Decreasing the number of false positives in sequence classification

Abstract Background A large number of probabilistic models used in sequence analysis assign non-zero probability values to most input sequences. To decide when a given probability is sufficient the most common way is bayesian binary classification, where the probability of the model characterizing the sequence family of interest is compared to that of an alternative probability model. We can use as alternative model a null model. This is the scoring technique used by sequence analysis tools such as HMMER, SAM and INFERNAL. The most prevalent null models are position-independent residue distributions that include: the uniform distribution, genomic distribution, family-specific distribution and the target sequence distribution. This paper presents a study to evaluate the impact of the choice of a null model in the final result of classifications. In particular, we are interested in minimizing the number of false predictions in a classification. This is a crucial issue to reduce costs of biological validation. Results For all the tests, the target null model presented the lowest number of false positives, when using random sequences as a test. The study was performed in DNA sequences using GC content as the measure of content bias, but the results should be valid also for protein sequences. To broaden the application of the results, the study was performed using randomly generated sequences. Previous studies were performed on aminoacid sequences, using only one probabilistic model (HMM) and on a specific benchmark, and lack more general conclusions about the performance of null models. Finally, a benchmark test with P. falciparum confirmed these results. Conclusions Of the evaluated models the best suited for classification are the uniform model and the target model. However, the use of the uniform model presents a GC bias that can cause more false positives for candidate sequences with extreme compositional bias, a characteristic not described in previous studies. In these cases the target model is more dependable for biological validation due to its higher specificity.

RNA interference-mediated knockdown of CD49e (α5 integrin chain) in human thymic epithelial cells modulates the expression of multiple genes and decreases thymocyte adhesion

Abstract Background The thymus is a central lymphoid organ, in which bone marrow-derived T cell precursors undergo a complex process of maturation. Developing thymocytes interact with thymic microenvironment in a defined spatial order. A component of thymic microenvironment, the thymic epithelial cells, is crucial for the maturation of T-lymphocytes through cell-cell contact, cell matrix interactions and secretory of cytokines/chemokines. There is evidence that extracellular matrix molecules play a fundamental role in guiding differentiating thymocytes in both cortical and medullary regions of the thymic lobules. The interaction between the integrin α5β1 (CD49e/CD29; VLA-5) and fibronectin is relevant for thymocyte adhesion and migration within the thymic tissue. Our previous results have shown that adhesion of thymocytes to cultured TEC line is enhanced in the presence of fibronectin, and can be blocked with anti-VLA-5 antibody. Results Herein, we studied the role of CD49e expressed by the human thymic epithelium. For this purpose we knocked down the CD49e by means of RNA interference. This procedure resulted in the modulation of more than 100 genes, some of them coding for other proteins also involved in adhesion of thymocytes; others related to signaling pathways triggered after integrin activation, or even involved in the control of F-actin stress fiber formation. Functionally, we demonstrated that disruption of VLA-5 in human TEC by CD49e-siRNA-induced gene knockdown decreased the ability of TEC to promote thymocyte adhesion. Such a decrease comprised all CD4/CD8-defined thymocyte subsets. Conclusion Conceptually, our findings unravel the complexity of gene regulation, as regards key genes involved in the heterocellular cell adhesion between developing thymocytes and the major component of the thymic microenvironment, an interaction that is a mandatory event for proper intrathymic T cell differentiation.

Endosymbiosis in trypanosomatids: the genomic cooperation between bacterium and host in the synthesis of essential amino acids is heavily influenced by multiple horizontal gene transfers

Background Trypanosomatids of the genera Angomonas and Strigomonas live in a mutualistic association characterized by extensive metabolic cooperation with obligate endosymbiotic Betaproteobacteria. However, the role played by the symbiont has been more guessed by indirect means than evidenced. Symbiont-harboring trypanosomatids, in contrast to their counterparts lacking symbionts, exhibit lower nutritional requirements and are autotrophic for essential amino acids. To evidence the symbiont’s contributions to this autotrophy, entire genomes of symbionts and trypanosomatids with and without symbionts were sequenced here. Results Analyses of the essential amino acid pathways revealed that most biosynthetic routes are in the symbiont genome. By contrast, the host trypanosomatid genome contains fewer genes, about half of which originated from different bacterial groups, perhaps only one of which (ornithine cyclodeaminase, EC:4.3.1.12) derived from the symbiont. Nutritional, enzymatic, and genomic data were jointly analyzed to construct an integrated view of essential amino acid metabolism in symbiont-harboring trypanosomatids. This comprehensive analysis showed perfect concordance among all these data, and revealed that the symbiont contains genes for enzymes that complete essential biosynthetic routes for the host amino acid production, thus explaining the low requirement for these elements in symbiont-harboring trypanosomatids. Phylogenetic analyses show that the cooperation between symbionts and their hosts is complemented by multiple horizontal gene transfers, from bacterial lineages to trypanosomatids, that occurred several times in the course of their evolution. Transfers occur preferentially in parts of the pathways that are missing from other eukaryotes. Conclusion We have herein uncovered the genetic and evolutionary bases of essential amino acid biosynthesis in several trypanosomatids with and without endosymbionts, explaining and complementing decades of experimental results. We uncovered the remarkable plasticity in essential amino acid biosynthesis pathway evolution in these protozoans, demonstrating heavy influence of horizontal gene transfer events, from Bacteria to trypanosomatid nuclei, in the evolution of these pathways.

