemic Sclerosis

Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10−5 were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10−8, OR = 0.69, 95% CI [0.60–0.79]; rs6457617, P = 1.14×10−7 and rs9275245, P = 1.39×10−7. Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10−5, OR = 1.36 [1.18–1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10−5) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10−10, OR:1.25), TNIP1 (P = 4.68×10−9, OR:1.31), and RHOB loci (P = 3.17×10−6, OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes