Longitudinal familial analysis of blood pressure involving parametric (co)variance functions

Abstract Background For analyzing longitudinal familial data we adopted a log-linear form to incorporate heterogeneity in genetic variance components over the time, and additionally a serial correlation term in the genetic effects at different levels of ages. Due to the availability of multiple measures on the same individual, we permitted environmental correlations that may change across time. Results Systolic blood pressure from family members from the first and second cohort was used in the current analysis. Measures of subjects receiving hypertension treatment were set as censored values and they were corrected. An initial check of the variance and covariance functions proposed for analyzing longitudinal familial data, using empirical semi-variogram plots, indicated that the observed trait dispersion pattern follows the assumptions adopted. Conclusion The corrections for censored phenotypes based on ordinary linear models may be an appropriate simple model to correct the data, ensuring that the original variability in the data was retained. In addition, empirical semi-variogram plots are useful for diagnosis of the (co)variance model adopted.

A quantitative view of the transcriptome of Schistosoma mansoni adult-worms using SAGE

Abstract Background Five species of the genus Schistosoma, a parasitic trematode flatworm, are causative agents of Schistosomiasis, a disease that is endemic in a large number of developing countries, affecting millions of patients around the world. By using SAGE (Serial Analysis of Gene Expression) we describe here the first large-scale quantitative analysis of the Schistosoma mansoni transcriptome, one of the most epidemiologically relevant species of this genus. Results After extracting mRNA from pooled male and female adult-worms, a SAGE library was constructed and sequenced, generating 68,238 tags that covered more than 6,000 genes expressed in this developmental stage. An analysis of the ordered tag-list shows the genes of F10 eggshell protein, pol-polyprotein, HSP86, 14-3-3 and a transcript yet to be identified to be the five top most abundant genes in pooled adult worms. Whereas only 8% of the 100 most abundant tags found in adult worms of S. mansoni could not be assigned to transcripts of this parasite, 46.9% of the total ditags could not be mapped, demonstrating that the 3 sequence of most of the rarest transcripts are still to be identified. Mapping of our SAGE tags to S. mansoni genes suggested the occurrence of alternative-polyadenylation in at least 13 gene transcripts. Most of these events seem to shorten the 3 UTR of the mRNAs, which may have consequences over their stability and regulation. Conclusion SAGE revealed the frequency of expression of the majority of the S. mansoni genes. Transcriptome data suggests that alternative polyadenylation is likely to be used in the control of mRNA stability in this organism. When transcriptome was compared with the proteomic data available, we observed a correlation of about 50%, suggesting that both transcriptional and post-transcriptional regulation are important for determining protein abundance in S. mansoni. The generation of SAGE tags from other life-cycle stages should contribute to reveal the dynamics of gene expression in this important parasite.

Gene by environment QTL mapping through multiple trait analyses in blood pressure salt-sensitivity: identification of a novel QTL in rat chromosome 5

Background The genetic mechanisms underlying interindividual blood pressure variation reflect the complex interplay of both genetic and environmental variables. The current standard statistical methods for detecting genes involved in the regulation mechanisms of complex traits are based on univariate analysis. Few studies have focused on the search for and understanding of quantitative trait loci responsible for gene × environmental interactions or multiple trait analysis. Composite interval mapping has been extended to multiple traits and may be an interesting approach to such a problem. Methods We used multiple-trait analysis for quantitative trait locus mapping of loci having different effects on systolic blood pressure with NaCl exposure. Animals studied were 188 rats, the progenies of an F2 rat intercross between the hypertensive and normotensive strain, genotyped in 179 polymorphic markers across the rat genome. To accommodate the correlational structure from measurements taken in the same animals, we applied univariate and multivariate strategies for analyzing the data. Results We detected a new quantitative train locus on a region close to marker R589 in chromosome 5 of the rat genome, not previously identified through serial analysis of individual traits. In addition, we were able to justify analytically the parametric restrictions in terms of regression coefficients responsible for the gain in precision with the adopted analytical approach. Conclusion Future work should focus on fine mapping and the identification of the causative variant responsible for this quantitative trait locus signal. The multivariable strategy might be valuable in the study of genetic determinants of interindividual variation of antihypertensive drug effectiveness.

