PDB-Explorer: a web-based interactive map of the protein data bank in shape space

Background The RCSB Protein Data Bank (PDB) provides public access to experimentally determined 3D-structures of biological macromolecules (proteins, peptides and nucleic acids). While various tools are available to explore the PDB, options to access the global structural diversity of the entire PDB and to perceive relationships between PDB structures remain very limited. Methods A 136-dimensional atom pair 3D-fingerprint for proteins (3DP) counting categorized atom pairs at increasing through-space distances was designed to represent the molecular shape of PDB-entries. Nearest neighbor searches examples were reported exemplifying the ability of 3DP-similarity to identify closely related biomolecules from small peptides to enzyme and large multiprotein complexes such as virus particles. The principle component analysis was used to obtain the visualization of PDB in 3DP-space. Results The 3DP property space groups proteins and protein assemblies according to their 3D-shape similarity, yet shows exquisite ability to distinguish between closely related structures. An interactive website called PDB-Explorer is presented featuring a color-coded interactive map of PDB in 3DP-space. Each pixel of the map contains one or more PDB-entries which are directly visualized as ribbon diagrams when the pixel is selected. The PDB-Explorer website allows performing 3DP-nearest neighbor searches of any PDB-entry or of any structure uploaded as protein-type PDB file. All functionalities on the website are implemented in JavaScript in a platform-independent manner and draw data from a server that is updated daily with the latest PDB additions, ensuring complete and up-to-date coverage. The essentially instantaneous 3DP-similarity search with the PDB-Explorer provides results comparable to those of much slower 3D-alignment algorithms, and automatically clusters proteins from the same superfamilies in tight groups. Conclusion A chemical space classification of PDB based on molecular shape was obtained using a new atom-pair 3D-fingerprint for proteins and implemented in a web-based database exploration tool comprising an interactive color-coded map of the PDB chemical space and a nearest neighbor search tool. The PDB-Explorer website is freely available at www.​cheminfo.​org/​pdbexplorer and represents an unprecedented opportunity to interactively visualize and explore the structural diversity of the PDB.

Vitamin D Deficiency and Depressive Symptomatology in Psychiatric Patients Hospitalized with a Current Depressive Episode: A Factor Analytic Study.

BACKGROUND Low vitamin D levels have been associated with depressive symptoms in population-based studies and non-clinical samples as well as with clinical depression. This study aimed to examine the association of vitamin D levels with the severity and dimensions of depressive symptoms in hospitalized patients with a current episode of depression taking into account confounding variables. METHODS We investigated 380 patients (mean age 47 ± 12 years, 70% women) who were consecutively hospitalized with a main diagnosis of an ICD-10 depressive episode. All patients self-rated depressive symptom severity with the Hospital Anxiety and Depression Scale (HADS-D), the Beck Depression Inventory-II (BDI-II), and the Brief Symptom Inventory. A principal component analysis was performed with all 34 items of these questionnaires and serum levels of 25-hydroxyvitamin D3 (25-OH D) were measured. RESULTS Vitamin D deficiency (< 50 nmol/l), insufficiency (50-75 nmol/l), and sufficiency (> 75 nmol/l) were present in 55.5%, 31.8% and 12.6%, respectively, of patients. Patients with vitamin D deficiency scored higher on the HADS-D scale and on an anhedonia symptom factor than those with insufficient (p-values ≤ 0.023) or sufficient (p-values ≤ 0.008) vitamin D. Vitamin D deficient patients also scored higher on the BDI-II scale than those with sufficient vitamin D (p = 0.007); BDI-II cognitive/affective symptoms, but not somatic/affective symptoms, were higher in patients with vitamin D deficiency (p = 0.005) and insufficiency (p = 0.041) relative to those with sufficient vitamin D. Effect sizes suggested clinically relevant findings. CONCLUSIONS Low vitamin D levels are frequent in hospitalized patients with a current episode of depression. Especially 25-OH D levels < 50 nmol/l were associated with cognitive/affective depressive symptoms, and anhedonia symptoms in particular.

