Meeting report of the European mouse complex genetics network SYSGENET.

The second scientific meeting of the European systems genetics network for the study of complex genetic human disease using genetic reference populations (SYSGENET) took place at the Center for Cooperative Research in Biosciences in Bilbao, Spain, December 10-12, 2012. SYSGENET is funded by the European Cooperation in the Field of Scientific and Technological Research (COST) and represents a network of scientists in Europe that use mouse genetic reference populations (GRPs) to identify complex genetic factors influencing disease phenotypes (Schughart, Mamm Genome 21:331-336, 2010). About 50 researchers working in the field of systems genetics attended the meeting, which consisted of 27 oral presentations, a poster session, and a management committee meeting. Participants exchanged results, set up future collaborations, and shared phenotyping and data analysis methodologies. This meeting was particularly instrumental for conveying the current status of the US, Israeli, and Australian Collaborative Cross (CC) mouse GRP. The CC is an open source project initiated nearly a decade ago by members of the Complex Trait Consortium to aid the mapping of multigenetic traits (Threadgill, Mamm Genome 13:175-178, 2002). In addition, representatives of the International Mouse Phenotyping Consortium were invited to exchange ongoing activities between the knockout and complex genetics communities and to discuss and explore potential fields for future interactions.

Analysis of the mitochondrial DNA of Schizophrenia patients by next generation sequencing

Mitochondrial DNA (mtDNA), a maternally inherited 16.6-Kb molecule crucial for energy production, is implicated in numerous human traits and disorders. It has been hypothesized that the presence of mutations in the mtDNA may contribute to the complex genetic basis of schizophreniadisease, due to the evidence of maternal inheritance and the presence of schizophrenia symptoms in patients affected of a mitochondrial disorder related to a mtDNA mutation. The present project aims to study the association of variants of mitochondrial DNA (mtDNA), and an increased risk of schizophrenia in a cohort of patients and controls from the same population. The entire mtDNA of 55 schizophrenia patients with an apparent maternal transmission of the disease and 38 controls was sequenced by Next Generation Sequencing (Ion Torrent PGM, Life Technologies) and compared to the reference sequence. The current method for establishing mtDNA haplotypes is Sanger sequencing, which is laborious, timeconsuming, and expensive. With the emergence of Next Generation Sequencing technologies, this sequencing process can be much more quickly and cost-efficiently. We have identified 14 variants that have not been previously reported. Two of them were missense variants: MTATP6 p.V113M and MTND5 p.F334L ,and also three variants encoding rRNA and one variant encoding tRNA. Not significant differences have been found in the number of variants between the two groups. We found that the sequence alignment algorithm employed to align NGS reads played a significant role in the analysis of the data and the resulting mtDNA haplotypes. Further development of the bioinformatics analysis and annotation step would be desirable to facilitate the application of NGS in mtDNA analysis.

Systematics and phylogeography of the Dysdera erythrina species complex (Araneae, Dysderidae) in Sardinia

Sardinia is the second largest island in the Mediterranean and, together with Corsica and nearby mainland areas, one of the top biodiversity hotspots in the region. The origin of Sardinia traces back to the opening of the western Mediterranean in the late Oligocene. This geological event and the subsequent Messinian Salinity Crisis and Pleistocene glacial cycles have had a major impact on local biodiversity. The Dysdera woodlouse hunter spiders are one of the most diverse ground-dweller groups in the Mediterranean. Here we describe the first two species of this genus endemic to Sardinia: Dysdera jana sp. n. and Dysdera shardana sp. n. The two species show contrasting allopatric distribution: D. jana sp. n. is a narrow endemic while D. shardana sp. n. is distributed throughout most of the island. A multi-gene DNA sequence phylogenetic analys based on mitochondrial and nuclear genes supports the close relationships of the new species to the type species of the genus Dysdera erythrina. Age estimates reject Oligocene origin of the new Dysdera species and identify the Messinian Salinity Crises as the most plausible period for the split between Sardinian endemics and their closest relatives. Phylogeographic analysis reveals deep genetic divergences and population structure in Dysdera shardana sp. n., suggesting that restriction to gene flow probably due to environmental factors could explain local speciation events. Taxonomy, phylogeny, DNA sequencing, Mediterranean biogeography, phylogeography