SLCO1B1 rs4149056 polymorphism associated with statin-induced myopathy is differently distributed according to ethnicity in the Brazilian general population: Amerindians as a high risk ethnic group

Background Recent studies reported the association between SLCO1B1 polymorphisms and the development of statin-induced myopathy. In the scenario of the Brazilian population, being one of the most heterogeneous in the world, the main aim here was to evaluate SLCO1B1 polymorphisms according to ethnic groups as an initial step for future pharmacogenetic studies. Methods One hundred and eighty-two Amerindians plus 1,032 subjects from the general urban population were included. Genotypes for the SLCO1B1 rs4149056 (c.T521C, p.V174A, exon 5) and SLCO1B1 rs4363657 (g.T89595C, intron 11) polymorphisms were detected by polymerase chain reaction followed by high resolution melting analysis with the Rotor Gene 6000® instrument. Results The frequencies of the SLCO1B1 rs4149056 and rs4363657 C variant allele were higher in Amerindians (28.3% and 26.1%) and were lower in African descent subjects (5.7% and 10.8%) compared with Mulatto (14.9% and 18.2%) and Caucasian descent (14.8% and 15.4%) ethnic groups (p < 0.001 and p < 0.001, respectively). Linkage disequilibrium analysis show that these variant alleles are in different linkage disequilibrium patterns depending on the ethnic origin. Conclusion Our findings indicate interethnic differences for the SLCO1B1 rs4149056 C risk allele frequency among Brazilians. These data will be useful in the development of effective programs for stratifying individuals regarding adherence, efficacy and choice of statin-type.

Denominal Verbs in Brazilian Portuguese: distinguishing between diachronic and synchronic structures within Distributed Morphology approach

Recent work on argument structure has shown that there must be a synchronic relation between nouns and derived verbs that can be treated in structural terms. However, a simple phonological/morphological identity or diachronic derivation between a verb and a noun cannot guarantee that there is a denominal structure in a synchronic approach. In this paper we observe the phenomenon of Denominal Verbs in Brazilian Portuguese and argue for a distinction between etymological and synchronic morphological derivation. The objectives of this paper are 1) to identify synchronic and formal criteria to define which diachronic Denominal Verbs can also be considered denominal under a synchronic analysis; and 2) to detect in which cases the label "denominal" can be justifiably abandoned. Based on results of argument structure tests submitted to the judgments of native speakers, it was possible to classify the supposed homogenous Denominal Verbs class into three major groups: Real Denominal Verbs, Root-derived Verbs, and Ambiguous Verbs. In a Distributed Morphology approach, it was possible to explain the distinction between these groups based on the ideia of phases in words and the locality of restriction in the interpretation of roots.

Development and characterization of a distributed measurement system for the evaluation of voltage quality in electric power networks

