In silico pathway reconstruction: Iron-sulfur cluster biogenesis in Saccharomyces cerevisiae

Background: Current advances in genomics, proteomics and other areas of molecular biology make the identification and reconstruction of novel pathways an emerging area of great interest. One such class of pathways is involved in the biogenesis of Iron-Sulfur Clusters (ISC). Results: Our goal is the development of a new approach based on the use and combination of mathematical, theoretical and computational methods to identify the topology of a target network. In this approach, mathematical models play a central role for the evaluation of the alternative network structures that arise from literature data-mining, phylogenetic profiling, structural methods, and human curation. As a test case, we reconstruct the topology of the reaction and regulatory network for the mitochondrial ISC biogenesis pathway in S. cerevisiae. Predictions regarding how proteins act in ISC biogenesis are validated by comparison with published experimental results. For example, the predicted role of Arh1 and Yah1 and some of the interactions we predict for Grx5 both matches experimental evidence. A putative role for frataxin in directly regulating mitochondrial iron import is discarded from our analysis, which agrees with also published experimental results. Additionally, we propose a number of experiments for testing other predictions and further improve the identification of the network structure. Conclusion: We propose and apply an iterative in silico procedure for predictive reconstruction of the network topology of metabolic pathways. The procedure combines structural bioinformatics tools and mathematical modeling techniques that allow the reconstruction of biochemical networks. Using the Iron Sulfur cluster biogenesis in S. cerevisiae as a test case we indicate how this procedure can be used to analyze and validate the network model against experimental results. Critical evaluation of the obtained results through this procedure allows devising new wet lab experiments to confirm its predictions or provide alternative explanations for further improving the models.

Teaching fundamentals of computing theory: a constructivist approach

A Fundamentals of Computing Theory course involves different topics that are core to the Computer Science curricula and whose level of abstraction makes them difficult both to teach and to learn. Such difficulty stems from the complexity of the abstract notions involved and the required mathematical background. Surveys conducted among our students showed that many of them were applying some theoretical concepts mechanically rather than developing significant learning. This paper shows a number of didactic strategies that we introduced in the Fundamentals of Computing Theory curricula to cope with the above problem. The proposed strategies were based on a stronger use of technology and a constructivist approach. The final goal was to promote more significant learning of the course topics.

Zim17/Tim15 links mitochondrial iron–sulfur cluster biosynthesis to nuclear genome stability

Genomic instability is related to a wide-range of human diseases. Here, we show that mitochondrial iron–sulfur cluster biosynthesis is important for the maintenance of nuclear genome stability in Saccharomyces cerevisiae. Cells lacking the mitochondrial chaperone Zim17 (Tim15/Hep1), a component of the iron–sulfur biosynthesis machinery, have limited respiration activity, mimic the metabolic response to iron starvation and suffer a dramatic increase in nuclear genome recombination. Increased oxidative damage or deficient DNA repair do not account for the observed genomic hyperrecombination. Impaired cell-cycle progression and genetic interactions of ZIM17 with components of the RFC-like complex involved in mitotic checkpoints indicate that replicative stress causes hyperrecombination in zim17Δ mutants. Furthermore, nuclear accumulation of pre-ribosomal particles in zim17Δ mutants reinforces the importance of iron–sulfur clusters in normal ribosome biosynthesis. We propose that compromised ribosome biosynthesis and cell-cycle progression are interconnected, together contributing to replicative stress and nuclear genome instability in zim17Δ mutants.

Acute schistosomiasis: a risk underestimated by travelers and a diagnosis frequently missed by general practitioners-a cluster analysis of 42 travelers.