Conservation banking and the economization of nature : an institutional analysis

During the last decade, conservation banking mechanisms have emerged in the environmental discourse as new market instruments to promote biodiversity conservation. Compensation was already provided for in environmental law in many countries, as the last step of the mitigation hierarchy. The institutional arrangements developed in this context have been redefined and reshaped as market-based instruments (MBIs). As such, they are discursively disentangled from the complex legal-economic nexus they are part of. Monetary transactions are given prominence and tend to be presented as stand alone agreements, whereas they take place in the context of prescriptive regulations. The pro-market narrative featuring conservation banking systems as market-like arrangements as well as their denunciation as instances of nature commodification tend to obscure their actual characteristics. The purpose of this paper is to describe the latter, adopting an explicitly analytical stance on these complex institutional arrangements and their performative dimensions. Beyond the discourse supporting them and notwithstanding the diversity of national policies and regulatory frameworks for compensation, the constitutive force of these mechanisms probably lies in their ability to redefine control, power and the distribution of costs and in their impacts in terms of land use rather than in their efficiency.

The Combined Pedicled Anterolateral Thigh and Vastus Lateralis Flap as Filler for Complex Perineal Defects.

Extensive defects of the pelvis and genitoperineal region are a reconstructive challenge. We discuss a consecutive series of 25 reconstructions with the pedicled anterolateral thigh (ALT) flap including muscle part of the vastus lateralis (VL) in 23 patients from October 1999 to September 2012.Only surface defects larger than 100 cm and reconstructions by composite ALT + VL were included in this retrospective analysis. Of the 23 patients, 19 underwent oncologic resection, whereas 4 cases presented Fournier gangrene. Three patients did not reach 6 months of follow-up and were excluded from further data analysis. Among the remaining 20 patients (22 reconstructions), average follow-up period was 14 months (range, 10-18 months). Patient's average age was 60 years. Average size of the defect was 182 cm.Postoperative complications included 1 (4.5%) flap necrosis out of 22 raised flaps, 1 partial flap necrosis after venous congestion, and 2 cases where a complementary reconstructive procedure was performed due to remaining defect or partial flap failure. In 6 cases, peripheral wound dehiscence (27%) was treated by debridement followed by split-thickness skin graft or advancement local flaps. Defect size was significantly related to postoperative complications and increased hospital stay, especially in those patients who underwent preoperative radiotherapy. At the end of the follow-up period, a long-term and satisfactory coverage was obtained in all patients without functional deficits.This consecutive series of composite ALT + VL flap shows that, in case of extended defects, the flap provides an excellent and adjustable muscle mass, is reliable with minimal donor-site morbidity, and can even be designed as a sensate flap.

Analysis of SKI-1/S1P prodomain provides insight on maturation and activation of SKI-1/S1P zymogen

