A critical evaluation of methods for the reconstruction of tissue-specific models

Under the framework of constraint based modeling, genome-scale metabolic models (GSMMs) have been used for several tasks, such as metabolic engineering and phenotype prediction. More recently, their application in health related research has spanned drug discovery, biomarker identification and host-pathogen interactions, targeting diseases such as cancer, Alzheimer, obesity or diabetes. In the last years, the development of novel techniques for genome sequencing and other high-throughput methods, together with advances in Bioinformatics, allowed the reconstruction of GSMMs for human cells. Considering the diversity of cell types and tissues present in the human body, it is imperative to develop tissue-specific metabolic models. Methods to automatically generate these models, based on generic human metabolic models and a plethora of omics data, have been proposed. However, their results have not yet been adequately and critically evaluated and compared. This work presents a survey of the most important tissue or cell type specific metabolic model reconstruction methods, which use literature, transcriptomics, proteomics and metabolomics data, together with a global template model. As a case study, we analyzed the consistency between several omics data sources and reconstructed distinct metabolic models of hepatocytes using different methods and data sources as inputs. The results show that omics data sources have a poor overlapping and, in some cases, are even contradictory. Additionally, the hepatocyte metabolic models generated are in many cases not able to perform metabolic functions known to be present in the liver tissue. We conclude that reliable methods for a priori omics data integration are required to support the reconstruction of complex models of human cells.Acknowledgments. S.C. thanks the FCT for the Ph.D. Grant SFRH/BD/ 80925/2011. The authors thank the FCT Strategic Project of UID/BIO/04469/2013 unit, the project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and the project “BioInd - Biotechnology and Bioengineering for improved Industrial and Agro-Food processes”, REF. NORTE-07-0124-FEDER-000028 Co-funded by the Programa Operacional Regional do Norte (ON.2 - O Novo Norte), QREN, FEDER

Optimizing Performance of Continuous-Time Stochastic Systems using Timeout Synthesis

We consider parametric version of fixed-delay continuous-time Markov chains (or equivalently deterministic and stochastic Petri nets, DSPN) where fixed-delay transitions are specified by parameters, rather than concrete values. Our goal is to synthesize values of these parameters that, for a given cost function, minimise expected total cost incurred before reaching a given set of target states. We show that under mild assumptions, optimal values of parameters can be effectively approximated using translation to a Markov decision process (MDP) whose actions correspond to discretized values of these parameters

A critical evaluation of automatic atom mapping algorithms and tools

The identification of the atoms which change their position in chemical reactions is an important knowledge within the field of Metabolic Engineering. This can lead to new advances at different levels from the reconstruction of metabolic networks to the classification of chemical reactions, through the identification of the atomic changes inside a reaction. The Atom Mapping approach was initially developed in the 1960s, but recently suffered important advances, being used in diverse biological and biotechnological studies. The main methodologies used for atom mapping are the Maximum Common Substructure and the Linear Optimization methods, which both require computational know-how and powerful resources to run the underlying tools. In this work, we assessed a number of previously implemented atom mapping frameworks, and built a framework able of managing the different data inputs and outputs, as well as the mapping process provided by each of these third-party tools. We evaluated the admissibility of the calculated atom maps from different algorithms, also assessing if with different approaches we were capable of returning equivalent atom maps for the same chemical reaction.ERDF -European Regional Development Fund(UID/BIO/04469/2013)info:eu-repo/semantics/publishedVersio

Peripheral Arterial Disease and Risk of Atrial Fibrillation and Stroke: The Multi�Ethnic Study of Atherosclerosis

Background Peripheral arterial disease (PAD) shares several risk factors with atrial fibrillation (AF), and persons with PAD have an increased risk of stroke. It is unclear if PAD is associated with an increased risk for AF and whether this potential association explains the increased risk of stroke observed in those with PAD. Methods and Results We examined the association between PAD, measured by ankle�brachial index (ABI), and incident AF and incident stroke, separately, in 6568 participants (mean age 62±10 years, 53% women, 62% nonwhite) from the Multi�Ethnic Study of Atherosclerosis (MESA). ABI values 1.4 defined PAD. AF was ascertained through review of hospital discharge records and from Medicare claims data until December 31, 2010. An independent adjudication committee ascertained stroke events. Cox regression was used to estimate hazard ratios and 95% CIs for the association between PAD and AF and stroke. Over a median follow�up of 8.5 years, 301 (4.6%) participants developed AF and 140 (2.1%) developed stroke. In a model adjusted for sociodemographics, cardiovascular risk factors, and potential confounders, PAD was associated with an increased risk of AF (hazard ratio 1.5, 95% CI 1.1 to 2.0). In a similar model, PAD was associated with incident stroke (hazard ratio 1.7, 95% CI 1.1 to 2.5), and the magnitude of risk was not different after inclusion of AF as a time�dependent covariate (hazard ratio 1.7, 95% CI 1.1 to 2.5). Conclusions PAD is associated with an increased risk of AF and stroke in MESA. Potentially, the relationship between PAD and stroke is not mediated by AF

Characteristics and prevalence of hardcore smokers attending UK general practitioners