BACKGROUND: In 2011, a patient was admitted to our hospital with acute schistosomiasis after having returned from Madagascar and having bathed at the Lily waterfalls. On the basis of this patient's indication, infection was suspected in 41 other subjects. This study investigated (1) the knowledge of the travelers about the risks of schistosomiasis and their related behavior to evaluate the appropriateness of prevention messages and (2) the diagnostic workup of symptomatic travelers by general practitioners to evaluate medical care of travelers with a history of freshwater exposure in tropical areas. METHODS: A questionnaire was sent to the 42 travelers with potential exposure to schistosomiasis. It focused on pre-travel knowledge of the disease, bathing conditions, clinical presentation, first suspected diagnosis, and treatment. RESULTS: Of the 42 questionnaires, 40 (95%) were returned, among which 37 travelers (92%) reported an exposure to freshwater, and 18 (45%) were aware of the risk of schistosomiasis. Among these latter subjects, 16 (89%) still reported an exposure to freshwater. Serology was positive in 28 (78%) of 36 exposed subjects at least 3 months after exposure. Of the 28 infected travelers, 23 (82%) exhibited symptoms and 16 (70%) consulted their general practitioner before the information about the outbreak had spread, but none of these patients had a serology for schistosomiasis done during the first consultation. CONCLUSIONS: The usual prevention message of avoiding freshwater contact when traveling in tropical regions had no impact on the behavior of these travelers, who still went swimming at the Lily waterfalls. This prevention message should, therefore, be either modified or abandoned. The clinical presentation of acute schistosomiasis is often misleading. General practitioners should at least request an eosinophil count, when confronted with a returning traveler with fever. If eosinophilia is detected, it should prompt the search for a parasitic disease.

Evolution and cellular function of monothiol glutaredoxins: involvement in iron-sulphur cluster assembly

A number of bacterial species, mostly proteobacteria, possess monothiol glutaredoxins homologous to the Saccharomyces cerevisiae mitochondrial protein Grx5, which is involved in iron–sulphur cluster synthesis. Phylogenetic profiling is used to predict that bacterial monothiol glutaredoxins also participate in the iron–sulphur cluster (ISC) assembly machinery, because their phylogenetic profiles are similar to the profiles of the bacterial homologues of yeast ISC proteins. High evolutionary cooccurrence is observed between the Grx5 homologues and the homologues of the Yah1 ferredoxin, the scaffold proteins Isa1 and Isa2, the frataxin protein Yfh1 and the Nfu1 protein. This suggests that a specific functional interaction exists between these ISC machinery proteins. Physical interaction analyses using low-definition protein docking predict the formation of strong and specific complexes between Grx5 and several components of the yeast ISC machinery. Two-hybrid analysis has confirmed the in vivo interaction between Grx5 and Isa1. Sequence comparison techniques and cladistics indicate that the other two monothiol glutaredoxins of S. cerevisiae, Grx3 and Grx4, have evolved from the fusion of a thioredoxin gene with a monothiol glutaredoxin gene early in the eukaryotic lineage, leading to differential functional specialization. While bacteria do not contain these chimaeric glutaredoxins, in many eukaryotic species Grx5 and Grx3/4-type monothiol glutaredoxins coexist in the cell.

Subtypes of adolescents with substance use disorders and psychiatric comorbidity using cluster and discriminant analysis of MMPI-A profiles

The main aim of this study was to replicate and extend previous results on subtypes of adolescents with substance use disorders (SUD), according to their Minnesota Multiphasic Personality Inventory for adolescents (MMPI-A) profiles. Sixty patients with SUD and psychiatric comorbidity (41.7% male, mean age = 15.9 years old) completed the MMPI-A, the Teen Addiction Severity Index (T-ASI), the Child Behaviour Checklist (CBCL), and were interviewed in order to determine DSMIV diagnoses and level of substance use. Mean MMPI-A personality profile showed moderate peaks in Psychopathic Deviate, Depression and Hysteria scales. Hierarchical cluster analysis revealed four profiles (acting-out, 35% of the sample; disorganized-conflictive, 15%; normative-impulsive, 15%; and deceptive-concealed, 35%). External correlates were found between cluster 1, CBCL externalizing symptoms at a clinical level and conduct disorders, and between cluster 2 and mixed CBCL internalized/externalized symptoms at a clinical level. Discriminant analysis showed that Depression, Psychopathic Deviate and Psychasthenia MMPI-A scales correctly classified 90% of the patients into the clusters obtained.

