The abrupt climate change at the Eocene-Oligocene boundary and the emergence of South-East Asia triggered the spread of sapindaceous lineages.

Background and Aims Paleoclimatic data indicate that an abrupt climate change occurred at the Eocene-Oligocene (E-O) boundary affecting the distribution of tropical forests on Earth. The same period has seen the emergence of South-East (SE) Asia, caused by the collision of the Eurasian and Australian plates. How the combination of these climatic and geomorphological factors affected the spatio-temporal history of angiosperms is little known. This topic is investigated by using the worldwide sapindaceous clade as a case study. Methods Analyses of divergence time inference, diversification and biogeography (constrained by paleogeography) are applied to a combined plastid and nuclear DNA sequence data set. Biogeographical and diversification analyses are performed over a set of trees to take phylogenetic and dating uncertainty into account. Results are analysed in the context of past climatic fluctuations. Key Results An increase in the number of dispersal events at the E-O boundary is recorded, which intensified during the Miocene. This pattern is associated with a higher rate in the emergence of new genera. These results are discussed in light of the geomorphological importance of SE Asia, which acted as a tropical bridge allowing multiple contacts between areas and additional speciation across landmasses derived from Laurasia and Gondwana. Conclusions This study demonstrates the importance of the combined effect of geomorphological (the emergence of most islands in SE Asia approx. 30 million years ago) and climatic (the dramatic E-O climate change that shifted the tropical belt and reduced sea levels) factors in shaping species distribution within the sapindaceous clade.

Evolutionary trajectories of primate genes involved in HIV pathogenesis.

The current availability of five complete genomes of different primate species allows the analysis of genetic divergence over the last 40 million years of evolution. We hypothesized that the interspecies differences observed in susceptibility to HIV-1 would be influenced by the long-range selective pressures on host genes associated with HIV-1 pathogenesis. We established a list of human genes (n = 140) proposed to be involved in HIV-1 biology and pathogenesis and a control set of 100 random genes. We retrieved the orthologous genes from the genome of humans and of four nonhuman primates (Pan troglodytes, Pongo pygmaeus abeli, Macaca mulatta, and Callithrix jacchus) and analyzed the nucleotide substitution patterns of this data set using codon-based maximum likelihood procedures. In addition, we evaluated whether the candidate genes have been targets of recent positive selection in humans by analyzing HapMap Phase 2 single-nucleotide polymorphisms genotyped in a region centered on each candidate gene. A total of 1,064 sequences were used for the analyses. Similar median K(A)/K(S) values were estimated for the set of genes involved in HIV-1 pathogenesis and for control genes, 0.19 and 0.15, respectively. However, genes of the innate immunity had median values of 0.37 (P value = 0.0001, compared with control genes), and genes of intrinsic cellular defense had K(A)/K(S) values around or greater than 1.0 (P value = 0.0002). Detailed assessment allowed the identification of residues under positive selection in 13 proteins: AKT1, APOBEC3G, APOBEC3H, CD4, DEFB1, GML, IL4, IL8RA, L-SIGN/CLEC4M, PTPRC/CD45, Tetherin/BST2, TLR7, and TRIM5alpha. A number of those residues are relevant for HIV-1 biology. The set of 140 genes involved in HIV-1 pathogenesis did not show a significant enrichment in signals of recent positive selection in humans (intraspecies selection). However, we identified within or near these genes 24 polymorphisms showing strong signatures of recent positive selection. Interestingly, the DEFB1 gene presented signatures of both interspecies positive selection in primates and intraspecies recent positive selection in humans. The systematic assessment of long-acting selective pressures on primate genomes is a useful tool to extend our understanding of genetic variation influencing contemporary susceptibility to HIV-1.

Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project.

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.

Estimating sex-specific dispersal rates with autosomal markers in hierarchically structured populations.

A recent study suggests that sex-specific dispersal rates can be quantitatively estimated on the basis of sex- and state-specific (pre- vs. postdispersal) F-statistics. In the present paper, we extend this approach to account for the hierarchical structure of natural populations, and we validate it through individual-based simulations. The model is applied to an empirical data set consisting of 536 individuals (males, females, and predispersal juveniles) of greater white-toothed shrews (Crocidura russula), sampled according to a hierarchical design and typed for seven autosomal microsatellite loci. From this dataset, dispersal is significantly female biased at the local scale (breeding-group level), but not at the larger scale (among local populations). We argue that selective pressures on dispersal are likely to depend on the spatial scale considered, and that short-distance dispersal should mainly respond to kin interactions (inbreeding or kin competition avoidance), which exert differential pressure on males and females.

