The InterPro Database, 2003 brings increased coverage and new features.

InterPro, an integrated documentation resource of protein families, domains and functional sites, was created in 1999 as a means of amalgamating the major protein signature databases into one comprehensive resource. PROSITE, Pfam, PRINTS, ProDom, SMART and TIGRFAMs have been manually integrated and curated and are available in InterPro for text- and sequence-based searching. The results are provided in a single format that rationalises the results that would be obtained by searching the member databases individually. The latest release of InterPro contains 5629 entries describing 4280 families, 1239 domains, 95 repeats and 15 post-translational modifications. Currently, the combined signatures in InterPro cover more than 74% of all proteins in SWISS-PROT and TrEMBL, an increase of nearly 15% since the inception of InterPro. New features of the database include improved searching capabilities and enhanced graphical user interfaces for visualisation of the data. The database is available via a webserver (http://www.ebi.ac.uk/interpro) and anonymous FTP (ftp://ftp.ebi.ac.uk/pub/databases/interpro).

Pressing the right buttons: signaling in lymphangiogenesis.

Lymphatic vasculature is increasingly recognized as an important factor both in the regulation of normal tissue homeostasis and immune response and in many diseases, such as inflammation, cancer, obesity, and hypertension. In the last few years, in addition to the central role of vascular endothelial growth factor (VEGF)-C/VEGF receptor-3 signaling in lymphangiogenesis, significant new insights were obtained about Notch, transforming growth factor β/bone morphogenetic protein, Ras, mitogen-activated protein kinase, phosphatidylinositol 3 kinase, and Ca(2+)/calcineurin signaling pathways in the control of growth and remodeling of lymphatic vessels. An emerging picture of lymphangiogenic signaling is complex and in many ways distinct from the regulation of angiogenesis. This complexity provides new challenges, but also new opportunities for selective therapeutic targeting of lymphatic vasculature.

Cryo-negative staining reveals conformational flexibility within yeast RNA polymerase I.

The structure of the yeast DNA-dependent RNA polymerase I (RNA Pol I), prepared by cryo-negative staining, was studied by electron microscopy. A structural model of the enzyme at a resolution of 1.8 nm was determined from the analysis of isolated molecules and showed an excellent fit with the atomic structure of the RNA Pol II Delta4/7. The high signal-to-noise ratio (SNR) of the stained molecular images revealed a conformational flexibility within the image data set that could be recovered in three-dimensions after implementation of a novel strategy to sort the "open" and "closed" conformations in our heterogeneous data set. This conformational change mapped in the "wall/flap" domain of the second largest subunit (beta-like) and allows a better accessibility of the DNA-binding groove. This displacement of the wall/flap domain could play an important role in the transition between initiation and elongation state of the enzyme. Moreover, a protrusion was apparent in the cryo-negatively stained model, which was absent in the atomic structure and was not detected in previous 3D models of RNA Pol I. This structure could, however, be detected in unstained views of the enzyme obtained from frozen hydrated 2D crystals, indicating that this novel feature is not induced by the staining process. Unexpectedly, negatively charged molybdenum compounds were found to accumulate within the DNA-binding groove, which is best explained by the highly positive electrostatic potential of this region of the molecule, thus, suggesting that the stain distribution reflects the overall surface charge of the molecule.

E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.

E2F transcriptional regulators control human-cell proliferation by repressing and activating the transcription of genes required for cell-cycle progression, particularly the S phase. E2F proteins repress transcription in association with retinoblastoma pocket proteins, but less is known about how they activate transcription. Here, we show that the human G1 phase regulator HCF-1 associates with both activator (E2F1 and E2F3a) and repressor (E2F4) E2F proteins, properties that are conserved in insect cells. Human HCF-1-E2F interactions are versatile: their associations and binding to E2F-responsive promoters are cell-cycle selective, and HCF-1 displays coactivator properties when bound to the E2F1 activator and corepressor properties when bound to the E2F4 repressor. During the G1-to-S phase transition, HCF-1 recruits the mixed-lineage leukemia (MLL) and Set-1 histone H3 lysine 4 methyltransferases to E2F-responsive promoters and induces histone methylation and transcriptional activation. These results suggest that HCF-1 induces cell-cycle-specific transcriptional activation by E2F proteins to promote cell proliferation.

