An integrated approach of software development and test processes to distributed teams

The Distributed Software Development (DSD) is a development strategy that meets the globalization needs concerned with the increase productivity and cost reduction. However, the temporal distance, geographical dispersion and the socio-cultural differences, increased some challenges and, especially, added new requirements related with the communication, coordination and control of projects. Among these new demands there is the necessity of a software process that provides adequate support to the distributed software development. This paper presents an integrated approach of software development and test that considers distributed teams peculiarities. The approach purpose is to offer support to DSD, providing a better project visibility, improving the communication between the development and test teams, minimizing the ambiguity and difficulty to understand the artifacts and activities. This integrated approach was conceived based on four pillars: (i) to identify the DSD peculiarities concerned with development and test processes, (ii) to define the necessary elements to compose the integrated approach of development and test to support the distributed teams, (iii) to describe and specify the workflows, artifacts, and roles of the approach, and (iv) to represent appropriately the approach to enable the effective communication and understanding of it.

CYP2C9 and VKORC1 Polymorphisms Are Differently Distributed in the Brazilian Population According to Self-Declared Ethnicity or Genetic Ancestry

Background: Warfarin-dosing pharmacogenetic algorithms have presented different performances across ethnicities, and the impact in admixed populations is not fully known. Aims: To evaluate the CYP2C9 and VKORC1 polymorphisms and warfarin-predicted metabolic phenotypes according to both self-declared ethnicity and genetic ancestry in a Brazilian general population plus Amerindian groups. Methods: Two hundred twenty-two Amerindians (Tupinikin and Guarani) were enrolled and 1038 individuals from the Brazilian general population who were self-declared as White, Intermediate (Brown, Pardo in Portuguese), or Black. Samples of 274 Brazilian subjects from Sao Paulo were analyzed for genetic ancestry using an Affymetrix 6.0 (R) genotyping platform. The CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), and VKORC1 g.-1639G>A (rs9923231) polymorphisms were genotyped in all studied individuals. Results: The allelic frequency for the VKORC1 polymorphism was differently distributed according to self-declared ethnicity: White (50.5%), Intermediate (46.0%), Black (39.3%), Tupinikin (40.1%), and Guarani (37.3%) (p < 0.001), respectively. The frequency of intermediate plus poor metabolizers (IM + PM) was higher in White (28.3%) than in Intermediate (22.7%), Black (20.5%), Tupinikin (12.9%), and Guarani (5.3%), (p < 0.001). For the samples with determined ancestry, subjects carrying the GG genotype for the VKORC1 had higher African ancestry and lower European ancestry (0.14 +/- 0.02 and 0.62 +/- 0.02) than in subjects carrying AA (0.05 +/- 0.01 and 0.73 +/- 0.03) (p = 0.009 and 0.03, respectively). Subjects classified as IM + PM had lower African ancestry (0.08 +/- 0.01) than extensive metabolizers (0.12 +/- 0.01) (p = 0.02). Conclusions: The CYP2C9 and VKORC1 polymorphisms are differently distributed according to self-declared ethnicity or genetic ancestry in the Brazilian general population plus Amerindians. This information is an initial step toward clinical pharmacogenetic implementation, and it could be very useful in strategic planning aiming at an individual therapeutic approach and an adverse drug effect profile prediction in an admixed population.

Unique Alterations of an Ultraconserved Non-Coding Element in the 3 ' UTR of ZIC2 in Holoprosencephaly

Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3' untranslated region (3'UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases.