The research activity carried out during the PhD course in Electrical Engineering belongs to the branch of electric and electronic measurements. The main subject of the present thesis is a distributed measurement system to be installed in Medium Voltage power networks, as well as the method developed to analyze data acquired by the measurement system itself and to monitor power quality. In chapter 2 the increasing interest towards power quality in electrical systems is illustrated, by reporting the international research activity inherent to the problem and the relevant standards and guidelines emitted. The aspect of the quality of voltage provided by utilities and influenced by customers in the various points of a network came out only in recent years, in particular as a consequence of the energy market liberalization. Usually, the concept of quality of the delivered energy has been associated mostly to its continuity. Hence the reliability was the main characteristic to be ensured for power systems. Nowadays, the number and duration of interruptions are the “quality indicators” commonly perceived by most customers; for this reason, a short section is dedicated also to network reliability and its regulation. In this contest it should be noted that although the measurement system developed during the research activity belongs to the field of power quality evaluation systems, the information registered in real time by its remote stations can be used to improve the system reliability too. Given the vast scenario of power quality degrading phenomena that usually can occur in distribution networks, the study has been focused on electromagnetic transients affecting line voltages. The outcome of such a study has been the design and realization of a distributed measurement system which continuously monitor the phase signals in different points of a network, detect the occurrence of transients superposed to the fundamental steady state component and register the time of occurrence of such events. The data set is finally used to locate the source of the transient disturbance propagating along the network lines. Most of the oscillatory transients affecting line voltages are due to faults occurring in any point of the distribution system and have to be seen before protection equipment intervention. An important conclusion is that the method can improve the monitored network reliability, since the knowledge of the location of a fault allows the energy manager to reduce as much as possible both the area of the network to be disconnected for protection purposes and the time spent by technical staff to recover the abnormal condition and/or the damage. The part of the thesis presenting the results of such a study and activity is structured as follows: chapter 3 deals with the propagation of electromagnetic transients in power systems by defining characteristics and causes of the phenomena and briefly reporting the theory and approaches used to study transients propagation. Then the state of the art concerning methods to detect and locate faults in distribution networks is presented. Finally the attention is paid on the particular technique adopted for the same purpose during the thesis, and the methods developed on the basis of such approach. Chapter 4 reports the configuration of the distribution networks on which the fault location method has been applied by means of simulations as well as the results obtained case by case. In this way the performance featured by the location procedure firstly in ideal then in realistic operating conditions are tested. In chapter 5 the measurement system designed to implement the transients detection and fault location method is presented. The hardware belonging to the measurement chain of every acquisition channel in remote stations is described. Then, the global measurement system is characterized by considering the non ideal aspects of each device that can concur to the final combined uncertainty on the estimated position of the fault in the network under test. Finally, such parameter is computed according to the Guide to the Expression of Uncertainty in Measurements, by means of a numeric procedure. In the last chapter a device is described that has been designed and realized during the PhD activity aiming at substituting the commercial capacitive voltage divider belonging to the conditioning block of the measurement chain. Such a study has been carried out aiming at providing an alternative to the used transducer that could feature equivalent performance and lower cost. In this way, the economical impact of the investment associated to the whole measurement system would be significantly reduced, making the method application much more feasible.

Cooperative communication and distributed detection in wireless sensor networks

Recent progress in microelectronic and wireless communications have enabled the development of low cost, low power, multifunctional sensors, which has allowed the birth of new type of networks named wireless sensor networks (WSNs). The main features of such networks are: the nodes can be positioned randomly over a given field with a high density; each node operates both like sensor (for collection of environmental data) as well as transceiver (for transmission of information to the data retrieval); the nodes have limited energy resources. The use of wireless communications and the small size of nodes, make this type of networks suitable for a large number of applications. For example, sensor nodes can be used to monitor a high risk region, as near a volcano; in a hospital they could be used to monitor physical conditions of patients. For each of these possible application scenarios, it is necessary to guarantee a trade-off between energy consumptions and communication reliability. The thesis investigates the use of WSNs in two possible scenarios and for each of them suggests a solution that permits to solve relating problems considering the trade-off introduced. The first scenario considers a network with a high number of nodes deployed in a given geographical area without detailed planning that have to transmit data toward a coordinator node, named sink, that we assume to be located onboard an unmanned aerial vehicle (UAV). This is a practical example of reachback communication, characterized by the high density of nodes that have to transmit data reliably and efficiently towards a far receiver. It is considered that each node transmits a common shared message directly to the receiver onboard the UAV whenever it receives a broadcast message (triggered for example by the vehicle). We assume that the communication channels between the local nodes and the receiver are subject to fading and noise. The receiver onboard the UAV must be able to fuse the weak and noisy signals in a coherent way to receive the data reliably. It is proposed a cooperative diversity concept as an effective solution to the reachback problem. In particular, it is considered a spread spectrum (SS) transmission scheme in conjunction with a fusion center that can exploit cooperative diversity, without requiring stringent synchronization between nodes. The idea consists of simultaneous transmission of the common message among the nodes and a Rake reception at the fusion center. The proposed solution is mainly motivated by two goals: the necessity to have simple nodes (to this aim we move the computational complexity to the receiver onboard the UAV), and the importance to guarantee high levels of energy efficiency of the network, thus increasing the network lifetime. The proposed scheme is analyzed in order to better understand the effectiveness of the approach presented. The performance metrics considered are both the theoretical limit on the maximum amount of data that can be collected by the receiver, as well as the error probability with a given modulation scheme. Since we deal with a WSN, both of these performance are evaluated taking into consideration the energy efficiency of the network. The second scenario considers the use of a chain network for the detection of fires by using nodes that have a double function of sensors and routers. The first one is relative to the monitoring of a temperature parameter that allows to take a local binary decision of target (fire) absent/present. The second one considers that each node receives a decision made by the previous node of the chain, compares this with that deriving by the observation of the phenomenon, and transmits the final result to the next node. The chain ends at the sink node that transmits the received decision to the user. In this network the goals are to limit throughput in each sensor-to-sensor link and minimize probability of error at the last stage of the chain. This is a typical scenario of distributed detection. To obtain good performance it is necessary to define some fusion rules for each node to summarize local observations and decisions of the previous nodes, to get a final decision that it is transmitted to the next node. WSNs have been studied also under a practical point of view, describing both the main characteristics of IEEE802:15:4 standard and two commercial WSN platforms. By using a commercial WSN platform it is realized an agricultural application that has been tested in a six months on-field experimentation.