Nonlinear dimension reduction in pathway-based genome-wide association analysis

Pathway based genome wide association study evolves from pathway analysis for microarray gene expression and is under rapid development as a complementary for single-SNP based genome wide association study. However, it faces new challenges, such as the summarization of SNP statistics to pathway statistics. The current study applies the ridge regularized Kernel Sliced Inverse Regression (KSIR) to achieve dimension reduction and compared this method to the other two widely used methods, the minimal-p-value (minP) approach of assigning the best test statistics of all SNPs in each pathway as the statistics of the pathway and the principal component analysis (PCA) method of utilizing PCA to calculate the principal components of each pathway. Comparison of the three methods using simulated datasets consisting of 500 cases, 500 controls and100 SNPs demonstrated that KSIR method outperformed the other two methods in terms of causal pathway ranking and the statistical power. PCA method showed similar performance as the minP method. KSIR method also showed a better performance over the other two methods in analyzing a real dataset, the WTCCC Ulcerative Colitis dataset consisting of 1762 cases, 3773 controls as the discovery cohort and 591 cases, 1639 controls as the replication cohort. Several immune and non-immune pathways relevant to ulcerative colitis were identified by these methods. Results from the current study provided a reference for further methodology development and identified novel pathways that may be of importance to the development of ulcerative colitis.^

Cenozoic magnetostratigraphy of ODP holes 113-689B and 113-690B

A detailed paleomagnetic study was carried out on biosiliceous and calcareous sediments drilled on Maud Rise, Antarctica, during ODP Leg 113. High-quality APC sections were retrieved in the upper 220 m of Holes 689B and 690B. Average deposition rates range from 3 to 15 m/m.y. A close (25 cm) paleomagnetic sample spacing provided a medium-resolution magnetostratigraphic sequence for the Paleogene and Neogene. Paleomagnetic samples were demagnetized stepwise by alternating fields, and characteristic remanent magnetization directions were derived from detailed vector and difference vector component analysis. A magnetochronologic framework has been established for the first time for the Southern Ocean sedimentary sequences spanning Paleocene to Oligocene and middle Miocene to early Pliocene times. Biosiliceous and calcareous microfossil stratigraphies were used to constrain magnetostratigraphic age assignments. Although average sedimentation rates were rather low, nearly complete sections of the geomagnetic polarity time scale (e.g., Chrons C5 and C5A) could be correlated with the inferred polarity pattern. Miocene and Pliocene records are marked by a high number of hiatuses mainly identified by diatom biostratigraphy. Good paleomagnetic correlation between the two holes is afforded in particular in the middle to upper Miocene. Oligocene magnetostratigraphy reveals a high-quality paleomagnetic record with a mostly complete Oligocene section in Hole 689B at ~5 m/m.y. deposition rate. Hole 690B exhibits higher deposition rates (7-12 m/m.y.), although two hiatuses are present. Early and late Eocene sedimentary sequences could be analyzed in both holes, but in Hole 689B middle Eocene chrons were disrupted by hiatuses and only incomplete polarity intervals C21 and C24 were encountered. Highest resolution (14 m/m.y.) was achieved in Hole 690B in a complete early Eocene and late Paleocene sequence from Chrons C23 to C26, with a number of short polarity intervals detected within Chrons C24 and C25.

(Table 2) Atmospheric electric measurements during the Atlantic Expedition 1965 of METEOR

During the Atlantic expedition potential gradient, small ion density and space charge density have been recorded. Laborious efforts have been taken for receiving an exact estimation of the reduction factor for the field measurements. The mean value of the potential gradient on the free Atlantic Ocean was 105 V/m. The mean daily course is in very good agreement with the results of the Carnegie Institution. Even records taken on individual days near the quator show this course. For the first time it has been attempted to correlate the potential gradient at sea and the voltage between ionosphere and earth measured over land. A narrow relation has been found in 10 cases of balloon ascents with radiosondes. A further remarkable result is, that the short periodical fluctuations of the air electric field at sea with periods of 2 to 20 minutes have amplitudes of the magnitude of the mean field strength and exist all over the oceans. Recordings of the space charge density show, that positively charged air parcels drift in the first hectometer of the air near the sea surface and produce the fluctuation of the potential gradient. A period analysis did not indicate a recognizable relation to the wind velocity up to now, although an effect of air turbulence must be involved. The concentration of small ions also has been measured occasionally. With this and mean values of the potential gradient the air earth curent density has been computed. With n+ = 310 cm**-3, n- = 220 cm**-3 the air conductivity would be Lambda = 1,14 * 10**-14 Ohm**-1 m**-1. These values are smaller than values of other authors by a factor of 2 or 3. Therefore the computed air earth current density is also smaller. The discrepancy could not be explained yet.