Polymorphic toxin systems: Comprehensive characterization of trafficking modes, processing, mechanisms of action, immunity and ecology using comparative genomics

Background: Proteinaceous toxins are observed across all levels of inter-organismal and intra-genomic conflicts. These include recently discovered prokaryotic polymorphic toxin systems implicated in intra-specific conflicts. They are characterized by a remarkable diversity of C-terminal toxin domains generated by recombination with standalone toxin-coding cassettes. Prior analysis revealed a striking diversity of nuclease and deaminase domains among the toxin modules. We systematically investigated polymorphic toxin systems using comparative genomics, sequence and structure analysis. Results: Polymorphic toxin systems are distributed across all major bacterial lineages and are delivered by at least eight distinct secretory systems. In addition to type-II, these include type-V, VI, VII (ESX), and the poorly characterized "Photorhabdus virulence cassettes (PVC)", PrsW-dependent and MuF phage-capsid-like systems. We present evidence that trafficking of these toxins is often accompanied by autoproteolytic processing catalyzed by HINT, ZU5, PrsW, caspase-like, papain-like, and a novel metallopeptidase associated with the PVC system. We identified over 150 distinct toxin domains in these systems. These span an extraordinary catalytic spectrum to include 23 distinct clades of peptidases, numerous previously unrecognized versions of nucleases and deaminases, ADP-ribosyltransferases, ADP ribosyl cyclases, RelA/SpoT-like nucleotidyltransferases, glycosyltranferases and other enzymes predicted to modify lipids and carbohydrates, and a pore-forming toxin domain. Several of these toxin domains are shared with host-directed effectors of pathogenic bacteria. Over 90 families of immunity proteins might neutralize anywhere between a single to at least 27 distinct types of toxin domains. In some organisms multiple tandem immunity genes or immunity protein domains are organized into polyimmunity loci or polyimmunity proteins. Gene-neighborhood-analysis of polymorphic toxin systems predicts the presence of novel trafficking-related components, and also the organizational logic that allows toxin diversification through recombination. Domain architecture and protein-length analysis revealed that these toxins might be deployed as secreted factors, through directed injection, or via inter-cellular contact facilitated by filamentous structures formed by RHS/YD, filamentous hemagglutinin and other repeats. Phyletic pattern and life-style analysis indicate that polymorphic toxins and polyimmunity loci participate in cooperative behavior and facultative 'cheating' in several ecosystems such as the human oral cavity and soil. Multiple domains from these systems have also been repeatedly transferred to eukaryotes and their viruses, such as the nucleo-cytoplasmic large DNA viruses. Conclusions: Along with a comprehensive inventory of toxins and immunity proteins, we present several testable predictions regarding active sites and catalytic mechanisms of toxins, their processing and trafficking and their role in intra-specific and inter-specific interactions between bacteria. These systems provide insights regarding the emergence of key systems at different points in eukaryotic evolution, such as ADP ribosylation, interaction of myosin VI with cargo proteins, mediation of apoptosis, hyphal heteroincompatibility, hedgehog signaling, arthropod toxins, cell-cell interaction molecules like teneurins and different signaling messengers.

Identical sequence patterns in the ends of exons and introns of human protein-coding genes

Intron splicing is one of the most important steps involved in the maturation process of a pre-mRNA. Although the sequence profiles around the splice sites have been studied extensively, the levels of sequence identity between the exonic sequences preceding the donor sites and the intronic sequences preceding the acceptor sites has not been examined as thoroughly. In this study we investigated identity patterns between the last 15 nucleotides of the exonic sequence preceding the 5' splice site and the intronic sequence preceding the 3' splice site in a set of human protein-coding genes that do not exhibit intron retention. We found that almost 60% of consecutive exons and introns in human protein-coding genes share at least two identical nucleotides at their 3' ends and, on average, the sequence identity length is 2.47 nucleotides. Based on our findings we conclude that the 3' ends of exons and introns tend to have longer identical sequences within a gene than when being taken from different genes. Our results hold even if the pairs are non-consecutive in the transcription order. (C) 2012 Elsevier Ltd. All rights reserved.