Topological analysis of singularity loci for serial and parallel manipulators

Singularities of robot manipulators have been intensely studied in the last decades by researchers of many fields. Serial singularities produce some local loss of dexterity of the manipulator, therefore it might be desirable to search for singularityfree trajectories in the jointspace. On the other hand, parallel singularities are very dangerous for parallel manipulators, for they may provoke the local loss of platform control, and jeopardize the structural integrity of links or actuators. It is therefore utterly important to avoid parallel singularities, while operating a parallel machine. Furthermore, there might be some configurations of a parallel manipulators that are allowed by the constraints, but nevertheless are unreachable by any feasible path. The present work proposes a numerical procedure based upon Morse theory, an important branch of differential topology. Such procedure counts and identify the singularity-free regions that are cut by the singularity locus out of the configuration space, and the disjoint regions composing the configuration space of a parallel manipulator. Moreover, given any two configurations of a manipulator, a feasible or a singularity-free path connecting them can always be found, or it can be proved that none exists. Examples of applications to 3R and 6R serial manipulators, to 3UPS and 3UPU parallel wrists, to 3UPU parallel translational manipulators, and to 3RRR planar manipulators are reported in the work.

Large-scale Network Analysis on Distributed Architectures

Questa dissertazione esamina le sfide e i limiti che gli algoritmi di analisi di grafi incontrano in architetture distribuite costituite da personal computer. In particolare, analizza il comportamento dell'algoritmo del PageRank così come implementato in una popolare libreria C++ di analisi di grafi distribuiti, la Parallel Boost Graph Library (Parallel BGL). I risultati qui presentati mostrano che il modello di programmazione parallela Bulk Synchronous Parallel è inadatto all'implementazione efficiente del PageRank su cluster costituiti da personal computer. L'implementazione analizzata ha infatti evidenziato una scalabilità negativa, il tempo di esecuzione dell'algoritmo aumenta linearmente in funzione del numero di processori. Questi risultati sono stati ottenuti lanciando l'algoritmo del PageRank della Parallel BGL su un cluster di 43 PC dual-core con 2GB di RAM l'uno, usando diversi grafi scelti in modo da facilitare l'identificazione delle variabili che influenzano la scalabilità. Grafi rappresentanti modelli diversi hanno dato risultati differenti, mostrando che c'è una relazione tra il coefficiente di clustering e l'inclinazione della retta che rappresenta il tempo in funzione del numero di processori. Ad esempio, i grafi Erdős–Rényi, aventi un basso coefficiente di clustering, hanno rappresentato il caso peggiore nei test del PageRank, mentre i grafi Small-World, aventi un alto coefficiente di clustering, hanno rappresentato il caso migliore. Anche le dimensioni del grafo hanno mostrato un'influenza sul tempo di esecuzione particolarmente interessante. Infatti, si è mostrato che la relazione tra il numero di nodi e il numero di archi determina il tempo totale.

