On estimation and identifiability issues of sex-linked inheritance with a case study of pigmentation in Swiss barn owl (Tyto alba)

Genetic evaluation using animal models or pedigree-based models generally assume only autosomal inheritance. Bayesian animal models provide a flexible framework for genetic evaluation, and we show how the model readily can accommodate situations where the trait of interest is influenced by both autosomal and sex-linked inheritance. This allows for simultaneous calculation of autosomal and sex-chromosomal additive genetic effects. Inferences were performed using integrated nested Laplace approximations (INLA), a nonsampling-based Bayesian inference methodology. We provide a detailed description of how to calculate the inverse of the X- or Z-chromosomal additive genetic relationship matrix, needed for inference. The case study of eumelanic spot diameter in a Swiss barn owl (Tyto alba) population shows that this trait is substantially influenced by variation in genes on the Z-chromosome (sigma(2)(z) = 0.2719 and sigma(2)(a) = 0.4405). Further, a simulation study for this study system shows that the animal model accounting for both autosomal and sex-chromosome-linked inheritance is identifiable, that is, the two effects can be distinguished, and provides accurate inference on the variance components.

Integrated assessment of agricultural sustainability: the pros and cons of reductionism

In this paper I review a series of theoretical concepts that are relevant for the integrated assessment of agricultural sustainability but that are not generally included in the curriculum of the various scientific disciplines dealing with quantitative analysis of agriculture. I first illustrate with plain narratives and concrete examples that sustainability is an extremely complex issue requiring the simultaneous consideration of several aspects, which cannot be reduced into a single indicator of performance. Following, I justify this obvious need for multi-criteria analysis with theoretical concepts dealing with the epistemological predicament of complexity, starting from classic philosophical lessons to arrive to recent developments in complex system theory, in particular Rosen´s theory of modelling relation which is essential to analyze the quality of any quantitative representation. The implications of these theoretical concepts are then illustrated with applications of multi-criteria analysis to the sustainability of agriculture. I wrap up by pointing out the crucial difference between "integrated assessment" and "integrated analysis". An integrated analysis is a set of indicators and analytical models generating an analytical output. An integrated assessment is much more than that. It is about finding an effective way to deal with three key issues: (i) legitimacy – how to handle the unavoidable existence of legitimate but contrasting points of view about different meanings given by social actors to the word "development"; (ii) pertinence – how to handle in a coherent way scientific analyses referring to different scales and dimensions; and (iii) credibility – how to handle the unavoidable existence of uncertainty and genuine ignorance, when dealing with the analysis of future scenarios.

A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues.

Tobacco consumption is a global epidemic responsible for a vast burden of disease. With pharmacological properties sought-after by consumers and responsible for addiction issues, nicotine is the main reason of this phenomenon. Accordingly, smokeless tobacco products are of growing popularity in sport owing to potential performance enhancing properties and absence of adverse effects on the respiratory system. Nevertheless, nicotine does not appear on the 2011 World Anti-Doping Agency (WADA) Prohibited List or Monitoring Program by lack of a comprehensive large-scale prevalence survey. Thus, this work describes a one-year monitoring study on urine specimens from professional athletes of different disciplines covering 2010 and 2011. A method for the detection and quantification of nicotine, its major metabolites (cotinine, trans-3-hydroxycotinine, nicotine-N'-oxide and cotinine-N-oxide) and minor tobacco alkaloids (anabasine, anatabine and nornicotine) was developed, relying on ultra-high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-TQ-MS/MS). A simple and fast dilute-and-shoot sample treatment was performed, followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. After method validation, assessing the prevalence of nicotine consumption in sport involved analysis of 2185 urine samples, accounting for 43 different sports. Concentrations distribution of major nicotine metabolites, minor nicotine metabolites and tobacco alkaloids ranged from 10 (LLOQ) to 32,223, 6670 and 538 ng/mL, respectively. Compounds of interest were detected in trace levels in 23.0% of urine specimens, with concentration levels corresponding to an exposure within the last three days for 18.3% of samples. Likewise, hypothesizing conservative concentration limits for active nicotine consumption prior and/or during sport practice (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N'-oxide, cotinine-N-oxide, anabasine, anatabine and nornicotine) revealed a prevalence of 15.3% amongst athletes. While this number may appear lower than the worldwide smoking prevalence of around 25%, focusing the study on selected sports highlighted more alarming findings. Indeed, active nicotine consumption in ice hockey, skiing, biathlon, bobsleigh, skating, football, basketball, volleyball, rugby, American football, wrestling and gymnastics was found to range between 19.0 and 55.6%. Therefore, considering the adverse effects of smoking on the respiratory tract and numerous health threats detrimental to sport practice at top level, likelihood of smokeless tobacco consumption for performance enhancement is greatly supported.

TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha.

Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor kappaB (NF-kappaB) signaling, and sensitize cells to tumor necrosis factor alpha (TNFalpha). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1-Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1-TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF-kappaB signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNFalpha-induced death occurs. TWEAK-induced loss of the cIAP1-TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNFalpha-induced death, whereas primary cells remain resistant. Conversely, cIAP1-TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNFalpha sensitization. Lysosomal degradation of cIAP1-TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells.

Data bases for the assessment of medical technologies: examples from Europe.

The assessment of medical technologies has to answer several questions ranging from safety and effectiveness to complex economical, social, and health policy issues. The type of data needed to carry out such evaluation depends on the specific questions to be answered, as well as on the stage of development of a technology. Basically two types of data may be distinguished: (a) general demographic, administrative, or financial data which has been collected not specifically for technology assessment; (b) the data collected with respect either to a specific technology or to a disease or medical problem. On the basis of a pilot inquiry in Europe and bibliographic research, the following categories of type (b) data bases have been identified: registries, clinical data bases, banks of factual and bibliographic knowledge, and expert systems. Examples of each category are discussed briefly. The following aims for further research and practical goals are proposed: criteria for the minimal data set required, improvement to the registries and clinical data banks, and development of an international clearinghouse to enhance information diffusion on both existing data bases and available reports on medical technology assessments.

Validation of two echocardiographic indexes to improve the diagnosis of complex coarctations

Rapport de synthèse: Enjeux et contexte de recherche : la coarctation de l'aorte, rétrécissement de l'aorte thoracique descendante, est une des malformations cardiaques congénitales les plus fréquentes. Son diagnostic reste cependant difficile surtout lorsqu'elle est associée à la présence d'un canal artériel ou à une malformation cardiaque plus complexe. Dans ces contextes, les signes échographiques classiques qui posent habituellement le diagnostic (visualisation d'un rétrécissement juxtaductal et accélération au Doppler au niveau de l'isthme aortique) peuvent faire défaut ou être difficile à imager. La validation d'index basé sur des mesures anatomiques faciles à acquérir par échographie cardiaque, indépendantes de l'âge, de la situation hémodynamique et des malformations cardiaques associées représente une aide significative dans le diagnostic de la coarctation de l'aorte. Nous avons donc voulu valider par une étude rétrospective la fiabilité de deux index dans cette indication : l'index des artères carotido-sous-clavière (index CSA; rapport du diamètre de l'arc aortique transverse distal sur la distance entre les artères carotide et sous-clavière gauches) et l'index de l'aorte isthmique-descendante (index I/D; rapport des diamètres de l'aorte isthmique sur celui de l'aorte descendante). Notre article : nous avons rétrospectivement calculé la valeur des deux index (CSA et I/D) chez un groupe de 68 enfants avec coarctation et un groupe 24 cas contrôles apparenté pour l'âge et le sexe. Les enfants avec coarctation ont un index CSA et I/D significativement plus bas que le groupe contrôle (Index CSA : 0.84 ± 0.39 vs. 2.65 ± 0.82, p<0.0001 - Index I/D : 0.58 ± 0.18 vs. 0.98 ± 0.19, p<0.0001). Pour les deux index, ni la présence d'une autre malformation cardiaque, ni l'âge n'ont un impact sur la différence significative entre les deux groupes. Conclusions: notre recherche à permis de valider qu'un index CSA de moins de 1,5 est fortement suggestif d'une coarctation, indépendamment de l'âge du patient et de la présence d'une autre malformation cardiaque. L'index I/D (valeur limite 0,64) est moins spécifique que l'index CSA. L'association des deux index augmente la sensibilité et permet rétrospectivement le diagnostic de tous les cas de coarctation seulement sur la base d'une échographie cardiaque standard faite au lit du patient. Perspectives : cette étude rétrospective mérite d'être vérifiée par une étude prospective afin de confirmer la contribution de ces index à la prise en charge des patients suspects d'une coarctation de l'aorte. Cependant, la situation dans laquelle ces index pourraient avoir le plus grand impact reste encore à explorer. En effet, si le diagnostic postnatal de la coarctation est parfois difficile, son diagnostic prénatal l'est nettement plus. La présence obligatoire du canal artériel et l'existence d'une hypoplasie isthmique physiologique chez le foetus obligent le cardiologue foetale à observer des signes indirects, peu sensibles, d'une possible coarctation (prépondérance des cavités droites). La validation de l'index CSA et/ou de l'index I/D chez le foetus constituerait donc une avancée majeure dans le diagnostic prénatal de la coarctation de l'aorte.

Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene.

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-gamma-induced MHCII expression on a wide variety of non-bone marrow-derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4(+) T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-gamma-activated cells of the macrophage lineage. pIV(-/-) mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease.

Analysis of Mycobacterium avium Complex Serovars Isolated from AIDS Patients from Southeast Brazil

The purpose of this study was to assess the distribution of Mycobacterium avium serovars isolated from AIDS patients in São Paulo and Rio de Janeiro. Ninety single site or multiple site isolates from 75 patients were examined. The most frequent serovars found were 8 (39.2%), 4 (21.4%) and 1 (10.7%). The frequency of mixed infections with serovar 8 or 4 was 37.8%. Among the 90 strains examined, M. intracellulare serovars (7 strains) and M. scrofulaceum (4 strains) were found in 11 isolates (12%) indicating that M. avium (88%) was the major opportunistic species in the M. avium complex isolates in Brazilian AIDS patients

Investigation of the hepatitis C virus replication complex.

Formation of a membrane-associated replication complex, composed of viral proteins, replicating RNA, altered cellular membranes, and other host factors, is a hallmark of all positive-strand RNA viruses. In the case of HCV, RNA replication takes place in a likely endoplasmic reticulum-derived membrane alteration referred to as the "membranous web." In vitro transcription-translation, membrane extraction and flotation analyses, immunofluorescence microscopy, fluorescent in situ hybridization, and RNA metabolic labeling followed by confocal laser scanning microscopy have yielded insights into the structure and function of the HCV replication complex. We describe these techniques and highlight selected results.

Protein-protein interaction investigated by steered molecular dynamics: the TCR-pMHC complex.

We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered, which only differ by the mutation of a single amino acid on the peptide; one is a strong agonist that produces T cell activation in vivo, while the other is an antagonist. We investigate the interaction mechanism from a large number of unbinding trajectories by analyzing van der Waals and electrostatic interactions and by computing energy changes in proteins and solvent. In addition, dissociation potentials of mean force are calculated with the Jarzynski identity, using an averaging method developed for our steering scheme. We analyze the convergence of the Jarzynski exponential average, which is hampered by the large amount of dissipative work involved and the complexity of the system. The resulting dissociation free energies largely underestimate experimental values, but the simulations are able to clearly differentiate between wild-type and mutated TCR-pMHC and give insights into the dissociation mechanism.

The complex history of the olive tree: from Late Quaternary diversification of Mediterranean lineages to primary domestication in the northern Levant.

The location and timing of domestication of the olive tree, a key crop in Early Mediterranean societies, remain hotly debated. Here, we unravel the history of wild olives (oleasters), and then infer the primary origins of the domesticated olive. Phylogeography and Bayesian molecular dating analyses based on plastid genome profiling of 1263 oleasters and 534 cultivated genotypes reveal three main lineages of pre-Quaternary origin. Regional hotspots of plastid diversity, species distribution modelling and macrofossils support the existence of three long-term refugia; namely the Near East (including Cyprus), the Aegean area and the Strait of Gibraltar. These ancestral wild gene pools have provided the essential foundations for cultivated olive breeding. Comparison of the geographical pattern of plastid diversity between wild and cultivated olives indicates the cradle of first domestication in the northern Levant followed by dispersals across the Mediterranean basin in parallel with the expansion of civilizations and human exchanges in this part of the world.

Adolescent substance-use assessment: methodological issues in the use of the Adolescent Drug Abuse Diagnosis (ADAD).

During the past twenty years, various instruments have been developed for the assessment of substance use in adolescents, mainly in the United States. However, few of them have been adapted to, and validated in, French-speaking populations. Consequently, although increasing alcohol and drug use among teenagers has become a major concern, the various health and social programs developed in response to this specific problem have received little attention with regard to follow-up and outcome assessment. A standardized multidimensional assessment instrument adapted for adolescents is needed to assess the individual needs of adolescents and assign them to the most appropriate treatment setting, to provide a single measurement within and across health and social systems, and to conduct treatment outcome evaluations. Moreover, having an available instrument makes it possible to develop longitudinal and transcultural research studies. For this reason, a French version of the Adolescent Drug Abuse Diagnosis (ADAD) was developed and validated at the University Child and Adolescent Psychiatric Clinic in Lausanne, Switzerland. This article aims to discuss the methodological issues that we faced when using the ADAD instrument in a 4-year longitudinal study including adolescent substance users. Methodological aspects relating to the content and format of the instrument, the assessment administration and the statistical analyses are discussed.