SKI-l/SlP protease is a member of the proprotein convertase family, with several functions in cellular metabolism and homeostasis. It is responsible for the processing of several cellular substrates, including ATF6, SREBPs, and GlcNAc-1- phosphotranspherase. Furthermore, SKI-1/SlP is also responsible for maturation of arenavirus surface glycoprotein into GP1 and GP2 subunits. This processing is a strict requirement in order to achieve fully mature and fusion-competent virions. Furthermore, SKI-1/SlP itself is synthesized as an inactive zymogen, requiring sequential autocatalytic processing at several sites (B'/B and C) in its prodomain in order to mature and become fully active. Our project focused on the analysis of SKI- 1/S1P prodomain in the biogenesis of the active enzyme. In this context we have additionally developed and characterized a novel cell-based sensor for assessment of cellular activity of the enzyme, with a potential application in screening for novel SKI- 1/S1P inhibitors. In a first aim we have analysed the relevance of cleavage motifs found in the enzyme prodomain. Using molecular and biochemistry tools we have identified and characterized a novel C' maturation site. Furthermore, we found that SKI-1/SlP autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. Contrasting with other proprotein convertases, incompletely matured intermediates of SKI-1/SlP exhibit full catalytic activity toward selected substrates. In a second aim, we turned our attention to the structural basis of SKI-1/SlP N- terminus assisted folding. Studying the folding and activity of prodomain-truncated forms of the enzyme we found that a minimal folding unit is contained in the AB region. Deletion of the BC sequence affected auto-maturation but not folding, and partial activity was retained. However, the BC region seemed required for complete and full activity. Phylogenetic analyses showed that the AB sequence is highly conserved, while the BC fragment is variable in sequence and length. Specifically, replacement of the human prodomain with that of Drosophila, resulted in a fully mature and active chimeric enzyme, suggesting an evolution process of SKI-1/SlP prodomain towards a more complex arrangement and steps of activation. Overall, the additional data we have produced might provide fundamental knowledge crucial for the development of novel SKI-1/SlP inhibitors while also providing new SKI- 1/S1P variants with potential use in crystallization purpose. -- SKI-l/SlP est une protéase membre de la famille des proprotéines convertases (PCs), avec plusieurs fonctions dans le métabolisme cellulaire et de l'homéostasie. Il est responsable pour la maturation de plusieurs substrats cellulaires, y compris ATF6, SREBPs et GlcNAc-1-phosphotranspherase. SKI-l/SlP est également responsable pour la maturation de la glycoprotéine des arénavirus, une exigence stricte pour atteindre des virions infectieuse. Synthétisé comme un zymogène inactif, SKI-l/SlP nécessite d'un traitement autocatalytique séquentiel sur plusieurs sites (B'/B et C) de son prodomaine afin de devenir pleinement active. Notre projet était axé sur l'analyse de SKI-l/SlP prodomaine dans la biogenèse de l'enzyme. Dans ce contexte, nous avons développé un nouveau senseur-cellulaire pour l'évaluation de l'activité de l'enzyme. Ce dernier pourrait avoir une potentielle application dans l'identification de nouveaux inhibiteurs de SKI-l/SlP. Premièrement, nous avons analysé la pertinence des motifs de clivage trouvés dans le prodomaine de l'enzyme. En utilisant des outils moléculaires et biochimiques, nous avons identifié et caractérisé un nouveau site de maturation (C'). Aussi, nous avons constaté que la maturation de SKI-l/SlP a des intermédiaires dont le domaine catalytique reste associé à des fragments du prodomaine de différentes longueurs. Contrastant avec d'autres PCs, les intermédiaires partiellement matures de SKI-1 / SIP présentent une activité catalytique complète envers des substrats spécifiques. Dans un deuxième but nous avons tourné notre attention sur la base structurelle du pliage de SKI-l/SlP assisté par son N-terminus: En étudiant l'activité et pliage des formes tronquées dans le prodomaine de l'enzyme, nous avons constaté qu'une unité de pliage minimale est contenue dans la région de l'AB. La suppression de la séquence d'auto-BC affecte la maturation mais pas le pliage, et l'activité partielle est maintenue. Cependant, la région BC semble nécessaire pour une activité complète. Les analyses phylogénétiques ont montré que la séquence AB est fortement conservée, tandis que le fragment de BC est variable en longueur et en séquence. En particulier, le remplacement du prodomaine humain avec celui de la drosophile, a donné lieu à une enzyme chimérique complètement mature et active. Suggérant un processus d'évolution du prodomaine vers un arrangement et des mesures d'activation plus complexe. Globalement, ces donnees supplémentaires augment les connaissances fondamentales cruciales pour le développement de nouveaux inhibiteurs de SKI-1/ SIP, tout en offrant de nouvelles variantes SKI-1 / SIP dans le but d'obtenir la structure cristallographique de l'enzyme.

First principles analysis of the stability and diffusion of oxygen vacancies in meetal oxides

Oxygen vacancies in metal oxides are known to determine their chemistry and physics. The properties of neutral oxygen vacancies in metal oxides of increasing complexity (MgO, CaO, alpha-Al2O3, and ZnO) have been studied using density functional theory. Vacancy formation energies, vacancy-vacancy interaction, and the barriers for vacancy migration are determined and rationalized in terms of the ionicity, the Madelung potential, and lattice relaxation. It is found that the Madelung potential controls the oxygen vacancy properties of highly ionic oxides whereas a more complex picture arises for covalent ZnO.