A rigorous approach to facilitate and guarantee the correctness of the genetic testing management in human genome information systems

Abstract Background Recent medical and biological technology advances have stimulated the development of new testing systems that have been providing huge, varied amounts of molecular and clinical data. Growing data volumes pose significant challenges for information processing systems in research centers. Additionally, the routines of genomics laboratory are typically characterized by high parallelism in testing and constant procedure changes. Results This paper describes a formal approach to address this challenge through the implementation of a genetic testing management system applied to human genome laboratory. We introduced the Human Genome Research Center Information System (CEGH) in Brazil, a system that is able to support constant changes in human genome testing and can provide patients updated results based on the most recent and validated genetic knowledge. Our approach uses a common repository for process planning to ensure reusability, specification, instantiation, monitoring, and execution of processes, which are defined using a relational database and rigorous control flow specifications based on process algebra (ACP). The main difference between our approach and related works is that we were able to join two important aspects: 1) process scalability achieved through relational database implementation, and 2) correctness of processes using process algebra. Furthermore, the software allows end users to define genetic testing without requiring any knowledge about business process notation or process algebra. Conclusions This paper presents the CEGH information system that is a Laboratory Information Management System (LIMS) based on a formal framework to support genetic testing management for Mendelian disorder studies. We have proved the feasibility and showed usability benefits of a rigorous approach that is able to specify, validate, and perform genetic testing using easy end user interfaces.

Involvement of the atrial natriuretic peptide in cardiovascular pathophysiology and its relationship with exercise

In this minireview we describe the involvement of the atrial natriuretic peptide (ANP) in cardiovascular pathophysiology and exercise. The ANP has a broad homeostatic role and exerts complex effects on the cardio-circulatory hemodynamics, it is produced by the left atrium and has a key role in regulating sodium and water balance in mammals and humans. The dominant stimulus for its release is atrial wall tension, commonly caused by exercise. The ANP is involved in the process of lipolysis through a cGMP signaling pathway and, as a consequence, reducing blood pressure by decreasing the sensitivity of vascular smooth muscle to the action of vasoconstrictors and regulate fluid balance. The increase of this hormone is associated with better survival in patients with chronic heart failure (CHF). This minireview provides new evidence based on recent studies related to the beneficial effects of exercise in patients with cardiovascular disease, focusing on the ANP.

Lifetime Prevalence, age and gender distribution and age-of-onset of psychiatric disorders in the São Paulo Metropolitan Area, Brazil: results from the São Paulo Megacity Mental Health Survey

OBJECTIVES: To estimate prevalence, age-of-onset, gender distribution and identify correlates of lifetime psychiatric disorders in the São Paulo Metropolitan Area (SPMA). METHODS: The São Paulo Megacity Mental Health Survey assessed psychiatric disorders on a probabilistic sample of 5,037 adult residents in the SPMA, using the World Mental Health Survey Version of the Composite International Diagnostic Interview. Response rate was 81.3%. RESULTS: Lifetime prevalence for any disorder was 44.8%; estimated risk at age 75 was 57.7%; comorbidity was frequent. Major depression, specific phobias and alcohol abuse were the most prevalent across disorders; anxiety disorders were the most frequent class. Early age-of-onset for phobic and impulse-control disorders and later age-of-onset for mood disorders were observed. Women were more likely to have anxiety and mood disorders, whereas men, substance use disorders. Apart from conduct disorders, more frequent in men, there were no gender differences in impulse-control disorders. There was a consistent trend of higher prevalence in the youngest cohorts. Low education level was associated to substance use disorders. CONCLUSIONS: Psychiatric disorders are highly prevalent among the general adult population in the SPMA, with frequent comorbidity, early age-of-onset for most disorders, and younger cohorts presenting higher rates of morbidity. Such scenario calls for vigorous public health action.