Creative process in globally distributed teams: a study of new product development in Volvo

With the business environments no longer confined to geographical borders, the new wave of digital technologies has given organizations an enormous opportunity to bring together their distributed workforce and develop the ability to work together despite being apart (Prasad & Akhilesh, 2002). resupposing creativity to be a social process, the way that this phenomenon occurs when the configuration of the team is substantially modified will be questioned. Very little is known about the impact of interpersonal relationships in the creativity (Kurtzberg & Amabile, 2001). In order to analyse the ways in which the creative process may be developed, we ought to be taken into consideration the fact that participants are dealing with a quite an atypical situation. Firstly, in these cases socialization takes place amongst individuals belonging to a geographically dispersed workplace, where interpersonal relationships are mediated by the computer, and where trust must be developed among persons who have never met one another. Participants not only have multiple addresses and locations, but above all different nationalities, and different cultures, attitudes, thoughts, and working patterns, and languages. Therefore, the central research question of this thesis is as follows: “How does the creative process unfold in globally distributed teams?” With a qualitative approach, we used the case study of the Business Unit of Volvo 3P, an arm of Volvo Group. Throughout this research, we interviewed seven teams engaged in the development of a new product in the chassis and cab areas, for the brands Volvo and Renault Trucks, teams that were geographically distributed in Brazil, Sweden, France and India. Our research suggests that corporate values, alongside with intrinsic motivation and task which lay down the necessary foundations for the development of the creative process in GDT.

Reverse genetic studies of Benyvirus - Polymyxa betae molecular interaction: Role of the RNA4-encoded protein in virus transmission