Repetitive Deliberate Fires: Critical Review of the Situation and Proposal of a Follow-Up Process and Systematic Analysis

Deliberate fires appear to be borderless and timeless events creating a serious security problem. There have been many attempts to develop approaches to tackle this problem, but unfortunately acting effectively against deliberate fires has proven a complex challenge. This article reviews the current situation relating to deliberate fires: what do we know, how serious is the situation, how is it being dealt with, and what challenges are faced when developing a systematic and global methodology to tackle the issues? The repetitive nature of some types of deliberate fires will also be discussed. Finally, drawing on the reality of repetition within deliberate fires and encouraged by successes obtained in previous repetitive crimes (such as property crimes or drug trafficking), we will argue that the use of the intelligence process cycle as a framework to allow a follow-up and systematic analysis of fire events is a relevant approach. This is the first article of a series of three articles. This first part is introducing the context and discussing the background issues in order to provide a better underpinning knowledge to managers and policy makers planning on tackling this issue. The second part will present a methodology developed to detect and identify repetitive fire events from a set of data, and the third part will discuss the analyses of these data to produce intelligence.

Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension

Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes.

IN DUBIO PRO NATURA? A Philosophical Analysis of the Precautionary Principle in Environmental and Health Risk Governance

In this book, I apply a philosophical approach to study the precautionary principle in environmental (and health) risk decision-making. The principle says that unacceptable environmental and health risks should be anticipated, and they ought to be forestalled before the damage comes to fruition even if scientific understanding of the risks is inadequate. The study consists of introductory chapters, summary and seven original publications which aim at explicating the principle, critically analysing the debate on the principle, and constructing a basis for the well-founded use of the principle. Papers I-V present the main thesis of this research. In the two last papers, the discussion is widened to new directions. The starting question is how well the currently embraced precautionary principle stands up to critical philosophical scrutiny. The approach employed is analytical: mainly conceptual, argumentative and ethical. The study draws upon Anglo-American style philosophy on the one hand, and upon sources of law as well as concrete cases and decision-making practices at the European Union level and in its member countries on the other. The framework is environmental (and health) risk governance, including the related law and policy. The main thesis of this study is that the debate on the precautionary principle needs to be shifted from the question of whether the principle (or its weak or strong interpretation) is well-grounded in general to questions about the theoretical plausibility and ethical and socio-political justifiability of specific understandings of the principle. The real picture of the precautionary principle is more complex than that found (i.e. presumed) in much of the current academic, political and public debate surrounding it. While certain presumptions and interpretations of the principle are found to be sound, others are theoretically flawed or include serious practical problems. The analysis discloses conceptual and ethical presumptions and elementary understandings of the precautionary principle, critically assesses current practices invoked in the name of the precautionary principle and public participation, and seeks to build bridges between precaution, engagement and philosophical ethics. Hence, it is intended to provide a sound basis upon which subsequent academic scrutiny can build.

Multifactor Performance Study on Complex Systems for the Benefit of Management

The primary objective is to identify the critical factors that have a natural impact on the performance measurement system. It is important to make correct decisions related to measurement systems, which are based on the complex business environment. The performance measurement system is combined with a very complex non-linear factor. The Six Sigma methodology is seen as one potential approach at every organisational level. It will be linked to the performance and financial measurement as well as to the analytical thinking on which the viewpoint of management depends. The complex systems are connected to the customer relationship study. As the primary throughput can be seen in a new well-defined performance measurement structure that will also be facilitated as will an analytical multifactor system. These critical factors should also be seen as a business innovation opportunity at the same time. This master's thesis has been divided into two different theoretical parts. The empirical part consists of both action-oriented and constructive research approaches with an empirical case study. The secondary objective is to seek a competitive advantage factor with a new analytical tool and the Six Sigma thinking. Process and product capabilities will be linked to the contribution of complex system. These critical barriers will be identified by the performance measuring system. The secondary throughput can be recognised as the product and the process cost efficiencies which throughputs are achieved with an advantage of management. The performance measurement potential is related to the different productivity analysis. Productivity can be seen as one essential part of the competitive advantage factor.

