Positional bias of general and tissue-specific regulatory motifs in mouse gene promoters

Background: The arrangement of regulatory motifs in gene promoters, or promoterarchitecture, is the result of mutation and selection processes that have operated over manymillions of years. In mammals, tissue-specific transcriptional regulation is related to the presence ofspecific protein-interacting DNA motifs in gene promoters. However, little is known about therelative location and spacing of these motifs. To fill this gap, we have performed a systematic searchfor motifs that show significant bias at specific promoter locations in a large collection ofhousekeeping and tissue-specific genes.Results: We observe that promoters driving housekeeping gene expression are enriched inparticular motifs with strong positional bias, such as YY1, which are of little relevance in promotersdriving tissue-specific expression. We also identify a large number of motifs that show positionalbias in genes expressed in a highly tissue-specific manner. They include well-known tissue-specificmotifs, such as HNF1 and HNF4 motifs in liver, kidney and small intestine, or RFX motifs in testis,as well as many potentially novel regulatory motifs. Based on this analysis, we provide predictionsfor 559 tissue-specific motifs in mouse gene promoters.Conclusion: The study shows that motif positional bias is an important feature of mammalianproximal promoters and that it affects both general and tissue-specific motifs. Motif positionalconstraints define very distinct promoter architectures depending on breadth of expression andtype of tissue.

Comparative analysis of amino acid repeats in rodents and humans

Amino acid tandem repeats, also called homopolymeric tracts, are extremely abundant in eukaryotic proteins. To gain insight into the genome-wide evolution of these regions in mammals, we analyzed the repeat content in a large data set of rat-mouse-human orthologs. Our results show that human proteins contain more amino acid repeats than rodent proteins and that trinucleotide repeats are also more abundant in human coding sequences. Using the human species as an outgroup, we were able to address differences in repeat loss and repeat gain in the rat and mouse lineages. In this data set, mouse proteins contain substantially more repeats than rat proteins, which can be at least partly attributed to a higher repeat loss in the rat lineage. The data are consistent with a role for trinucleotide slippage in the generation of novel amino acid repeats. We confirm the previously observed functional bias of proteins with repeats, with overrepresentation of transcription factors and DNA-binding proteins. We show that genes encoding amino acid repeats tend to have an unusually high GC content, and that differences in coding GC content among orthologs are directly related to the presence/absence of repeats. We propose that the different GC content isochore structure in rodents and humans may result in an increased amino acid repeat prevalence in the human lineage.

Stepwise evaluation of unexplained syncope in a large ambulatory population

La syncope est un symptôme clinique fréquent mais son origine demeure indéterminée jusque dans 60% des cas de patients admis dans un centre d'urgences. Le développement de consultations spécialisées de la syncope a considérablement modifié l'évaluation des patients avec une syncope inexpliquée en les orientant vers des stratégies d'investigations non-invasives, tels que le tilt-test, le massage du sinus carotidien et le test ^hyperventilation. Cependant, il existe peu de données dans 10 la littérature concernant dans la performance diagnostique réelle de ces tests fonctionnels.Notre travail de recherche porte sur l'analyse des données des 939 premiers patients adressés à la consultation ambulatoire de la syncope du CHUV pour l'investigation d'une syncope d'origine indéterminée. L'objectif de notre travail de thèse est 1) d'évaluer la performance diagnostique de l'algorithme de prise en charge standardisé et de ses différents tests pratiqués dans le cadre de notre 15 consultation et 2) de déterminer les caractéristiques cliniques communes des patients avec un diagnostic final de syncope d'origine rythmique ou vaso-vagale.Notre travail de thèse démontre qu'un algorithme de prise en charge standardisé basé sur des tests non-invasifs permet de déterminer 2/3 des causes de syncope initialement d'origine indéterminée. Par ailleurs, notre travail montre que des étiologies bénignes, telles que la syncope d'origine vaso- 20 vagale ou psychogène, représentent la moitié des causes syncopales alors que les arythmies cardiaques demeurent peu fréquentes. Finalement, notre travail démontre que l'absence de symptomatologie prodromique, en particulier chez les patients âgés avec une limitation fonctionnelle ou un allongement de la durée de l'onde Ρ à l'électrocardiogramme, suggère une syncope d'origine rythmique. Ce travail de thèse contribuera à optimaliser notre algorithme de prise 25 en charge standardisée de la syncope d'origine indéterminée et ouvre de nouvelles perspectives de recherche dans le développement de modèles basés sur des facteurs cliniques permettant de prédire les principales causes syncopales.