Beet necrotic yellow vein virus (BNYVV), the leading infectious agent that affects sugar beet, is included within viruses transmitted through the soil from plasmodiophorid as Polymyxa betae. BNYVV is the causal agent of Rhizomania, which induces abnormal rootlet proliferation and is widespread in the sugar beet growing areas in Europe, Asia and America; for review see (Peltier et al., 2008). In this latter continent, Beet soil-borne mosaic virus (BSBMV) has been identified (Lee et al., 2001) and belongs to the benyvirus genus together with BNYVV, both vectored by P. betae. BSBMV is widely distributed only in the United States and it has not been reported yet in others countries. It was first identified in Texas as a sugar beet virus morphologically similar but serologically distinct to BNYVV. Subsequent sequence analysis of BSBMV RNAs evidenced similar genomic organization to that of BNYVV but sufficient molecular differences to distinct BSBMV and BNYVV in two different species (Rush et al., 2003). Benyviruses field isolates usually consist of four RNA species but some BNYVV isolates contain a fifth RNA. RNAs -1 contains a single long ORF encoding polypeptide that shares amino acid homology with known viral RNA-dependent RNA polymerases (RdRp) and helicases. RNAs -2 contains six ORFs: capsid protein (CP), one readthrough protein, triple gene block proteins (TGB) that are required for cell-to-cell virus movement and the sixth 14 kDa ORF is a post-translation gene silencing suppressor. RNAs -3 is involved on disease symptoms and is essential for virus systemic movement. BSBMV RNA-3 can be trans-replicated, trans-encapsidated by the BNYVV helper strain (RNA-1 and -2) (Ratti et al., 2009). BNYVV RNA-4 encoded one 31 kDa protein and is essential for vector interactions and virus transmission by P. betae (Rahim et al., 2007). BNYVV RNA-5 encoded 26 kDa protein that improve virus infections and accumulation in the hosts. We are interest on BSBMV effect on Rhizomania studies using powerful tools as full-length infectious cDNA clones. B-type full-length infectious cDNA clones are available (Quillet et al., 1989) as well as A/P-type RNA-3, -4 and -5 from BNYVV (unpublished). A-type BNYVV full-length clones are also available, but RNA-1 cDNA clone still need to be modified. During the PhD program, we start production of BSBMV full-length cDNA clones and we investigate molecular interactions between plant and Benyviruses exploiting biological, epidemiological and molecular similarities/divergences between BSBMV and BNYVV. During my PhD researchrs we obtained full length infectious cDNA clones of BSBMV RNA-1 and -2 and we demonstrate that they transcripts are replicated and packaged in planta and able to substitute BNYVV RNA-1 or RNA-2 in a chimeric viral progeny (BSBMV RNA-1 + BNYVV RNA-2 or BNYVV RNA-1 + BSBMV RNA-2). During BSBMV full-length cDNA clones production, unexpected 1,730 nts long form of BSBMV RNA-4 has been detected from sugar beet roots grown on BSBMV infected soil. Sequence analysis of the new BSBMV RNA-4 form revealed high identity (~100%) with published version of BSBMV RNA-4 sequence (NC_003508) between nucleotides 1-608 and 1,138-1,730, however the new form shows 528 additionally nucleotides between positions 608-1,138 (FJ424610). Two putative ORFs has been identified, the first one (nucleotides 383 to 1,234), encode a protein with predicted mass of 32 kDa (p32) and the second one (nucleotides 885 to 1,244) express an expected product of 13 kDa (p13). As for BSBMV RNA-3 (Ratti et al., 2009), full-length BSBMV RNA-4 cDNA clone permitted to obtain infectious transcripts that BNYVV viral machinery (Stras12) is able to replicate and to encapsidate in planta. Moreover, we demonstrated that BSBMV RNA-4 can substitute BNYVV RNA-4 for an efficient transmission through the vector P. betae in Beta vulgaris plants, demonstrating a very high correlation between BNYVV and BSBMV. At the same time, using BNYVV helper strain, we studied BSBMV RNA-4’s protein expression in planta. We associated a local necrotic lesions phenotype to the p32 protein expression onto mechanically inoculated C. quinoa. Flag or GFP-tagged sequences of p32 and p13 have been expressed in viral context, using Rep3 replicons, based on BNYVV RNA-3. Western blot analyses of local lesions contents, using FLAG-specific antibody, revealed a high molecular weight protein, which suggest either a strong interaction of BSBMV RNA4’s protein with host protein(s) or post translational modifications. GFP-fusion sequences permitted the subcellular localization of BSBMV RNA4’s proteins. Moreover we demonstrated the absence of self-activation domains on p32 by yeast two hybrid system approaches. We also confirmed that p32 protein is essential for virus transmission by P. betae using BNYVV helper strain and BNYVV RNA-3 and we investigated its role by the use of different deleted forms of p32 protein. Serial mechanical inoculation of wild-type BSBMV on C. quinoa plants were performed every 7 days. Deleted form of BSBMV RNA-4 (1298 bp) appeared after 14 passages and its sequence analysis shows deletion of 433 nucleotides between positions 611 and 1044 of RNA-4 new form. We demonstrated that this deleted form can’t support transmission by P. betae using BNYVV helper strain and BNYVV RNA-3, moreover we confirmed our hypothesis that BSBMV RNA-4 described by Lee et al. (2001) is a deleted form. Interesting after 21 passages we identifed one chimeric form of BSBMV RNA-4 and BSBMV RNA-3 (1146 bp). Two putative ORFs has been identified on its sequence, the first one (nucleotides 383 to 562), encode a protein with predicted mass of 7 kDa (p7), corresponding to the N-terminal of p32 protein encoded by BSBMV RNA-4; the second one (nucleotides 562 to 789) express an expected product of 9 kDa (p9) corresponding to the C-terminal of p29 encoded by BSBMV RNA-3. Results obtained by our research in this topic opened new research lines that our laboratories will develop in a closely future. In particular BSBMV p32 and its mutated forms will be used to identify factors, as host or vector protein(s), involved in the virus transmission through P. betae. The new results could allow selection or production of sugar beet plants able to prevent virus transmission then able to reduce viral inoculum in the soil.