Analytical tools to assess the voltage stability of induction-based distributed generators

The installation of induction distributed generators should be preceded by a careful study in order to determine if the point of common coupling is suitable for transmission of the generated power, keeping acceptable power quality and system stability. In this sense, this paper presents a simple analytical formulation that allows a fast and comprehensive evaluation of the maximum power delivered by the induction generator, without losing voltage stability. Moreover, this formulation can be used to identify voltage stability issues that limit the generator output power. All the formulation is developed by using the equivalent circuit of squirrel-cage induction machine. Simulation results are used to validate the method, which enables the approach to be used as a guide to reduce the simulation efforts necessary to assess the maximum output power and voltage stability of induction generators. (C) 2011 Elsevier Ltd. All rights reserved.

Expression of Mitochondrial Non-coding RNAs (ncRNAs) Is Modulated by High Risk Human Papillomavirus (HPV) Oncogenes

The study of RNA and DNA oncogenic viruses has proved invaluable in the discovery of key cellular pathways that are rendered dysfunctional during cancer progression. An example is high risk human papillomavirus (HPV), the etiological agent of cervical cancer. The role of HPV oncogenes in cellular immortalization and transformation has been extensively investigated. We reported the differential expression of a family of human mitochondrial non-coding RNAs (ncRNAs) between normal and cancer cells. Normal cells express a sense mitochondrial ncRNA (SncmtRNA) that seems to be required for cell proliferation and two antisense transcripts (ASncmtRNAs). In contrast, the ASncmtRNAs are down-regulated in cancer cells. To shed some light on the mechanisms that trigger down-regulation of the ASncmtRNAs, we studied human keratinocytes (HFK) immortalized with HPV. Here we show that immortalization of HFK with HPV-16 or 18 causes down-regulation of the ASncmtRNAs and induces the expression of a new sense transcript named SncmtRNA-2. Transduction of HFK with both E6 and E7 is sufficient to induce expression of SncmtRNA-2. Moreover, E2 oncogene is involved in down-regulation of the ASncmtRNAs. Knockdown of E2 in immortalized cells reestablishes in a reversible manner the expression of the ASncmtRNAs, suggesting that endogenous cellular factors(s) could play functions analogous to E2 during non-HPV-induced oncogenesis.

Improving the Robustness of Distributed Failure Detectors in Adverse Conditions

Failure detection is at the core of most fault tolerance strategies, but it often depends on reliable communication. We present new algorithms for failure detectors which are appropriate as components of a fault tolerance system that can be deployed in situations of adverse network conditions (such as loosely connected and administered computing grids). It packs redundancy into heartbeat messages, thereby improving on the robustness of the traditional protocols. Results from experimental tests conducted in a simulated environment with adverse network conditions show significant improvement over existing solutions.

Molecular mapping of the regenerative niche in a murine model of myocardial infarction

Adult stem cells are distributed through the whole organism, and present a great potential for the therapy of different types of disease. For the design of efficient therapeutic strategies, it is important to have a more detailed understanding of their basic biological characteristics, as well as of the signals produced by damaged tissues and to which they respond. Myocardial infarction (MI), a disease caused by a lack of blood flow supply in the heart, represents the most common cause of morbidity and mortality in the Western world. Stem cell therapy arises as a promising alternative to conventional treatments, which are often ineffective in preventing loss of cardiomyocytes and fibrosis. Cell therapy protocols must take into account the molecular events that occur in the regenerative niche of MI. In the present study, we investigated the expression profile of ten genes coding for chemokines or cytokines in a murine model of MI, aiming at the characterization of the regenerative niche. MI was induced in adult C57BL/6 mice and heart samples were collected after 24 h and 30 days, as well as from control animals, for quantitative RT-PCR. Expression of the chemokine genes CCL2, CCL3, CCL4, CCL7, CXCL2 and CXCL10 was significantly increased 24 h after infarction, returning to baseline levels on day 30. Expression of the CCL8 gene significantly increased only on day 30, whereas gene expression of CXCL12 and CX3CL1 were not significantly increased in either ischemic period. Finally, expression of the IL-6 gene increased 24 h after infarction and was maintained at a significantly higher level than control samples 30 days later. These results contribute to the better knowledge of the regenerative niche in MI, allowing a more efficient selection or genetic manipulation of cells in therapeutic protocols.