The topic normalized impact factor

[EN] The journal impact factor is not comparable among fields of science because of systematic differences in publication and citation behaviour across disciplines. In this work, a source normalization of the journal impact factor is proposed. We use the aggregate impact factor of the citing journals as a measure of the citation potential in the journal topic, and we employ this citation potential in the normalization of the journal impact factor. An empirical application in a set of 224 journals from four different fields shows that our normalization, using the citation potential in the journal topic, reduces the between-group variance with respect to the within-group variance in a higher proportion than the rest of indicators analysed.

The meccano method for isogeometric solid modeling

[EN]We present a new method to construct a trivariate T-spline representation of complex solids for the application of isogeometric analysis. The proposed technique only demands the surface of the solid as input data. The key of this method lies in obtaining a volumetric parameterization between the solid and a simple parametric domain. To do that, an adaptive tetrahedral mesh of the parametric domain is isomorphically transformed onto the solid by applying the meccano method. The control points of the trivariate T-spline are calculated by imposing the interpolation conditions on points situated both on the inner and on the surface of the solid...

Politiche di sviluppo e questione etnica. La cooperazione italiana IN Bosnia Erzegovina

The globalization process of the last twenty years has changed the world through international flows of people, policies and practices. International cooperation to development is a part of that process and brought International Organizations (IOs) and Non Governmental Organizations (NGOs) from the West to the rest of the world. In my thesis I analyze the Italian NGOs that worked in Bosnia Herzegovina (BH) to understand which development projects they realized and how they faced the ethnic issue that characterized BH. I consider the relation shaped between Italian NGOs and Bosnian civil society as an object of ethnic interests. In BH, once part of former Yugoslavia, the transition from the communist regime to a democratic country has not been completed. BH’s social conditions are characterized by strong ethnic divisions. The legacy of the early 1990s crisis was a phenomenon of ethnic identities created before the war and that still endure today. The Dayton Peace Agreement signed in 1995 granted the peace and reinforced the inter-ethnic hate between the newly recognized three principal ethnicities: Serbs, Croats and Bosniak. Through the new constitution, the institutions were characterized by division at every level, from the top to the bottom of society. Besides it was the first constitution ever written and signed outside the own country; that was the root of the state of exception that characterized BH. Thus ethnic identities culture survived through the international political involvement. At the same time ethnic groups that dominated the political debate clashed with the international organization’s democratic purpose to build a multicultural and democratic state. Ethnic and also religious differences were the instruments for a national statement that might cause the transition and development projects failure. Fifteen years later social fragmentation was still present and it established an atmosphere of daily cultural violence. Civil society suffered this condition and attended to recreate the ethnic fragmentation in every day life. Some cities became physically divided and other cities don’t tolerated the minority presence. In rural areas, the division was more explicit, from village to village, without integration. In my speech, the anthropology for development – the derivative study from applied anthropology – constitutes the point of view that I used to understand how ethnic identities still influenced the development process in BH. I done ethnographic research about the Italian cooperation for development projects that were working there in 2007. The target of research were the Italian NGOs that created a relation with Bosnian civil society; they were almost twenty divided in four main field of competences: institutional building, education, agriculture and democratization. I assumed that NGOs work needed a deep study because the bottom of society is the place where people could really change their representation and behavior. Italian NGOs operated in BH with the aim of creating sustainable development. They found cultural barricade that both institutions and civil society erected when development projects have been applied. Ethnic and religious differences were stressed to maintain boundaries and fragmented power. Thus NGOs tried to negotiate development projects by social integration. I found that NGOs worked among ethnic groups by pursuing a new integration. They often gained success among people; civil society was ready to accept development projects and overcome differences. On the other hand NGOs have been limited by political level that sustained the ethnic talk and by their representation of Bosnian issue. Thus development policies have been impeded by ethnic issue and by cooperation practices established on a top down perspective. Paradoxically, since international community has approved the political ethnic division within DPA, then the willing of development followed by funding NGOs cooperation projects was not completely successful.