Combining probabilistic land-use change and tree population dynamics modelling to simulate responses in mountain forests

Altitudinal tree lines are mainly constrained by temperature, but can also be influenced by factors such as human activity, particularly in the European Alps, where centuries of agricultural use have affected the tree-line. Over the last decades this trend has been reversed due to changing agricultural practices and land-abandonment. We aimed to combine a statistical land-abandonment model with a forest dynamics model, to take into account the combined effects of climate and human land-use on the Alpine tree-line in Switzerland. Land-abandonment probability was expressed by a logistic regression function of degree-day sum, distance from forest edge, soil stoniness, slope, proportion of employees in the secondary and tertiary sectors, proportion of commuters and proportion of full-time farms. This was implemented in the TreeMig spatio-temporal forest model. Distance from forest edge and degree-day sum vary through feed-back from the dynamics part of TreeMig and climate change scenarios, while the other variables remain constant for each grid cell over time. The new model, TreeMig-LAb, was tested on theoretical landscapes, where the variables in the land-abandonment model were varied one by one. This confirmed the strong influence of distance from forest and slope on the abandonment probability. Degree-day sum has a more complex role, with opposite influences on land-abandonment and forest growth. TreeMig-LAb was also applied to a case study area in the Upper Engadine (Swiss Alps), along with a model where abandonment probability was a constant. Two scenarios were used: natural succession only (100% probability) and a probability of abandonment based on past transition proportions in that area (2.1% per decade). The former showed new forest growing in all but the highest-altitude locations. The latter was more realistic as to numbers of newly forested cells, but their location was random and the resulting landscape heterogeneous. Using the logistic regression model gave results consistent with observed patterns of land-abandonment: existing forests expanded and gaps closed, leading to an increasingly homogeneous landscape.

Enriched basaltic andesites from mid-crustal fractional crystallization, recharge, and assimilation (Pilavo Volcano, Western Cordillera of Ecuador)

The origin of andesite is an important issue in petrology because andesite is the main eruptive product at convergent margins, corresponds to the average crustal composition and is often associated with major Cu-Au mineralization. In this study we present petrographic, mineralogical, geochemical and isotopic data for basaltic andesites of the latest Pleistocene Pilavo volcano, one of the most frontal volcanoes of the Ecuadorian Quaternary arc, situated upon thick (30-50 km) mafic crust composed of accreted Cretaceous oceanic plateau rocks and overlying mafic to intermediate Late Cretaceous-Late Tertiary magmatic arcs. The Pilavo rocks are basaltic andesites (54-57 center dot 5 wt % SiO(2)) with a tholeiitic affinity as opposed to the typical calc-alkaline high-silica andesites and dacites (SiO(2) 59-66 wt %) of other frontal arc volcanoes of Ecuador (e.g. Pichincha, Pululahua). They have much higher incompatible element contents (e.g. Sr 650-1350 ppm, Ba 650-1800 ppm, Zr 100-225 ppm, Th 5-25 ppm, La 15-65 ppm) and Th/La ratios (0 center dot 28-0 center dot 36) than Pichincha and Pululahua, and more primitive Sr ((87)Sr/(86)Sr similar to 0 center dot 7038-0 center dot 7039) and Nd (epsilon(Nd) similar to +5 center dot 5 to +6 center dot 1) isotopic signatures. Pilavo andesites have geochemical affinities with modern and recent high-MgO andesites (e.g. low-silica adakites, Setouchi sanukites) and, especially, with Archean sanukitoids, for both of which incompatible element enrichments are believed to result from interactions of slab melts with peridotitic mantle. Petrographic, mineral chemistry, bulk-rock geochemical and isotopic data indicate that the Pilavo magmatic rocks have evolved through three main stages: (1) generation of a basaltic magma in the mantle wedge region by flux melting induced by slab-derived fluids (aqueous, supercritical or melts); (2) high-pressure differentiation of the basaltic melt (at the mantle-crust boundary or at lower crustal levels) through sustained fractionation of olivine and clinopyroxene, leading to hydrous, high-alumina basaltic andesite melts with a tholeiitic affinity, enriched in incompatible elements and strongly impoverished in Ni and Cr; (3) establishment of one or more mid-crustal magma storage reservoirs in which the magmas evolved through dominant amphibole and clinopyroxene (but no plagioclase) fractionation accompanied by assimilation of the modified plutonic roots of the arc and recharge by incoming batches of more primitive magma from depth. The latter process has resulted in strongly increasing incompatible element concentrations in the Pilavo basaltic andesites, coupled with slightly increasing crustal isotopic signatures and a shift towards a more calc-alkaline affinity. Our data show that, although ultimately originating from the slab, incompatible element abundances in arc andesites with primitive isotopic signatures can be significantly enhanced by intra-crustal processes within a thick juvenile mafic crust, thus providing an additional process for the generation of enriched andesites.