An online data access prediction and optimization approach for distributed systems

Current scientific applications have been producing large amounts of data. The processing, handling and analysis of such data require large-scale computing infrastructures such as clusters and grids. In this area, studies aim at improving the performance of data-intensive applications by optimizing data accesses. In order to achieve this goal, distributed storage systems have been considering techniques of data replication, migration, distribution, and access parallelism. However, the main drawback of those studies is that they do not take into account application behavior to perform data access optimization. This limitation motivated this paper which applies strategies to support the online prediction of application behavior in order to optimize data access operations on distributed systems, without requiring any information on past executions. In order to accomplish such a goal, this approach organizes application behaviors as time series and, then, analyzes and classifies those series according to their properties. By knowing properties, the approach selects modeling techniques to represent series and perform predictions, which are, later on, used to optimize data access operations. This new approach was implemented and evaluated using the OptorSim simulator, sponsored by the LHC-CERN project and widely employed by the scientific community. Experiments confirm this new approach reduces application execution time in about 50 percent, specially when handling large amounts of data.

Analysis of Hepatitis C Virus Intrahost Diversity across the Coding Region by Ultradeep Pyrosequencing

Hepatitis C virus (HCV) is the leading cause of liver disease worldwide. In this study, we analyzed four treatment-naive patients infected with subtype 1a and performed Roche/454 pyrosequencing across the coding region. We report the presence of low-level drug resistance mutations that would most likely have been missed using conventional sequencing methods. The approach described here is broadly applicable to studies of viral diversity and could help to improve the efficacy of direct-acting antiviral agents (DAA) in the treatment of HCV-infected patients.

Optical parametric oscillation with distributed feedback in cold atoms

There is currently a strong interest in mirrorless lasing systems(1), in which the electromagnetic feedback is provided either by disorder (multiple scattering in the gain medium) or by order (multiple Bragg reflection). These mechanisms correspond, respectively, to random lasers(2) and photonic crystal lasers(3). The crossover regime between order and disorder, or correlated disorder, has also been investigated with some success(4-6). Here, we report one-dimensional photonic-crystal lasing (that is, distributed feedback lasing(7,8)) with a cold atom cloud that simultaneously provides both gain and feedback. The atoms are trapped in a one-dimensional lattice, producing a density modulation that creates a strong Bragg reflection with a small angle of incidence. Pumping the atoms with auxiliary beams induces four-wave mixing, which provides parametric gain. The combination of both ingredients generates a mirrorless parametric oscillation with a conical output emission, the apex angle of which is tunable with the lattice periodicity.

Nondetection Index of Anti-Islanding Passive Protection of Synchronous Distributed Generators

Synchronous distributed generators are prone to operate islanded after contingencies, which is usually not allowed due to safety and power-quality issues. Thus, there are several anti-islanding techniques; however, most of them present technical limitations so that they are likely to fail in certain situations. Therefore, it is important to quantify and determine whether the scheme under study is adequate or not. In this context, this paper proposes an index to evaluate the effectiveness of anti-islanding frequency-based relays commonly used to protect synchronous distributed generators. The method is based on the calculation of a numerical index that indicates the time period that the system is unprotected against islanding considering the global period of analysis. Although this index can precisely be calculated based on several electromagnetic transient simulations, a practical method is also proposed to calculate it directly from simple analytical formulas or lookup tables. The results have shown that the proposed approach can assist distribution engineers to assess and set anti-islanding protection schemes.