Testing a large-scale forestry scenario model by means of successive inventories on a forest property

Abstract

A large bullet in the bladder.

All manner of foreign bodies have been extracted from the bladder. Introduction into the bladder may be through self-insertion, iatrogenic means or migration from adjacent organs. Extraction should be tailored according to the nature of the foreign body and should minimise bladder and urethral trauma. We report a case of a bullet injury to the bladder, which finally presented as a gross hematuria after remaining asymptomatic for four years. We present here an alternative to suprapubic cystostomy with a large bladder foreign body treated via a combined transurethral unroofing followed by removal using a grasper passed through a suprapubic laparoscopic port.

Evaluation of the Confirmation Light System at Signalized Intersections in Medium to Large Iowa Communities to Reduce Red Light Running Violations”, TR-657, 2015

Red light running continues to be a serious safety concern for many communities in the United States. The Federal Highway Administration reported that in 2011, red light running accounted for 676 fatalities nationwide. Red light running crashes at a signalized intersections are more serious, especially in high speed corridors where speeds are above 35 mph. Many communities have invested in red light countermeasures including low-cost strategies (e.g. signal backplates, targeted enforcement, signal timing adjustments and improvement with signage) to high-cost strategies (e.g. automated enforcement and intersection geometric improvements). This research study investigated intersection confirmation lights as a low-cost strategy to reduce red light running violations. Two intersections in Altoona and Waterloo, Iowa were equipped with confirmation lights which targeted the through and left turning movements. Confirmation lights enable a single police officer to monitor a specific lane of traffic downstream of the intersection. A before-after analysis was conducted in which a change in red light running violations prior to- and 1 and 3 months after installation were evaluated. A test of proportions was used to determine if the change in red light running violation rates were statistically significant at the 90 and 95 percent levels of confidence. The two treatment intersections were then compared to the changes of red light running violation rates at spillover intersections (directly adjacent to the treatment intersections) and control intersections. The results of the analysis indicated a 10 percent reduction of red light running violations in Altoona and a 299 percent increase in Waterloo at the treatment locations. Finally, the research team investigated the time into red for each observed red light running violation. The analysis indicated that many of the violations occurred less than one second into the red phase and that most of the violation occurred during or shortly after the all-red phase.

MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma.

Myeloid cell leukemia-1 (MCL1) is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared with germinal center B-cell-like DLBCL patient samples (P=2.7 × 10(-10)). Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; P=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization data of 203 DLBCL samples and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1-positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.

Large-scale DNA sequencing in taxonomy and conservation : a case study with the mayfly family Heptageniidae (Ephemeroptera) in the Alps and Madagascar