The UniProt-GO Annotation database in 2011.

The GO annotation dataset provided by the UniProt Consortium (GOA: http://www.ebi.ac.uk/GOA) is a comprehensive set of evidenced-based associations between terms from the Gene Ontology resource and UniProtKB proteins. Currently supplying over 100 million annotations to 11 million proteins in more than 360,000 taxa, this resource has increased 2-fold over the last 2 years and has benefited from a wealth of checks to improve annotation correctness and consistency as well as now supplying a greater information content enabled by GO Consortium annotation format developments. Detailed, manual GO annotations obtained from the curation of peer-reviewed papers are directly contributed by all UniProt curators and supplemented with manual and electronic annotations from 36 model organism and domain-focused scientific resources. The inclusion of high-quality, automatic annotation predictions ensures the UniProt GO annotation dataset supplies functional information to a wide range of proteins, including those from poorly characterized, non-model organism species. UniProt GO annotations are freely available in a range of formats accessible by both file downloads and web-based views. In addition, the introduction of a new, normalized file format in 2010 has made for easier handling of the complete UniProt-GOA data set.

Sibling competition and the risk of falling out of the nest

In birds, sibling competition encompasses several activities, one of which is jostling for position, that is, competing for the location in the nest where parents predictably deliver food items. We hypothesized that nestlings that compete by jostling for position may fall out of the nest either accidentally or because siblings push each other to reduce brood size. This hypothesis predicts that in a competitive environment needy nestlings trade-off the benefit of being fed against the cost of falling out of the nest. As a first attempt to evaluate this hypothesis, we experimentally manipulated the number of young per brood in the colonial Alpine swift, Apus melba. Nestlings fell out of their colony more frequently when reared in enlarged than in reduced broods. Because brood size manipulation affects not only the number of young per nest but also their body condition, we analysed an extended data set to disentangle these two factors. This analysis showed that, independently of brood size, nestlings in poor condition and those reared in broods where sibling differed markedly in weight were more likely to disappear from the colony. Nestling disappearance also occurred predominantly in nests close to the colony entrances. Although nestling swifts can wander in the colony and become adopted in neighbouring nests, we found no evidence that wandering per se increased the risk of falling out of the colony. Our study therefore highlights a novel cost of scramble competition.

Genetic and karyotypic structure in the shrews of the Sorex araneus group: are they independent?

The species of the common shrew (Sorex araneus) group are morphologically very similar but exhibit high levels of karyotypic variation. Here we used genetic variation at 10 microsatellite markers in a data set of 212 individuals mostly sampled in the western Alps and composed of five karyotypic taxa (Sorex coronatus, Sorex antinorii and the S. araneus chromosome races Cordon, Bretolet and Vaud) to investigate the concordance between genetic and karyotypic structure. Bayesian analysis confirmed the taxonomic status of the three sampled species since individuals consistently grouped according to their taxonomical status. However, introgression can still be detected between S. antinorii and the race Cordon of S. araneus. This observation is consistent with the expected low karyotypic complexity of hybrids between these two taxa. Geographically based cryptic substructure was discovered within S. antinorii, a pattern consistent with the different postglaciation recolonization routes of this species. Additionally, we detected two genetic groups within S. araneus notwithstanding the presence of three chromosome races. This pattern can be explained by the probable hybrid status of the Bretolet race but also suggests a relatively low impact of chromosomal differences on genetic structure compared to historical factors. Finally, we propose that the current data set (available at http://www.unil.ch/dee/page7010_en.html#1) could be used as a reference by those wanting to identify Sorex individuals sampled in the western Alps.

A fast 3D approach for coronary MRA.