Oligocene magnetostratigraphy for equatorial Pacific ODP Sites

An Oligocene magnetostratigraphy from ODP Sites 1218 and 1219 (Equatorial Pacific) has been obtained by measurements made on u-channel samples, augmented by about 221 discrete samples. U-channel samples were measured at 1 cm intervals and were stepwise demagnetized in alternating fields (AF) up to a maximum peak field of 80 mT. The magnetization directions were determined at 1 cm intervals by principal component analysis of demagnetization steps in the 20 to 60 mT peak field range. A similar treatment was carried out on the discrete samples, which confirmed the results obtained with u-channel measurements. Sites 1218 and 1219 were precisely correlated based on multisensor track, paleontological and shipboard magnetostratigraphic data; this correlation is substantiated by u-channel measurements. Although the magnetostratigraphy obtained from the u-channels is similar to the interpretation deduced from shipboard measurements based on blanket demagnetization at peak AF of 20 mT, the u-channel results are substantially more robust since many interpretative uncertainties are resolved by the stepwise demagnetization and higher stratigraphic resolution. The temporal resolution of u-channel-based magnetic stratigraphy in the Oligocene section of Sites 1218 and 1219 is better than 5 kyr, and it is therefore suitable for detection of brief polarity subchrons. However, in spite of the high resolution, we did not find any reversals corresponding to the numerous cryptochrons identified in this time span by Cande and Kent (1995, doi:10.1029/94JB03098).

Miocene magnetostratigraphy of ODP Site 199-1218 in the equatorial Pacific

Pliocene and Miocene magnetostratigraphy from ODP Site 1218 (Equatorial Pacific) has been obtained by measurements made on u-channel samples, augmented by about 50 discrete samples. U-channel samples were measured at 1 cm intervals and stepwise demagnetized in alternating fields up to a maximum peak field of 80 mT. The component magnetization directions were determined by principal component analysis for demagnetization steps in the 20-60 mT peak field range. A relatively small number of discrete samples were subject to both thermal and alternating field (AF) demagnetization and gave results compatible with u-channel measurements. Magnetostratigraphy from u-channel samples are compared with shipboard data that were based on blanket demagnetization at peak AF fields of 20 mT. U-channel measurements add more detail to the magnetostratigraphic record and allow identification of thin polarity zones especially in the upper part of the section were the sedimentation rates are very low (~2 m/Myr). The component magnetization directions determined from u-channel measurements also gave more reliable and precise estimates of inclination (paleolatitude). The magnetostratigraphy from Site 1218 can be unambiguously correlated with the reference geomagnetic polarity time scale and gives a means of dating the sedimentary sequence. Both Miocene-Pliocene and Oligocene-Miocene stage boundaries were easily identified from the magnetostratigraphic record. Although calculation of paleomagnetic poles is hindered by the low precision of the cores' azimuthal orientation, the data from both u-channel and discrete samples allow determination of the paleolatitude of the Site through time with good precision. Paleomagnetic data indicate that the paleolatitude of Site 1218 has increased form nearly equatorial latitude in the Oligocene to its present-day latitude close to 9°N. Within the precision of the paleomagnetic data, this is in agreement with current predictions of plate motion models based on fixed hotspots.