Identification of proteoglycans as the APRIL-specific binding partners.

B cell activating factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferation-inducing ligand (APRIL) are closely related ligands within the TNF superfamily that play important roles in B lymphocyte biology. Both ligands share two receptors--transmembrane activator and calcium signal--modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA)--that are predominantly expressed on B cells. In addition, BAFF specifically binds BAFF receptor, whereas the nature of a postulated APRIL-specific receptor remains elusive. We show that the TNF homology domain of APRIL binds BCMA and TACI, whereas a basic amino acid sequence (QKQKKQ) close to the NH2 terminus of the mature protein is required for binding to the APRIL-specific "receptor." This interactor was identified as negatively charged sulfated glycosaminoglycan side chains of proteoglycans. Although T cell lines bound little APRIL, the ectopic expression of glycosaminoglycan-rich syndecans or glypicans conferred on these cells a high binding capacity that was completely dependent on APRIL's basic sequence. Moreover, syndecan-1-positive plasma cells and proteoglycan-rich nonhematopoietic cells displayed high specific, heparin-sensitive binding to APRIL. Inhibition of BAFF and APRIL, but not BAFF alone, prevented the survival and/or the migration of newly formed plasma cells to the bone marrow. In addition, costimulation of B cell proliferation by APRIL was only effective upon APRIL oligomerization. Therefore, we propose a model whereby APRIL binding to the extracellular matrix or to proteoglycan-positive cells induces APRIL oligomerization, which is the prerequisite for the triggering of TACI- and/or BCMA-mediated activation, migration, or survival signals.

Early Carboniferous age of the Versoyen ophiolites and consequences: non-existence of a "Valais ocean'' (Lower Penninic, western Alps)