Les larves aquatiques d'éphémères (Ephemeroptera) colonisent toutes les eaux douces du monde et sont couramment utilisées comme bio-indicateurs de la qualité de l'eau. Le genre Rhithrogena (Heptageniidae) est le deuxième plus diversifié chez les éphémères, et plusieurs espèces européennes ont une distribution restreinte dans des environnements alpins sensibles. Les espèces de Rhithrogena ont été classées en "groupes d'espèces" faciles à identifier. Cependant, malgré leur importance écologique et en terme de conservation, beaucoup d'espèces présentent des différences morphologiques ambiguës, suggérant que lataxonomie actuelle ne refléterait pas correctement leur diversité évolutive. De plus, aucune information sur leurs relations, leur origine, le taux de spéciation ou les mécanismes ayant provoqué leur remarquable diversification dans les Alpes n'est disponible. Nous avons d'abord examiné le statut spécifique d'environ 50% des espèces européennes de Rhithrogena en utilisant un large échantillonnage de populations alpines incluant 22 localités typiques, ainsi qu'une analyse basée sur le modèle général mixte de Yule et de coalescence (GMYC) appliqué à un gène mitochondrial standard (coxl) et à un gène nucléaire développé spécifiquement pour cette étude. Nous avons observé un regroupement significatif des séquences coxl en 31 espèces potentielles, et nos résultats ont fortement suggéré la présence d'espèces cryptiques et de fractionnements taxonomiques excessifs chez les Rhithrogena. Nos analyses phylogénétiques ont démontré la monophylie de quatre des six groupes d'espèces reconnus présents dans notre échantillonnage. La taxonomie ADN développée dans cette étude pose les bases d'une future révision de ce genre important mais cryptique en Europe. Puis nous avons mené une étude phylogénétique multi-gènes entre les espèces européennes de Rhithrogena. Les données provenant de trois gènes nucléaires et de deux gènes mitochondriaux ont été largement concordantes, et les relations entre les espèces bien résolues au sein de la plupart des groupes d'espèces dans une analyse combinant tous les gènes. En l'absence de points de calibration extérieurs tels que des fossiles, nous avons appliqué à nos données mitochondriales une horloge moléculaire standard pour les insectes, suggérant une origine des Rhithrogena alpins à la limite Oligocène / Miocène. Nos résultats ont montré le rôle prépondérant qu'ont joué les glaciations du quaternaire dans leur diversification, favorisant la spéciation d'au moins la moitié des espèces actuelle dans les Alpes. La biodiversité et le taux d'endémisme à Madagascar, notamment au niveau de la faune des eaux douces, sont parmi les plus extraordinaires et les plus menacés au monde. On pense que beaucoup d'espèces d'éphémères sont restreintes à un seul bassin versant (microendémisme) dans les zones forestières, ce qui les rendrait particulièrement sensibles à la réduction et à la dégradation de leur habitat. Mis à part deux espèces décrites, Afronurus matitensis et Compsoneuria josettae, les Heptageniidae sont pratiquement inconnus à Madagascar. Les deux genres ont une distribution discontinue en Afrique, à Madagascar et en Asie du Sud-Est, et leur taxonomie complexe est régulièrement révisée. L'approche standard pour comprendre leur diversité, leur endémisme et leur origine requerrait un échantillonnage étendu sur plusieurs continents et des années de travaux taxonomiques. Pour accélérer le processus, nous avons utilisé des collections de musées ainsi que des individus fraîchement collectés, et appliqué une approche combinant taxonomie ADN et phylogénie. L'analyses GMYC du gène coxl a délimité 14 espèces potentielles à Madagascar, dont 70% vraisemblablement microendémiques. Une analyse phylogénique incluant des espèces africaines et asiatiques portant sur deux gènes mitochondriaux et quatre gènes nucléaires a montré que les Heptageniidae malgaches sont monophylétiques et groupe frère des Compsoneuria africains. L'existence de cette lignée unique, ainsi qu'un taux élevé de microendémisme, mettent en évidence leur importance en terme de conservation. Nos résultats soulignent également le rôle important que peuvent jouer les collections de musées dans les études moléculaires et en conservation. - Aquatic nymphs of mayflies (Ephemeroptera) colonize all types of freshwaters throughout the world and are extensively used as bio-indicators of water quality. Rhithrogena (Heptageniidae) is the second most species-rich genus of mayflies, and several European species have restricted distributions in sensitive Alpine environments and therefore are of conservation interest. The European Rhithrogena species are arranged into "species groups" that are easily identifiable. However, despite their ecological and conservation importance, ambiguous morphological differences among many species suggest that the current taxonomy may not accurately reflect their evolutionary diversity. Moreover, no information about their relationships, origin, timing of speciation and mechanisms promoting their successful diversification in the Alps is available. We first examined the species status of ca. 50% of European Rhithrogena diversity using a widespread sampling scheme of Alpine species that included 22 type localities, general mixed Yule- coalescent (GMYC) model analysis of one standard mitochondrial (coxl) and one newly developed nuclear marker. We observed significant clustering of coxl into 31 GMYC species, and our results strongly suggest the presence of both cryptic diversity and taxonomic oversplitting in Rhithrogena. Phylogenetic analyses recovered four of the six recognized species groups in our samples as monophyletic. The DNA taxonomy developed here lays the groundwork for a future revision of this important but cryptic genus in Europe. Then we conducted a species-level, multiple-gene phylogenetic study of European Rhithrogena. Data from three nuclear and two mitochondrial loci were broadly congruent, and species-level relationships were well resolved within most species groups in a combined analysis. In the absence of external calibration points like fossils, we applied a standard insect molecular clock hypothesis to our mitochondrial data, suggesting an origin of Alpine Rhithrogena in the Oligocene / Miocene boundary. Our results highlighted the preponderant role that quaternary glaciations played in their diversification, promoting speciation of at least half of the current diversity in the Alps. Madagascar's biodiversity and endemism are among the most extraordinary and endangered in the world. This includes the island's freshwater biodiversity, although detailed knowledge of the diversity, endemism, and biogeographic origin of freshwater invertebrates is lacking. Many mayfly species are thought to be restricted to single river basins (microendemic species) in forested areas, making them particularly sensitive to habitat reduction and degradation. The Heptageniidae are practically unknown in Madagascar except for two described species, Afronurus matitensis and Compsoneuria josettae. Both genera have a disjunct distribution in Africa, Madagascar and Southeast Asia, and a complex taxonomic status still in flux. The standard approach to understanding their diversity, endemism, and origin would require extensive field sampling on several continents and years of taxonomic work. Here we circumvent this using museum collections and freshly collected individuals in a combined approach of DNA taxonomy and phylogeny. The cox/-based GMYC analysis revealed 14 putative species on Madagascar, 70% of which potentially microendemics. A phylogenetic analysis that included African and Asian species and data from two mitochondrial and four nuclear loci indicated the Malagasy Heptageniidae are monophyletic and sister to African Compsoneuria. The observed monophyly and high microendemism highlight their conservation importance. Our results also underline the important role that museum collections can play in molecular studies, especially in critically endangered biodiversity hotspots like Madagascar.

