Genome-wide screen of genes required for caffeine tolerance in fission yeast

Background: An excess of caffeine is cytotoxic to all eukaryotic cell types. We aim to study how cells become tolerant to atoxic dose of this drug, and the relationship between caffeine and oxidative stress pathways.Methodology/Principal Findings: We searched for Schizosaccharomyces pombe mutants with inhibited growth on caffeinecontainingplates. We screened a collection of 2,700 haploid mutant cells, of which 98 were sensitive to caffeine. The genes mutated in these sensitive clones were involved in a number of cellular roles including the H2O2-induced Pap1 and Sty1 stress pathways, the integrity and calcineurin pathways, cell morphology and chromatin remodeling. We have investigated the role of the oxidative stress pathways in sensing and promoting survival to caffeine. The Pap1 and the Sty1 pathways are both required for normal tolerance to caffeine, but only the Sty1 pathway is activated by the drug. Cells lacking Pap1 aresensitive to caffeine due to the decreased expression of the efflux pump Hba2. Indeed, ?hba2 cells are sensitive to caffeine, and constitutive activation of the Pap1 pathway enhances resistance to caffeine in an Hba2-dependent manner. Conclusions/Significance: With our caffeine-sensitive, genome-wide screen of an S. pombe deletion collection, we havedemonstrated the importance of some oxidative stress pathway components on wild-type tolerance to the drug.

Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

Background: Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results: This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC.Conclusion: This study proposes that variation at putative 8q24 cis-regulator(s) of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

Dynamic estimation of three-dimensional cerebrovascular deformation from rotational angiography

Purpose: The objective of this study is to investigate the feasibility of detecting and quantifying 3D cerebrovascular wall motion from a single 3D rotational x-ray angiography (3DRA) acquisition within a clinically acceptable time and computing from the estimated motion field for the further biomechanical modeling of the cerebrovascular wall. Methods: The whole motion cycle of the cerebral vasculature is modeled using a 4D B-spline transformation, which is estimated from a 4D to 2D + t image registration framework. The registration is performed by optimizing a single similarity metric between the entire 2D + t measured projection sequence and the corresponding forward projections of the deformed volume at their exact time instants. The joint use of two acceleration strategies, together with their implementation on graphics processing units, is also proposed so as to reach computation times close to clinical requirements. For further characterizing vessel wall properties, an approximation of the wall thickness changes is obtained through a strain calculation. Results: Evaluation on in silico and in vitro pulsating phantom aneurysms demonstrated an accurate estimation of wall motion curves. In general, the error was below 10% of the maximum pulsation, even in the situation when substantial inhomogeneous intensity pattern was present. Experiments on in vivo data provided realistic aneurysm and vessel wall motion estimates, whereas in regions where motion was neither visible nor anatomically possible, no motion was detected. The use of the acceleration strategies enabled completing the estimation process for one entire cycle in 5-10 min without degrading the overall performance. The strain map extracted from our motion estimation provided a realistic deformation measure of the vessel wall. Conclusions: The authors' technique has demonstrated that it can provide accurate and robust 4D estimates of cerebrovascular wall motion within a clinically acceptable time, although it has to be applied to a larger patient population prior to possible wide application to routine endovascular procedures. In particular, for the first time, this feasibility study has shown that in vivo cerebrovascular motion can be obtained intraprocedurally from a 3DRA acquisition. Results have also shown the potential of performing strain analysis using this imaging modality, thus making possible for the future modeling of biomechanical properties of the vascular wall.

Student modeling based on fuzzy inference mechanisms

The paper presents a competence-based instructional design system and a way to provide a personalization of navigation in the course content. The navigation aid tool builds on the competence graph and the student model, which includes the elements of uncertainty in the assessment of students. An individualized navigation graph is constructed for each student, suggesting the competences the student is more prepared to study. We use fuzzy set theory for dealing with uncertainty. The marks of the assessment tests are transformed into linguistic terms and used for assigning values to linguistic variables. For each competence, the level of difficulty and the level of knowing its prerequisites are calculated based on the assessment marks. Using these linguistic variables and approximate reasoning (fuzzy IF-THEN rules), a crisp category is assigned to each competence regarding its level of recommendation.

New Trends in Public Facility Location Modeling

The past four decades have witnessed an explosive growth in the field of networkbased facility location modeling. This is not at all surprising since location policy is one of the most profitable areas of applied systems analysis in regional science and ample theoretical and applied challenges are offered. Location-allocation models seek the location of facilities and/or services (e.g., schools, hospitals, and warehouses) so as to optimize one or several objectives generally related to the efficiency of the system or to the allocation of resources. This paper concerns the location of facilities or services in discrete space or networks, that are related to the public sector, such as emergency services (ambulances, fire stations, and police units), school systems and postal facilities. The paper is structured as follows: first, we will focus on public facility location models that use some type of coverage criterion, with special emphasis in emergency services. The second section will examine models based on the P-Median problem and some of the issues faced by planners when implementing this formulation in real world locational decisions. Finally, the last section will examine new trends in public sector facility location modeling.