Molecular determinants of caste differentiation in the highly eusocial honeybee Apis mellifera

Abstract Background In honeybees, differential feeding of female larvae promotes the occurrence of two different phenotypes, a queen and a worker, from identical genotypes, through incremental alterations, which affect general growth, and character state alterations that result in the presence or absence of specific structures. Although previous studies revealed a link between incremental alterations and differential expression of physiometabolic genes, the molecular changes accompanying character state alterations remain unknown. Results By using cDNA microarray analyses of >6,000 Apis mellifera ESTs, we found 240 differentially expressed genes (DEGs) between developing queens and workers. Many genes recorded as up-regulated in prospective workers appear to be unique to A. mellifera, suggesting that the workers' developmental pathway involves the participation of novel genes. Workers up-regulate more developmental genes than queens, whereas queens up-regulate a greater proportion of physiometabolic genes, including genes coding for metabolic enzymes and genes whose products are known to regulate the rate of mass-transforming processes and the general growth of the organism (e.g., tor). Many DEGs are likely to be involved in processes favoring the development of caste-biased structures, like brain, legs and ovaries, as well as genes that code for cytoskeleton constituents. Treatment of developing worker larvae with juvenile hormone (JH) revealed 52 JH responsive genes, specifically during the critical period of caste development. Using Gibbs sampling and Expectation Maximization algorithms, we discovered eight overrepresented cis-elements from four gene groups. Graph theory and complex networks concepts were adopted to attain powerful graphical representations of the interrelation between cis-elements and genes and objectively quantify the degree of relationship between these entities. Conclusion We suggest that clusters of functionally related DEGs are co-regulated during caste development in honeybees. This network of interactions is activated by nutrition-driven stimuli in early larval stages. Our data are consistent with the hypothesis that JH is a key component of the developmental determination of queen-like characters. Finally, we propose a conceptual model of caste differentiation in A. mellifera based on gene-regulatory networks.

SmTRC1, a novel Schistosoma mansoni DNA transposon, discloses new families of animal and fungi transposons belonging to the CACTA superfamily

Abstract Background The CACTA (also called En/Spm) superfamily of DNA-only transposons contain the core sequence CACTA in their Terminal Inverted Repeats (TIRs) and so far have only been described in plants. Large transcriptome and genome sequence data have recently become publicly available for Schistosoma mansoni, a digenetic blood fluke that is a major causative agent of schistosomiasis in humans, and have provided a comprehensive repository for the discovery of novel genes and repetitive elements. Despite the extensive description of retroelements in S. mansoni, just a single DNA-only transposon belonging to the Merlin family has so far been reported in this organism. Results We describe a novel S. mansoni transposon named SmTRC1, for S. mansoni Transposon Related to CACTA 1, an element that shares several characteristics with plant CACTA transposons. Southern blotting indicates approximately 30–300 copies of SmTRC1 in the S. mansoni genome. Using genomic PCR followed by cloning and sequencing, we amplified and characterized a full-length and a truncated copy of this element. RT-PCR using S. mansoni mRNA followed by cloning and sequencing revealed several alternatively spliced transcripts of this transposon, resulting in distinct ORFs coding for different proteins. Interestingly, a survey of complete genomes from animals and fungi revealed several other novel TRC elements, indicating new families of DNA transposons belonging to the CACTA superfamily that have not previously been reported in these kingdoms. The first three bases in the S. mansoni TIR are CCC and they are identical to those in the TIRs of the insects Aedes aegypti and Tribolium castaneum, suggesting that animal TRCs may display a CCC core sequence. Conclusion The DNA-only transposable element SmTRC1 from S. mansoni exhibits various characteristics, such as generation of multiple alternatively-spliced transcripts, the presence of terminal inverted repeats at the extremities of the elements flanked by direct repeats and the presence of a Transposase_21 domain, that suggest a distant relationship to CACTA transposons from Magnoliophyta. Several sequences from other Metazoa and Fungi code for proteins similar to those encoded by SmTRC1, suggesting that such elements have a common ancestry, and indicating inheritance through vertical transmission before separation of the Eumetazoa, Fungi and Plants.