Two-dimensional (2D)-breath-hold coronary magnetic resonance angiography (MRA) has been shown to be a fast and reliable method to depict the proximal coronary arteries. Recent developments, however, allow for free-breathing navigator gated and navigator corrected three-dimensional (3D) coronary MRA. These 3D approaches have potential for improved signal-to-noise ratio (SNR) and allow for the acquisition of adjacent thin slices without the misregistration problems known from 2D approaches. Still, a major impediment of a 3D acquisition is the increased scan time. The purpose of this study was the implementation of a free-breathing navigator gated and corrected ultra-fast 3D coronary MRA technique, which allows for scan times of less than 5 minutes. Twelve healthy adult subjects were examined in the supine position using a navigator gated and corrected ECG triggered ultra-fast 3D interleaved gradient echo planar imaging sequence (TFE-EPI). A 3D slab, consisting of 20 slices with a reconstructed slice thickness of 1.5 mm, was acquired with free-breathing. The diastolic TFE-EPI acquisition block was preceded by a T2prep pre-pulse, a diaphragmatic navigator pulse, and a fat suppression pre-pulse. With a TR of 19 ms and an effective TE of 5.4 ms, the duration of the data acquisition window duration was 38 ms. The in-plane spatial resolution was 1.0-1.3 mm*1.5-1.9 mm. In all cases, the entire left main (LM) and extensive portions of the left anterior descending (LAD) and right coronary artery (RCA) could be visualized with an average scan time for the entire 3D-volume data set of 2:57 +/- 0:51 minutes. Average contiguous vessel length visualized was 53 +/- 11 mm (range: 42 to 75 mm) for the LAD and 84 +/- 14 mm (range: 62 to 112 mm) for the RCA. Contrast-to-noise between coronary blood and myocardium was 5.0 +/- 2.3 for the LM/LAD and 8.0 +/- 2.9 for the RCA, resulting in an excellent suppression of myocardium. We present a new approach for free-breathing 3D coronary MRA, which allows for scan times superior to corresponding 2D coronary MRA approaches, and which takes advantage of the enhanced SNR of 3D acquisitions and the post-processing benefits of thin adjacent slices. The robust image quality and the short average scanning time suggest that this approach may be useful for screening the major coronary arteries or identification of anomalous coronary arteries. J. Magn. Reson. Imaging 1999;10:821-825.

Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome.

INTRODUCTION: We investigated whether mRNA levels of E2F1, a key transcription factor involved in proliferation, differentiation and apoptosis, could be used as a surrogate marker for the determination of breast cancer outcome. METHODS: E2F1 and other proliferation markers were measured by quantitative RT-PCR in 317 primary breast cancer patients from the Stiftung Tumorbank Basel. Correlations to one another as well as to the estrogen receptor and ERBB2 status and clinical outcome were investigated. Results were validated and further compared with expression-based prognostic profiles using The Netherlands Cancer Institute microarray data set reported by Fan and colleagues. RESULTS: E2F1 mRNA expression levels correlated strongly with the expression of other proliferation markers, and low values were mainly found in estrogen receptor-positive and ERBB2-negative phenotypes. Patients with low E2F1-expressing tumors were associated with favorable outcome (hazard ratio = 4.3 (95% confidence interval = 1.8-9.9), P = 0.001). These results were consistent in univariate and multivariate Cox analyses, and were successfully validated in The Netherlands Cancer Institute data set. Furthermore, E2F1 expression levels correlated well with the 70-gene signature displaying the ability of selecting a common subset of patients at good prognosis. Breast cancer patients' outcome was comparably predictable by E2F1 levels, by the 70-gene signature, by the intrinsic subtype gene classification, by the wound response signature and by the recurrence score. CONCLUSION: Assessment of E2F1 at the mRNA level in primary breast cancer is a strong determinant of breast cancer patient outcome. E2F1 expression identified patients at low risk of metastasis irrespective of the estrogen receptor and ERBB2 status, and demonstrated similar prognostic performance to different gene expression-based predictors.

A two-level analysis of the determinants of direct democratic choices in European, immigration and foreign policy in Switzerland

This article employs a unique data set - covering 25 popular votes on foreign, European and immigration/asylum policy held between 1992 and 2006 in Switzerland - in order to examine the conditional impact of context upon utilitarian, cultural, political and cognitive determinants of individual attitudes toward international openness. Our results reveal clear patterns of cross-level interactions between individual determinants and the project-related context of the vote. Thus, although party cues and political competence have a strong impact on individuals' support for international openness, this impact is substantially mediated by the type of coalition that is operating within the party elite. Similarly, subjective utilitarian and cultural considerations influence the voters' decision in interaction with the content of the proposal submitted to the voters as well as with the framing of the voting campaign.

Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma.

PURPOSE: Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide. PATIENTS AND METHODS: Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy. RESULTS: An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response. CONCLUSION: This study provides first clinical evidence for the implication of a "glioma stem cell" or "self-renewal" phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.

Infectious Disease Burden after Solid Organ Transplantation (SOT) in the Swiss Transplant Cohort Study (STCS).

Infectious diseases (ID) are a major cause of morbidity and mortality after SOT. Since May 2008, the STCS has registered 95% of all SOT recipients in Switzerland. The extensive data set includes pre- and post-transplant variables that are prospectively collected at transplantation, 6 months post-transplant, and yearly thereafter. All ID events are recorded using internationally validated defi nitions. We obtained data from 1101 patients (79 heart, 685 kidney, 29 kidney-pancreas, 212 liver, and 96 lung transplants). So far the median observation times were 0.8 (IQR 0.3-1.4; heart); 1.1 (0.6-1.8, kidney); 1.1 (0.6-1.9, kidney-pancreas); 1.0 (0.5-1.7, liver); and 0.9 years (0.5-1.5, lung). The highest rates of proven or probable ID events were seen in lung (76%), followed by liver (64%), heart (62%), kidney-pancreas (62%), kidney (58%). During the observation period, ID was the cause of death in 19 patients (1.7%). Rates of infections per person-years according to pathogen and type of transplantation are shown in Figure 1. The data indicate that virus infections are only second after bacteria whereas fungi occur at relatively low rates. This prospective and standardized long-term collection of all ID events will allow a comprehensive assessment of the burden of ID across all SOT types in Switzerland. Regular analysis will identify new trends, serve as a quality control and help design anti-infectious interventions aiming at increasing safety and improving overall transplantation outcome.

Reservoir compensation releases : impact on the macroinvertebrate community of the Derwent River, Northumberland, UK-A longitudinal

River regulation for the purposes of public water supply causes the flow regime downstream of a dam to change. Traditionally, in the UK, such regulation was accompanied by requirements for reservoir releases to compensate downstream water users (e.g. industry) for the loss of natural flow (compensation flows). In this article, we compare a unique pre-impoundment macroinvertebrate data set for a regulated upland river with survey data post-impoundment. This allows a longitudinal assessment of the response of the system to regulation. The Derwent River, Northumberland, was impounded in 1966. Impacts on the hydrological regime were quantified by comparing long-term hydrographs, flow duration curves, flow ranges and flashiness indices for the pre-impoundment and post-impoundment periods. The comparison of changes in macroinvertebrate richness and diversity post-impoundment showed that the change in flow regime has had limited effect on the ecological community structure. The flow regime of the Derwent River has become less flashy with fewer extreme events, and the richness and the diversity of macroinvertebrates have, in some cases, increased and at worst have not deteriorated. We suggest that this reflects the strict compensation regime, which has guaranteed minimum flows at all times. Copyright (c) 2012 John Wiley & Sons, Ltd.

Genomic copy number aberrations in glioblastoma, response to therapy and molecular machanisms