BACKGROUND: Smoking remains a public health problem and although unsolicited GPs' advice against smoking causes between one and three percent of smokers to stop, a significant proportion of smokers are particularly resistant to the notion of stopping smoking. These resistant smokers have been called "hardcore smokers" and although 16% of smokers in the community are hardcore, little is known about hardcore smokers presenting to primary care physicians. Consequently, this study reports the characteristics and prevalence of hardcore smokers attending UK GPs. METHODS: A cross-sectional survey using data from two different research projects was conducted. Data for this analysis had been collected from surgery consultation sessions with 73 GPs in Leicestershire, England, (42 GPs from one project). Research assistants distributed pre-consultation questionnaires to 4147 adults attending GPs' surgery sessions. Questionnaires identified regular smokers, the proportion of hardcore smokers and their characteristics. Non-hardcore and hardcore smokers' ages, gender and nicotine addiction levels were compared. RESULTS: 1170 regular smokers attended surgery sessions and, 16.1% (95% CI, 14.1 to 18.4) were hardcore smokers. Hardcore smokers had higher levels of nicotine addiction than others (p = 0.000), measured by the Heaviness of Smoking Index and were more likely to be male [50.5% hardcore versus 35.3% non-hardcore, (OR = 1.88, 95% CI = 1.4 to 2.6)] but no age differences were observed between groups. CONCLUSION: A significant minority of the smokers who present in general practice are resistant to the notion of smoking cessation and these smokers are more heavily nicotine addicted than others. Although clinical guidelines suggest that GPs should regularly advise all smokers against smoking, it is probable that hardcore smokers do not respond positively to this and help to make up the 97%–99% of smokers who do not quit after being advised to stop smoking by GPs. General practitioners need to find approaches for raising the issue of smoking during consultations in ways that do not reinforce the negative opinions of hardcore smokers concerning smoking cessation

The Pricing of Dutch Auction Rate Preferred Stock.

The emergence of dutch auction rate preferred stock (DARPS) in 1984 created a new security which offers features to meet the needs of short-term corporate investors. The instrument offers attractive after-tax yields due to the preferential dividend income exclusion and an adjustable yield. In addition, DARPS are recognized as being safer than unhedged "dividend-capture plans." Dividend-capture plans, where dividend income is "captured" by trading into and out of high yield stocks, have recently become popular as a means of earning attractive returns on cash reserves. The Wall Street Journal (1987:6) notes, that during the October 1987 stock market ,..."corporateorate treasurers who had been earning as much as 10% after taxes on dividend captures — much more than from traditional short-term investments like treasury bills — faced big losses." This research investigates the pricing of DARPS and focuses on the instrument's distinctive features to develop and test a pricing model. This study of factors which influence the pricing of the instrument is believed to be the first of its type in the finance literature. This work complements previous research by Sorensen and Hawkins (1981) on the pricing of regular preferred stock, Winger et al (1986) on the investment performance of adjustable rate preferred stock, and Alderson et al (1987) on the investment performance of DARPS. Further, the prior research by Alderson, et al, is limited to the 201 dutch auctions held during the introductory period of the instrument in the first six months of 1986. This paper utilizes a sample over five times larger than Alderson, et al, spanning a 21/2 year period

Cartan subalgebras and the UCT problem, II

We show that outer approximately represenbtable actions of a finite cyclic group on UCT Kirchberg algebras satisfy a certain quasi-freeness type property if the corresponding crossed products satisfy the UCT and absorb a suitable UHF algebra tensorially. More concretely, we prove that for such an action there exists an inverse semigroup of homogeneous partial isometries that generates the ambient C*-algebra and whose idempotent semilattice generates a Cartan subalgebra. We prove a similar result for actions of finite cyclic groups with the Rokhlin property on UCT Kirchberg algebras absorbing a suitable UHF algebra. These results rely on a new construction of Cartan subalgebras in certain inductive limits of Cartan pairs. We also provide a characterisation of the UCT problem in terms of finite order automorphisms, Cartan subalgebras and inverse semigroups of partial isometries of the Cuntz algebra $\mathcal{O}_2$. This generalizes earlier work of the authors.Comment: minor revisions; final version, accepted for publication in Math. Ann.; 26 page

Extralimital triradii as a putative marker of schizotypy

Dermatoglyphic anomalies are reported to occur at a higher rate in schizophrenic patients and schizotypic individuals than in the general population, supporting the hypothesis that they are a marker of vulnerability for such conditions. Dermatoglyphic anomalies are hypothesized to indicate severe disruptions in the second trimester of prenatal development, a time period that appears to be etiologically relevant to the development of schizophrenia and related conditions. The present study provides the first examination of extralimital triradii in schizotypic young adults (n=197) and control participants (n=135) identified by the Revised Social Anhedonia Scale [Eckblad, M., Chapman, L.J., Chapman, J.P., Mishlove, M., 1982. The Revised Social Anhedonia Scale. Unpublished test (copies available from T.R. Kwapil, Department of Psychology, University of North Carolina at Greensboro P.O. Box 26164 Greensboro, NC 27402-6164)], the Perceptual Aberration Scale [Chapman, L.J., Chapman, J.P., Raulin, M.L., 1978. Body image aberration in schizophrenia. J. Abnorm. Psychol. 87, 399–407], the Magical Ideation Scale [Eckblad, M.L., Chapman, L.J., 1983. Magical ideation as an indicator of schizotypy. J. Consult. Clin. Psychol. 51, 215–225], and the Physical Anhedonia Scale [Chapman, L.J., Chapman, J.P., Raulin, M.L., 1976. Scales for physical and social anhedonia. J. Abnorm. Psychol. 85, 374–382]. As hypothesized, the schizotypic participants (6.6%) exhibited significantly higher rates of extralimital triradii than control participants (1.5%). These findings strongly encourage the future investigation of extralimital triradii in at-risk and psychotic populations