Ophiolites occur at several places in the Lower Penninic of the W and Central Alps. They are generally ascribed to oceanic crust of a so-called ``Valais ocean'' of Cretaceous age which plays a fundamental role in many models of Alpine paleogeography and geodynamics. The type locality and only observational base for the definition of a ``Valais ocean'' in the W Alps is the Versoyen ophiolitic complex, on the French-Italian boundary W of the Petit St-Bernard col. The idea of a "Valais ocean'' is based on two propositions that are since 40 years the basis for most reconstructions of the Lower Penninic: (1) The Versoyen forms the (overturned) stratigraphic base of the Cretaceous-Tertiary Valais-Tarentaise series; and (2) it has a Cretaceous age. We present new field and isotopic data that severely challenge both propositions. (1) The base of the Versoyen ophiolite is a thrust. It overlies a wildflysch with blocks of Versoyen rocks, named the Mechandeur Formation. This ``supra-Tarentaise'' wildflysch has been confused with an (overturned) stratigraphic transition from the Versoyen to the Valais-Tarentaise series. Thus the contact Versoyen/Tarentaise is not stratigraphic but tectonic, and the Versoyen ophiolite has no link with the Valais basin. This thrust corresponds to an inverse metamorphic discontinuity and to an abrupt change in tectonic style. (2) The contact of the Versoyen complex with the overlying Triassic-Jurassic Petit St-Bernard (PSB) series is stratigraphic (and not tectonic as admitted by all authors since 50 years). Several types of sedimentary structures polarize it and show that the PSB series is younger than the Versoyen. Consequently the Versoyen ophiolitic complex is Paleozoic and forms the basement of the PSB Mesozoic sediments. They both belong to a single tectonic unit, named the Versoyen-Petit St-Bernard nappe. (3) Ion microprobe U-Pb isotopic data on zircons from the main gabbroic intrusion in the Versoyen complex give a crystallization age of 337.0 +/- 4.1 Ma (Visean, Early Carboniferous). These zircons show typical oscillatory zoning and no overgrowth or corrosion. and are interpreted to date the Versoyen magmatism. These U-Pb data are in excellent agreement with our field observations and confirm the Paleozoic age of the Versoyen ophiolite. The existence of a ``Valais ocean'' of Cretaceous age in the W Alps becomes very improbable. The eclogite facies metamorphism of the Versoyen-Petit St-Bernard nappe results from an Alpine intra-continental subduction, guided by a Paleozoic oceanic suture. This is an example of the lone term influence of inherited deep-seated structures on a Much younger orogeny. This might well be a major cause of of the inherent complexity of the Alps.

Referral patterns and outcomes in noncritically ill patients with hospital-acquired acute kidney injury.

Background and objectives Despite modern treatment, the case fatality rate of hospital-acquired acute kidney injury (HA-AKI) is still high. We retrospectively described the prevalence and the outcome of HA-AKI without nephrology referral (nrHA-AKI) and late referred HA-AKI patients to nephrologists (lrHA-AKI) compared with early referral patients (erHA-AKI) with respect to renal function recovery, renal replacement therapy (RRT) requirement, and in-hospital mortality of HA-AKI. Design, setting, participants, & measurements Noncritically ill patients admitted to the tertiary care academic center of Lausanne, Switzerland, between 2004 and 2008 in the medical and surgical services were included. Acute kidney injury was defined using the Acute Kidney Injury Network (AKIN) classification. Results During 5 years, 4296 patients (4.12% of admissions) experienced 4727 episodes of HA-AKI during their hospital stay. The mean ± SD age of the patients was 61 ± 15 years with a 55% male predominance. There were 958 patients with nrHA-AKI (22.3%) and 2504 patients with lrHA-AKI (58.3%). RRT was required in 31% of the patients with lrHA-AKI compared with 24% of the patients with erHA-AKI. In the multiple risk factor analysis, compared with erHA-AKI, nrHA-AKI and lrHA-AKI were significantly associated with worse renal outcome and higher in-hospital mortality. Conclusions These data suggest that HA-AKI is frequent and the patients with nrHA-AKI or lrHA-AKI are at increased risk for in-hospital morbidity and mortality.

Mandibular osteoradionecrosis in squamous cell carcinoma of the oral cavity and oropharynx: incidence and risk factors.