Résumé : Le glioblastome (GBM, WHO grade IV) est la tumeur cérébrale primaire la plus fréquente et la plus maligne, son pronostic reste très réservé et sa réponse aux différents traitements limitée. Récemment, une étude clinique randomisée (EORTC 26981/NCIC CE.3) a démontré que le traitement combiné de temozolomide et radiothérapie (RT/TMZ) est le meilleur dans les cas de GBM nouvellement diagnostiqués [1]. Cependant, seul un sous-groupe de patients bénéficie du traitement RT/TMZ et même parmi eux, leur survie reste très limitée. Pour tenter de mieux comprendre les réponses au traitement RT/TMZ, la biologie du GBM, identifier d'autres facteurs de résistance et découvrir de nouvelles cibles aux traitements, nous avons conduit une analyse moléculaire étendue à 73 patients inclus dans cette étude clinique. Nous avons complété les résultats moléculaires déjà obtenus par un profil génomique du nombre de copies par Array Comparative Genomic Hybridization. Afin d'atteindre nos objectifs, nous avons analysé en parallèle les données cliniques des patients et leurs profils moléculaires. Nos résultats confirment des analyses connues dans le domaine des aberrations du nombre de copies (CNA) et de profils du glioblastome. Nous avons observé une bonne corrélation entre le CNA génomique et l'expression de l'ARN messager dans le glioblastome et identifié un nouveau modèle de CNA du chromosome 7 pouvant présenter un intérêt clinique. Nous avons aussi observé par l'analyse du CNA que moins de 10% des glioblastomes conservent leurs mécanismes de suppression de tumeurs p53 et Rb1. Nous avons aussi observé que l'amplification du CDK4 peut constituer un facteur supplémentaire de résistance au traitement RT/TMZ, cette observation nécessite confirmation sur un plus grand nombre d'analyses. Nous avons montré que dans notre analyse des profils moléculaires et cliniques, il n'est pas possible de différencier le GBM à composante oligodendrogliale (GBM-O) du glioblastome. En superposant les profils moléculaires et les modèles expérimentaux in vitro, nous avons identifié WIF-1 comme un gène suppresseur de tumeur probable et une activation du signal WNT dans la pathologie du glioblastome. Ces observations pourraient servir à une meilleure compréhension de cette maladie dans le futur. Abstract : Glioblastoma, (GBM, WHO grade IV) is the most malignant and most frequent primary brain tumor with a very poor prognosis and response to therapy. A recent randomized clinical trial (EORTC26981/NCIC CE.3) established RT/TMZ as the 1St effective chemo-radiation therapy in newly diagnosed GBM [1]. However only a genetic subgroup of patients benefit from RT/TMZ and even in this subgroup overall survival remains very dismal. To explain the observed response to RT/TMZ, have a better understanding of GBM biology, identify other resistance factors and discover new drugable targets a comprehensive molecular analysis was performed in 73 of these GBM trial cohort. We complemented the available molecular data with a genomic copy number profiling by Array Comparative Genomic Hybridization. We proceeded to align the molecular profiles and the Clinical data, to meet our project objectives. Our data confirm known GBM Copy Number Aberrations and profiles. We observed a good correlation of genomic CN and mRNA expression in GBM, and identified new interesting CNA pattern for chromosome 7 with a potential clinical value. We also observed that by copy number aberration data alone, less than 10% of GBM have an intact p53 and Rb1 tumor .suppressor pathways. We equally observed that CDK4 amplification might constitute an additional RT/TMZ resistant factor, an observation that will need confirmation in a larger data set. We show that the molecular and clinical profiles in our data set, does not support the identification of GBM-O as a new entity in GBM. By combining the molecular profiles and in vitro model experiments we identify WIF1 as a potential GBM TSG and an activated WNT signaling as a pathologic event in GBM worth incorporation in attempts to better understand and impact outcome in this disease.

Delirium upon admission to Swiss nursing homes: a cross-sectional study.

QUESTIONS UNDER STUDY: We wished to investigate the prevalence of delirium in patients upon admission to nursing homes and whether or not the previous place of residence predicts delirium. METHODS: The Resident Assessment Instrument Minimum Data Set (RAI-MDS) and the Nursing Home Confusion Assessment Method (NHCAM) were used to determine whether the previous place of residence (community, nursing home, acute care, psychiatric, rehabilitation hospital) predicted the prevalence of sub-syndromal or full delirium in nursing home residents in three Swiss cantons (n = 11745). RESULTS: 39.7% had sub-syndromal and 6.5% had full delirium. Lower cognitive performance and increased depressive symptoms were significant predictors of higher NHCAM values independent of previous residence. Age, civil status, continence, newly introduced drugs, and basic activities of daily living were predictors in some resident groups. The variance of NHCAM scores explained varied between 25.1% and 32.3% depending on previous residence. CONCLUSIONS: Sub-syndromal and full delirium are common upon nursing home admission. Increased dependence and depression are consistently associated with higher NHCAM scores. Patients from psychiatric settings have an increased risk of delirium. Although factors associated with delirium depend on a patient's previous residence, all patients must be carefully screened for sub-syndromal and full delirium.