For God'sake! Lift the embargo to Spain

Intorno alla metà degli anni trenta la Spagna diventò il centro dell’attenzione del mondo e tutte le grandi potenze internazionali, vecchie e nuove, vennero coinvolte, in misura diversa, nella guerra civile. Già nell’agosto del 1936, un mese dopo l’esplosione del conflitto, tutti gli Stati più rappresentativi caldeggiavano l’ipotesi di una politica comune di “non intervento”. Il ruolo guida in tal senso venne assunto dal governo inglese, capace di dissuadere, in tempi estremamente rapidi, il governo frontista francese di Leon Blum dall’intento di sostenere economicamente e militarmente il legittimo governo repubblicano spagnolo. La preoccupazione che il conflitto potesse degenerare in uno scontro più generale fu quindi la ragione principale per la quale qualche settimana dopo nacque il “Comitato di Non Intervento”, cui aderirono ben ventisette nazioni europee tra cui Francia, Inghilterra, URSS, Italia, Germania e Portogallo. Il mio progetto di ricerca dottorale esamina il ruolo, le scelte ed i relativi dibattiti in merito all’unica grande potenza, gli Stati Uniti d’America, che, pur scegliendo di rimanere neutrale, si astenne dal partecipare al suddetto Comitato. In ambito statunitense particolare rilievo assumono due aspetti del dibattito politico sulla Spagna: il primo maturato in seno all’Amministrazione Roosevelt, il secondo elaborato dalla componente Liberal della coalizione del New Deal attraverso i settimanali, “The Nation” e “The New Republic”. Il confronto pubblico acceso dalla guerra civile spagnola fu infatti l’occasione per la società civile americana per dibattere apertamente e francamente circa l’opportunità e la capacità della nazione di assumere o meno un ruolo internazionale corrispondente al prestigio socio-economico in via di acquisizione a livello mondiale. Approfondire ed esaminare il dibattito sulla guerra civile spagnola negli USA significa dunque andare alla ricerca delle radici culturali di quello che sarà uno dei più vasti ed articolati confronti politici e teorici del ventesimo secolo: l’internazionalismo americano.

The Next 10 years in the Management of Peripheral Artery Disease: Perspectives from The 'PAD 2009' Conference

OBJECTIVES: To briefly inform on the conclusions from a conference on the next 10 years in the management of peripheral artery disease (PAD). DESIGN OF THE CONFERENCE: International participation, invited presentations and open discussion were based on the following issues: Why is PAD under-recognised? Health economic impact of PAD; funding of PAD research; changes of treatment options? Aspects on clinical trials and regulatory views; and the role of guidelines. RESULTS AND CONCLUSIONS: A relative lack of knowledge about cardiovascular risk and optimal management of PAD patients exists not only among the public, but also in parts of the health-care system. Specialists are required to act for improved information. More specific PAD research is needed for risk management and to apply the best possible evaluation of evidence for treatment strategies. Better strategies for funding are required based on, for example, public/private initiatives. The proportion of endovascular treatments is steadily increasing, more frequently based on observational studies than on randomised controlled trials. The role of guidelines is therefore important to guide the profession in the assessment of most relevant treatment.

Biomechanical model of tumor growth: application to the European ContraCancrum project

This abstract presents the biomechanical model that is used in the European ContraCancrum project, aiming at simulating tumor evolution in the brain and lung. The construction of the finite element model as well as a simulation of tumor growth are shown. The construction of the mesh is fully automatic and is therefore compatible with a clinical application. This biomechanical model will be later combined to a cellular level simulator also developed in the project.

Numerical model of the human cornea based on stromal microstructure: identification of mechanical properties for two age groups

The optical quality of the human eye mainly depends on the refractive performance of the cornea. The shape of the cornea is a mechanical balance between intraocular pressure and tissue intrinsic stiffness. Several surgical procedures in ophthalmology alter the biomechanics of the cornea to provoke local or global curvature changes for vision correction. Legitimated by the large number of surgical interventions performed every day, the demand for a deeper understanding of corneal biomechanics is rising to improve the safety of procedures and medical devices. The aim of our work is to propose a numerical model of corneal biomechanics, based on the stromal microstructure. Our novel anisotropic constitutive material law features a probabilistic weighting approach to model collagen fiber distribution as observed on human cornea by Xray scattering analysis (Aghamohammadzadeh et. al., Structure, February 2004). Furthermore, collagen cross-linking was explicitly included in the strain energy function. Results showed that the proposed model is able to successfully reproduce both inflation and extensiometry experimental data (Elsheikh et. al., Curr Eye Res, 2007; Elsheikh et. al., Exp Eye Res, May 2008). In addition, the mechanical properties calculated for patients of different age groups (Group A: 65-79 years; Group B: 80-95 years) demonstrate an increased collagen cross-linking, and a decrease in collagen fiber elasticity from younger to older specimen. These findings correspond to what is known about maturing fibrous biological tissue. Since the presented model can handle different loading situations and includes the anisotropic distribution of collagen fibers, it has the potential to simulate clinical procedures involving nonsymmetrical tissue interventions. In the future, such mechanical model can be used to improve surgical planning and the design of next generation ophthalmic devices.