Implicit collusion on wide spreads

Recent empirical findings suggest that spreads quoted in dealershipmarkets might be uncompetitive. This paper analyzes theoretically if pricecompetition between risk--averse market--makers leaves room for implicitcollusive behavior. We compare the spread and risk--sharing efficiencyarising in several market structures differing in terms of i) the priorityrule followed in case of ties, and ii) the type of schedules market makersmay use, namely: general schedules, linear schedules, or limit orders. Ingeneral, competitive pricing does not arise in equilibrium, and there isa conflict between risk sharing efficiency and the tightness of the spread.This conflict can be mitigated by an appropriate market structure design.The limit order market is the only market structure in which the competitiveequilibrium is the unique equilibrium.

On the relevance of modeling volatility for pricing purposes

This paper presents a two-factor (Vasicek-CIR) model of the term structure of interest rates and develops its pricing and empirical properties. We assume that default free discount bond prices are determined by the time to maturity and two factors, the long-term interest rate and the spread. Assuming a certain process for both factors, a general bond pricing equation is derived and a closed-form expression for bond prices is obtained. Empirical evidence of the model's performance in comparisson with a double Vasicek model is presented. The main conclusion is that the modeling of the volatility in the long-term rate process can help (in a large amount) to fit the observed data can improve - in a reasonable quantity - the prediction of the future movements in the medium- and long-term interest rates. However, for shorter maturities, it is shown that the pricing errors are, basically, negligible and it is not so clear which is the best model to be used.

How wide is the gap? An investigation of gender wage differences using quantile regression

In this paper we examine the determinants of wages and decompose theobserved differences across genders into the "explained by differentcharacteristics" and "explained by different returns components"using a sample of Spanish workers. Apart from the conditionalexpectation of wages, we estimate the conditional quantile functionsfor men and women and find that both the absolute wage gap and thepart attributed to different returns at each of the quantiles, farfrom being well represented by their counterparts at the mean, aregreater as we move up in the wage range.

Pitfalls in the modeling of forward-looking price setting and investment decisions

The present paper makes progress in explaining the role of capital for inflation and output dynamics. We followWoodford (2003, Ch. 5) in assuming Calvo pricing combined with a convex capital adjustment cost at the firm level. Our main result is that capital accumulation affects inflation dynamics primarily through its impact on the marginal cost. This mechanism is much simpler than the one implied by the analysis in Woodford's text. The reason is that his analysis suffers from a conceptual mistake, as we show. The latter obscures the economic mechanism through which capital affects inflation and output dynamics in the Calvo model, as discussed in Woodford (2004).

Flexible multivariate GARCH modeling with an application to international stock markets

The goal of this paper is to estimate time-varying covariance matrices.Since the covariance matrix of financial returns is known to changethrough time and is an essential ingredient in risk measurement, portfolioselection, and tests of asset pricing models, this is a very importantproblem in practice. Our model of choice is the Diagonal-Vech version ofthe Multivariate GARCH(1,1) model. The problem is that the estimation ofthe general Diagonal-Vech model model is numerically infeasible indimensions higher than 5. The common approach is to estimate more restrictive models which are tractable but may not conform to the data. Our contributionis to propose an alternative estimation method that is numerically feasible,produces positive semi-definite conditional covariance matrices, and doesnot impose unrealistic a priori restrictions. We provide an empiricalapplication in the context of international stock markets, comparing thenew estimator to a number of existing ones.

Macroeconomic modeling for monetary policy evaluation

We describe some of the main features of the recent vintage macroeconomic models used for monetary policy evaluation. We point to some of the key differences with respect to the earlier generation ofmacro models, and highlight the insights for policy that these new frameworks have to offer. Our discussion emphasizes two key aspects of the new models: the significant role of expectations of future policy actions in the monetary transmission mechanism, and the importance for the central bank of tracking of the flexible price equilibrium values of the natural levels of output and the real interest rate. We argue that both features have important implications for the conduct of monetary policy.

Eyes wide shut - unusual two stage repair of pectus excavatum and annuloaortic ectasia in a 37 year old marfan patient: Case report

We report about a 37 year old male patient with a pectus excavatum. The patient was in NYHA functional class III. After performed computed tomography the symptoms were thought to be related to the severity of chest deformation. A Ravitch-procedure had been accomplished in a district hospital in 2009. The crack of a metal bar led to a reevaluation 2010, in which surprisingly the presence of an annuloaortic ectasia (root 73 × 74 mm) in direct neighborhood of the formerly implanted metal-bars was diagnosed. Echocardiography revealed a severe aortic valve regurgitation, the left ventricle was massively dilated presenting a reduced ejection fraction of 45%. A marfan syndrome was suspected and the patient underwent a valve sparing aortic root replacement (David procedure) in our institution with an uneventful postoperative course. A review of the literature in combination with discussion of our case suggests the application of stronger recommendations towards preoperative cardiovascular assessment in patients with pectus excavatum.