Competitive Analysis of the Northwest Russian Transport Logistics Cluster – Finnish Perspective

Tutkimus tarkastelee Luoteis-Venäjän liikennelogistiikkaklusteria. Tarkoitus on selvittää klusterin nykyinen rakenne ja kilpailukyky sekä klusterin tarjoamat liiketoimintamahdollisuudet suomalaisille logistiikkayrityksille. Työssä käsitellään neljää perusliikennemuotoa: rautatie-, maantie-, meri- ja sisävesi-, sekä ilmaliikennettä. Tutkimuksen aineisto on kerätty tutkimusta varten laadituista kyselyistä, haastatteluista sekä aiemmin julkaistusta materiaalista. Venäjä on suunnitellut kehittävänsä voimakkaasti liikenneinfrastruktuuria, mm. julkaisemalla protektionistisen liikennestrategiasuunnitelman. Ongelmana ovat olleet toteutukset, jotka ovat jääneet yleensä puutteellisiksi. Tällä hetkellä todellista kilpailukykyä löytyy ainoastaan rautatieliikenteestä, muut kolme liikennemuotoa omaavat potentiaalisen kilpailukyvyn. Venäjällä on mahdollisuus hyötyä laajasta pinta-alastaan Aasian ja Euroopan liikenteen yhdistäjänä. Yksi konkreettisimmista esimerkeistä on Trans Siperian rautatie, joka kaipaisi vielä lisäkehitystä. Suomi on toiminut Venäjän liikenteessä arvotavaran kauttakulkumaana, vuonna 2003 noin 30–40 % Venäjän tuonnin arvosta kulki Suomen kautta. Venäjälle tullaan tuomaan arvotavaraa vielä useita vuosia, mutta reittien osalta kilpailu on tiukentunut. Suomalaisten yritysten liiketoimintamahdollisuuksiin esitetään kaksi mallia: kauttakulkuliikenteen lisäarvologistiset (VAL) operaatiot Suomessa tai etabloituminen Venäjän logistisiin ketjuihin. Suomalaisten olisi syytä parantaa yhteistyötään yritysten ja yliopistojen ym. koulutuslaitosten välillä. Myös yhteistyökumppaneiden hakeminen esimerkiksi Ruotsista voisi tuoda merkittäviä etuja. Suomalaista osaamista voitaisiin hyödyntää parhaiten etabloitumalla Venäjän markkinoille, esimerkiksi keskittymällä Venäjän logististen ketjujen johtamiseen. Myös VAL palveluiden johtamiseen Venäjällä olisi erittäin hyvä tilaisuus, koska Venäjän oma tietotaito logistiikassa ei ole vielä kehittynyt kansainväliselle tasolle, mutta kustannustaso on alhaisempi kuin Suomessa.

Soft Computing Methods in Metallurgy

In metallurgic plants a high quality metal production is always required. Nowadays soft computing applications are more often used for automation of manufacturing process and quality control instead of mechanical techniques. In this thesis an overview of soft computing methods presents. As an example of soft computing application, an effective model of fuzzy expert system for the automotive quality control of steel degassing process was developed. The purpose of this work is to describe the fuzzy relations as quality hypersurfaces by varying number of linguistic variables and fuzzy sets.