Reconstruction of the recent history of a large deep prealpine lake (Lake Bourget, France) using subfossil chironomids, diatoms, and organic matter analysis: towards the definition of a lake-specific reference state

This paper presents the recent history of a large prealpine lake (Lake Bourget) using chironomids, diatoms and organic matter analysis, and deals with the ability of paleolimnological approach to define an ecological reference state for the lake in the sense of the European Framework Directive. The study at low resolution of subfossil chironomids in a 4-m-long core shows the remarkable stability over the last 2.5 kyrs of the profundal community dominated by a Micropsectra-association until the beginning of the twentieth century, when oxyphilous taxa disappeared. Focusing on this key recent period, a high resolution and multiproxy study of two short cores reveals a progressive evolution of the lake's ecological state. Until AD 1880, Lake Bourget showed low organic matter content in the deep sediments (TOC less than 1%) and a well-oxygenated hypolimnion that allowed the development of a profundal oxyphilous chironomid fauna (Micropsectra-association). Diatom communities were characteristic of oligotrophic conditions. Around AD 1880, a slight increase in the TOC was the first sign of changes in lake conditions. This was followed by a first limited decline in oligotrophic diatom taxa and the disappearance of two oxyphilous chironomid taxa at the beginning of the twentieth century. The 1940s were a major turning point in recent lake history. Diatom assemblages and accumulation of well preserved planktonic organic matter in the sediment provide evidence of strong eutrophication. The absence of profundal chironomid communities reveals permanent hypolimnetic anoxia. From AD 1995 to 2006, the diatom assemblages suggest a reduction in nutrients, and a return to mesotrophic conditions, a result of improved wastewater management. However, no change in hypolimnion benthic conditions has been shown by either the organic matter or the subfossil chironomid profundal community. Our results emphasize the relevance of the paleolimnological approach for the assessment of reference conditions for modern lakes. Before AD 1900, the profundal Micropsectra-association and the Cyclotella dominated diatom community can be considered as the Lake Bourget reference community, which reflects the reference ecological state of the lake.