Tracking Invasion Histories in the Sea: Facing Complex Scenarios Using Multilocus Data

In recent years, new analytical tools have allowed researchers to extract historical information contained in molecular data, which has fundamentally transformed our understanding of processes ruling biological invasions. However, the use of these new analytical tools has been largely restricted to studies of terrestrial organisms despite the growing recognition that the sea contains ecosystems that are amongst the most heavily affected by biological invasions, and that marine invasion histories are often remarkably complex. Here, we studied the routes of invasion and colonisation histories of an invasive marine invertebrate Microcosmus squamiger (Ascidiacea) using microsatellite loci, mitochondrial DNA sequence data and 11 worldwide populations. Discriminant analysis of principal components, clustering methods and approximate Bayesian computation (ABC) methods showed that the most likely source of the introduced populations was a single admixture event that involved populations from two genetically differentiated ancestral regions - the western and eastern coasts of Australia. The ABC analyses revealed that colonisation of the introduced range of M. squamiger consisted of a series of non-independent introductions along the coastlines of Africa, North America and Europe. Furthermore, we inferred that the sequence of colonisation across continents was in line with historical taxonomic records - first the Mediterranean Sea and South Africa from an unsampled ancestral population, followed by sequential introductions in California and, more recently, the NE Atlantic Ocean. We revealed the most likely invasion history for world populations of M. squamiger, which is broadly characterized by the presence of multiple ancestral sources and non-independent introductions within the introduced range. The results presented here illustrate the complexity of marine invasion routes and identify a cause-effect relationship between human-mediated transport and the success of widespread marine non-indigenous species, which benefit from stepping-stone invasions and admixture processes involving different sources for the spread and expansion of their range.

Timing History: The Introduction of Graphical Analysis in 19th Century British Economics

The introduction of time-series graphs into British economics in the 19th century depended on the « timing » of history. This involved reconceptualizing history into events which were both comparable and measurable and standardized by time unit. Yet classical economists in Britain in the early 19th century viewed history as a set of heterogenous and complex events and statistical tables as giving unrelated facts. Both these attitudes had to be broken down before time-series graphs could be brought into use for revealing regularities in economic events by the century's end.

Study of tergal glands morphogenesis through an integrative analysis of genomic data

About 50% of living species are holometabolan insects. Therefore, unraveling the ori- gin of insect metamorphosis from the hemimetabolan (gradual metamorphosis) to the holometabolan (sudden metamorphosis at the end of the life cycle) mode is equivalent to explaining how all this biodiversity originated. One of the problems with studying the evolution from hemimetaboly to holometaboly is that most information is available only in holometabolan species. Within the hemimetabolan group, our model, the cock- roach Blattella germanica, is the most studied species. However, given that the study of adult morphogenesis at organismic level is still complex, we focused on the study of the tergal gland (TG) as a minimal model of metamorphosis. The TG is formed in tergites 7 and 8 (T7-8) in the last days of the last nymphal instar (nymph 6). The comparative study of four T7-T8 transcriptomes provided us with crucial keys of TG formation, but also essential information about the mechanisms and circuitry that allows the shift from nymphal to adult morphogenesis.

Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases.

Mapping perturbed molecular circuits that underlie complex diseases remains a great challenge. We developed a comprehensive resource of 394 cell type- and tissue-specific gene regulatory networks for human, each specifying the genome-wide connectivity among transcription factors, enhancers, promoters and genes. Integration with 37 genome-wide association studies (GWASs) showed that disease-associated genetic variants-including variants that do not reach genome-wide significance-often perturb regulatory modules that are highly specific to disease-relevant cell types or tissues. Our resource opens the door to systematic analysis of regulatory programs across hundreds of human cell types and tissues (http://regulatorycircuits.org).