Evolutionary computing in search-based software engineering

This master’s thesis aims to study and represent from literature how evolutionary algorithms are used to solve different search and optimisation problems in the area of software engineering. Evolutionary algorithms are methods, which imitate the natural evolution process. An artificial evolution process evaluates fitness of each individual, which are solution candidates. The next population of candidate solutions is formed by using the good properties of the current population by applying different mutation and crossover operations. Different kinds of evolutionary algorithm applications related to software engineering were searched in the literature. Applications were classified and represented. Also the necessary basics about evolutionary algorithms were presented. It was concluded, that majority of evolutionary algorithm applications related to software engineering were about software design or testing. For example, there were applications about classifying software production data, project scheduling, static task scheduling related to parallel computing, allocating modules to subsystems, N-version programming, test data generation and generating an integration test order. Many applications were experimental testing rather than ready for real production use. There were also some Computer Aided Software Engineering tools based on evolutionary algorithms.

Use of scenario analysis in studying emerging technology – Case Grid computing

Tutkimuksen selvitettiin miten skenaarioanalyysia voidaan käyttää uuden teknologian tutkimisessa. Työssä havaittiin, että skenaarioanalyysin soveltuvuuteen vaikuttaa eniten teknologisen muutoksen taso ja saatavilla olevan tiedon luonne. Skenaariomenetelmä soveltuu hyvin uusien teknologioiden tutkimukseen erityisesti radikaalien innovaatioiden kohdalla. Syynä tähän on niihin liittyvä suuri epävarmuus, kompleksisuus ja vallitsevan paradigman muuttuminen, joiden takia useat muut tulevaisuuden tutkimuksen menetelmät eivät ole tilanteessa käyttökelpoisia. Työn empiirisessä osiossa tutkittiin hilaverkkoteknologian tulevaisuutta skenaarioanalyysin avulla. Hilaverkot nähtiin mahdollisena disruptiivisena teknologiana, joka radikaalina innovaationa saattaa muuttaa tietokonelaskennan nykyisestä tuotepohjaisesta laskentakapasiteetin ostamisesta palvelupohjaiseksi. Tällä olisi suuri vaikutus koko nykyiseen ICT-toimialaan erityisesti tarvelaskennan hyödyntämisen ansiosta. Tutkimus tarkasteli kehitystä vuoteen 2010 asti. Teorian ja olemassa olevan tiedon perusteella muodostettiin vahvaan asiantuntijatietouteen nojautuen neljä mahdollista ympäristöskenaariota hilaverkoille. Skenaarioista huomattiin, että teknologian kaupallinen menestys on vielä monen haasteen takana. Erityisesti luottamus ja lisäarvon synnyttäminen nousivat tärkeimmiksi hilaverkkojen tulevaisuutta ohjaaviksi tekijöiksi.

Cluster glasses of ultrasoft particles

We present molecular dynamics (MD) simulations results for dense fluids of ultrasoft, fully penetrable particles. These are a binary mixture and a polydisperse system of particles interacting via the generalized exponential model, which is known to yield cluster crystal phases for the corresponding monodisperse systems. Because of the dispersity in the particle size, the systems investigated in this work do not crystallize and form disordered cluster phases. The clusteringtransition appears as a smooth crossover to a regime in which particles are mostly located in clusters, isolated particles being infrequent. The analysis of the internal cluster structure reveals microsegregation of the big and small particles, with a strong homo-coordination in the binary mixture. Upon further lowering the temperature below the clusteringtransition, the motion of the clusters" centers-of-mass slows down dramatically, giving way to a cluster glass transition. In the cluster glass, the diffusivities remain finite and display an activated temperature dependence, indicating that relaxation in the cluster glass occurs via particle hopping in a nearly arrested matrix of clusters. Finally we discuss the influence of the microscopic dynamics on the transport properties by comparing the MD results with Monte Carlo simulations.

Trust region versus line search for computing the optical flow

We consider the numerical treatment of the optical flow problem by evaluating the performance of the trust region method versus the line search method. To the best of our knowledge, the trust region method is studied here for the first time for variational optical flow computation. Four different optical flow models are used to test the performance of the proposed algorithm combining linear and nonlinear data terms with quadratic and TV regularization. We show that trust region often performs better than line search; especially in the presence of non-linearity and non-convexity in the model.