Objective. Mandibular osteoradionecrosis (ORN) is a serious complication of radiotherapy (RT) in head and neck cancer patients. The aim of this study was to analyze the incidence of and risk factors for mandibular ORN in squamous cell carcinoma (SCC) of the oral cavity and oropharynx.Study Design. Case series with chart review.Setting. University tertiary care center for head and neck oncology.Subjects and Methods. Seventy-three patients treated for stage I to IV SCC of the oral cavity and oropharynx between 2000 and 2007, with a minimum follow-up of 2 years, were included in the study. Treatment modalities included both RT with curative intent and adjuvant RT following tumor surgery. The log-rank test and Cox model were used for univariate and multivariate analyses.Results. The incidence of mandibular ORN was 40% at 5 years. Using univariate analysis, the following risk factors were identified: oral cavity tumors (P < .01), bone invasion (P < .02), any surgery prior to RT (P < .04), and bone surgery (P < .0001). By multivariate analysis, mandibular surgery proved to be the most important risk factor and the only one reaching statistical significance (P < .0002).Conclusion. Mandibular ORN is a frequent long-term complication of RT for oral cavity and oropharynx cancers. Mandibular surgery before irradiation is the only independent risk factor. These aspects must be considered when planning treatment for these tumors.

Electroencephalogram changes during inhalation with nitric oxide in the pediatric intensive care patient--a preliminary report.

OBJECTIVES: Although endogenous nitric oxide (NO) is an excitatory mediator in the central nervous system, inhaled NO is not considered to cause neurologic side effects because of its short half-life. This study was motivated by a recent case report about neurologic symptoms and our own observation of severe electroencephalogram (EEG) abnormalities during NO inhalation. DESIGN: Blind, retrospective analyses of EEGs which were registered before, during, and after NO inhalation. EEG was classified in a 5-point rating system by an independent electroencephalographer who was blinded to the patients' clinical histories. Comparisons were made with the previous evaluation documented at recording. Other EEG-influencing parameters such as oxygen saturation, hemodynamics, electrolytes, and pH were evaluated. SETTING: Pediatric intensive care unit of a tertiary care university children's hospital. PATIENTS: Eleven ventilated, long-term paralyzed, sedated children (1 mo to 14 yrs) who had EEG or clinical assessment before NO treatment and EEG during NO inhalation. They were divided into two groups according to the NO-indication (e.g., congenital heart defect, acute respiratory distress syndrome). MEASUREMENTS AND MAIN RESULTS: All 11 patients had an abnormal EEG during NO inhalation. EEG-controls without NO showed remarkable improvement. EEG abnormalities were background slowing, low voltage, suppression burst (n = 2), and sharp waves (n = 2) independent of patients' age, NO-indication, and other EEG-influencing parameters. CONCLUSIONS: These preliminary data suggest the occurrence of EEG-abnormalities after application of inhaled NO in critically ill children. We found no correlation with other potential EEG-influencing parameters, although clinical state, medication, or hypoxemia might contribute. Comprehensive, prospective, clinical assessment regarding a causal relationship between NO-inhalation and EEG-abnormalities and their clinical importance is needed.

Association between education and quality of diabetes care in Switzerland

PURPOSE: Low socioeconomic status is associated with higher prevalence of diabetes, worse outcomes, and worse quality of care. We explored the relationship between education, as a measure of socioeconomic status, and quality of care in the Swiss context. PATIENTS AND METHODS: Data were drawn from a population-based survey of 519 adults with diabetes during fall 2011 and summer 2012 in a canton of Switzerland. We assessed patients and diabetes characteristics. Eleven indicators of quality of care were considered (six of process and five of outcomes of care). After bivariate analyses, regression analyses adjusted for age, sex, and diabetic complications were performed to assess the relationship between education and quality of care. RESULTS: Of 11 quality-of-care indicators, three were significantly associated with education: funduscopy (patients with tertiary versus primary education were more likely to get the exam: odds ratio, 1.8; 95% confidence interval [CI], 1.004-3.3) and two indicators of health-related quality of life (patients with tertiary versus primary education reported better health-related quality of life: Audit of Diabetes-Dependent Quality of Life: β=0.6 [95% CI, 0.2-0.97]; SF-12 mean physical component summary score: β=3.6 [95% CI, 0.9-6.4]). CONCLUSION: Our results suggest the presence of educational inequalities in quality of diabetes care. These findings may help health professionals focus on individuals with increased needs to decrease health inequalities.