Fluid dynamical prediction of changed v1-flow at energies available at the CERN Large Hadron Collider

Substantial collective flow is observed in collisions between lead nuclei at Large Hadron Collider (LHC) as evidenced by the azimuthal correlations in the transverse momentum distributions of the produced particles. Our calculations indicate that the global v1-flow, which at RHIC peaked at negative rapidities (named third flow component or antiflow), now at LHC is going to turn toward forward rapidities (to the same side and direction as the projectile residue). Potentially this can provide a sensitive barometer to estimate the pressure and transport properties of the quark-gluon plasma. Our calculations also take into account the initial state center-of-mass rapidity fluctuations, and demonstrate that these are crucial for v1 simulations. In order to better study the transverse momentum flow dependence we suggest a new"symmetrized" vS1(pt) function, and we also propose a new method to disentangle global v1 flow from the contribution generated by the random fluctuations in the initial state. This will enhance the possibilities of studying the collective Global v1 flow both at the STAR Beam Energy Scan program and at LHC.

MGS Esmeralda: new large seed mungbean cultivar

Mungbean cultivar MGS Esmeralda was developed by Asian Vegetable Research and Development Center (Shanhua, Taiwan), as a result of crossing between the lines VC 1973A and VC 2768A. In ten trials conducted in the State of Minas Gerais, Brazil, it produced 13.5% more grains than 'Ouro Verde MG-2' (control cultivar), and its highest yield was 2,550 kg ha-1. The cultivar MGS Esmeralda is more susceptible to lodging, and its pods mature more uniformly than Ouro Verde MG-2 pods. One hundred-seed mass of 'MGS Esmeralda' ranged between 5.5 and 6.8 g. Both cultivars are susceptible to powdery mildew and cercospora leaf spot.

Goal setting and monetary incentives: when large stakes are not enough

The aim of this paper is to test the effectiveness of wage-irrelevant goal setting policies in a laboratory environment. In our design, managers can assign a goal to their workers by setting a certain level of performance on the work task. We establish our theoretical conjectures by developing a model where assigned goals act as reference points to workers’ intrinsic motivation. Consistent with our model, we find that managers set goals which are challenging but attainable for an average-ability worker. Workers respond to these goals by increasing effort, performance and by decreasing on-the-job leisure activities with respect to the no-goal setting baseline. Finally, we study the interaction between goal setting and monetary rewards and find that goal setting is most effective when monetary incentives are strong. These results suggest that goal setting may produce intrinsic motivation and increase workers’ performance beyond what is achieved using solely monetary incentives.

Oligogalacturonide defense signals in plants: large fragments interact with the plasma membrane in vitro.

Oligogalacturonides are plant cell wall-derived regulatory molecules which stimulate defense gene expression during pathogenesis. In vitro, these compounds enhance the phosphorylation of an approximately 34-kDa protein (pp34) in purified plasma membranes from potato and tomato leaves. We now show that polygalacturonate-enhanced phosphorylation of pp34 occurs in plasma membranes purified from tomato roots, hypocotyls, and stems and from undifferentiated potato cells. Furthermore, a similar phosphorylation is detected in leaf plasma membranes from soybean, a plant distantly related to tomato. Purified oligogalacturonides 13 to at least 26 residues long stimulate pp34 thiophosphorylation in vitro. This stimulation pattern differs from the induction of many known defense responses in vivo, where a narrower range of smaller fragments, between approximately 10 and 15 residues long, are active. On the basis of these differences we suggest that observed effects of applied exogenous oligogalacturonides on defense responses may not necessarily reflect the situation during pathogenesis. The cell wall could act as a barrier to many exogenous oligo- and polygalacturonides as well as other large regulatory ligands.