The vacuolar transporter chaperone (VTC) complex is required for microautophagy.

Microautophagy involves direct invagination and fission of the vacuolar/lysosomal membrane under nutrient limitation. This occurs by an autophagic tube, a specialized vacuolar membrane invagination that pinches off vesicles into the vacuolar lumen. In this study we have identified the VTC (vacuolar transporter chaperone) complex as required for microautophagy. The VTC complex is present on the ER and vacuoles and at the cell periphery. On induction of autophagy by nutrient limitation the VTC complex is recruited to and concentrated on vacuoles. The VTC complex is inhomogeneously distributed within the vacuolar membranes, showing an enrichment on autophagic tubes. Deletion of the VTC complex blocks microautophagic uptake into vacuoles. The mutants still form autophagic tubes but the production of microautophagic vesicles from their tips is impaired. In line with this, affinity-purified antibodies to the Vtc proteins inhibit microautophagic uptake in a reconstituted system in vitro. Our data suggest that the VTC complex is an important constituent of autophagic tubes and that it is required for scission of microautophagic vesicles from these tubes.

The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila.

S6 kinases (S6Ks) act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development. However, they also have been shown to play a key role in limiting insulin signaling and in mediating the autophagic response. To identify novel regulators of S6K signaling, we have used a Drosophila-based, sensitized, gain-of-function genetic screen. Unexpectedly, one of the strongest enhancers to emerge from this screen was the nuclear receptor (NR), Drosophila hormone receptor 3 (DHR3), a critical constituent in the coordination of Drosophila metamorphosis. Here we demonstrate that DHR3, through dS6K, also acts to regulate cell-autonomous growth. Moreover, we show that the ligand-binding domain (LBD) of DHR3 is essential for mediating this response. Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD. These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.

La nappe du Lebendun entre Alte Kaserne et le Val Cairasca (massif du Simplon): nouvelles observations et interprétations

The lithostratigraphic description of the covers of three Lower Penninic nappes (Monte Leone, Lebendun and Antigorio) allows the comparison of their sedimentary content and their thickness. It has been established that the Lebendun nappe is formed by an ante-Triassic paragneissic core (Valgrande gneiss), and a Mesozoic sedimentary cover in reversed position. The cover series shows a continuous detritic sedimentation, off which the material comes from a continental erosion related to the early Lias rifting phase of the Alpine Tethys. The erosion has reached the basement, resedimented as pebbles and sandstones. This can be observed in both Lebendun and Antigorio covers. The definition of a unit named <<serie intermediaire>> between the Lebendun and the Antigorio covers has important palinspastic implications for both nappes. The unit is composed of a banded marble, a garnet bearing gneiss and a calcschist with great blocks. The comparison between the thickness of Antigorio and Lebendun covers suggests a shoulder position for Antigorio. and a proximal rift basin position tor Lebendun. The general thickness decrease of the series towards the SW points to a NE origin for the Lebendun clastics, taking into account the increase of tectonic deformation in the region trending from east to west. The detritic sedimentation ends with the basin drowning during the Malm, represented by a pure marble sealing the erosive disconformity of the Antigorio cover, and the clastic deposits of Lebendun. Three hypotheses are proposed for the calcschists age and attribution of the <<serie intermediaire>>: A: they belong entirely or partially to the Lebendun cover and correspond to a conglomeratic deposit of Cretaceous-Tertiary Niesen flysch type, of proximal facies. The tectonic limit could be situated in the middle of the calcschists at the level of the huge blocks encountered. B: they belong to Antigorio and correspond to an upper Lias-Dogger synrift deposit, then the marble is liassic. C: they belong to Antigorio and have been deposited following the Lebendun basin inversion (Cretaceous-Tertiary). that generates Tertiary wildflysch deposits, coming from the South for the ultrahelvetic and from the North for the Niesen.