Early Oligocene dinoflagellate cysts from the Upper Rhine Graben

Using principal component analysis and cyst diversity and equity trends, we can recognize four distinct dinoflagellate cyst (dinocyst) assemblages from four Rupelian (Early Oligocene) cores in the Mainz Embayment of the northern Rhine Graben (SW Germany). These assemblages are the Spiniferites ramosus (PC1), Thalassiphora pelagica (PC2), Homotryblium tenuispinosum (PC3), and Vozzhennikovia spinula (PC4) assemblages. The four cores provide an onshore-offshore transect in the Mainz Embayment. The H. tenuispinosum assemblage shows high factor loadings in proximal to intermediate cores, which is interpreted to reflect temporary high-salinity conditions. Mean dinocyst diversity and equity increase with distance from the Mid-Rupelian shoreline, indicating increasingly stable paleoenvironmental conditions towards the center of the Mainz Embayment. Within individual cores, changes in dinocyst assemblages through time are related to paleoenvironmental and paleoclimatological changes. The three proximal to intermediate cores show dominance of the H. tenuispinosum assemblage repeatedly alternating with high factor loadings of the T. pelagica assemblage. In both cases, dinocyst diversity and equity tend to be reduced. Highest factor loadings of the S. ramosus assemblage occur in intervals where neither of the above assemblages is dominant and tend to coincide with dinocyst diversity and equity maxima. We interpret this distribution pattern to denote different paleoceanographic conditions, reflecting drier and more humid phases in the Early Oligocene of Central Europe. During relatively dry periods, increased salinity conditions prevailed in proximal to intermediate settings of the Mainz Embayment, as reflected by the dominance of the H. tenuispinosum assemblage. During more humid periods, increased runoff led to higher nutrient availability and the formation of a pycnocline separating slightly less saline surface waters from higher saline deeper waters, thus impeding vertical circulation. These environmental conditions are documented in high loadings of the T. pelagica assemblage which is indicative of increased eutrophication and/or oxygen-depleted bottom waters. Transitions between drier and more humid periods, i.e. episodes of normal marine conditions, are characterized by high loadings predominantly of the S. ramosus assemblage as well as increased dinocyst diversity and equity values. We propose that the alternations between drier and more humid phases may be related to variations in the ocean-atmosphere moisture flux from the North Atlantic into Central Europe bearing a high-latitude climate signal.

Fatty acid and stable isotope composition of calanoid copepods in the open eastern Atlantic Ocean during POLARSTERN cruise ANT-XXIX/1

The majority of global ocean production and total export production is attributed to oligotrophic oceanic regions due to their vast regional expanse. However, energy transfers, food-web structures and trophic relationships in these areas remain largely unknown. Regional and vertical inter- and intra-specific differences in trophic interactions and dietary preferences of calanoid copepods were investigated in four different regions in the open eastern Atlantic Ocean (38°N to 21°S) in October/November 2012 using a combination of fatty acid (FA) and stable isotope (SI) analyses. Mean carnivory indices (CI) based on FA trophic markers generally agreed with trophic positions (TP) derived from d15N analysis. Most copepods were classified as omnivorous (CI ~0.5, TP 1.8 to ~2.5) or carnivorous (CI >=0.7, TP >=2.9). Herbivorous copepods showed typical CIs of <=0.3. Geographical differences in d15N values of epi- (200-0 m) to mesopelagic (1000-200 m) copepods reflected corresponding spatial differences in baseline d15N of particulate organic matter from the upper 100 m. In contrast, species restricted to lower meso- and bathypelagic (2000-1000 m) layers did not show this regional trend. FA compositions were species-specific without distinct intra-specific vertical or spatial variations. Differences were only observed in the southernmost region influenced by the highly productive Benguela Current. Apparently, food availability and dietary composition were widely homogeneous throughout the oligotrophic oceanic regions of the tropical and subtropical Atlantic. Four major species clusters were identified by principal component analysis based on FA compositions. Vertically migrating species clustered with epi- to mesopelagic, non-migrating species, of which only Neocalanus gracilis was moderately enriched in lipids with 16% of dry mass (DM) and stored wax esters (WE) with 37% of total lipid (TL). All other species of this cluster had low lipid contents (< 10% DM) without WE. Of these, the tropical epipelagic Undinula vulgaris showed highest portions of bacterial markers. Rhincalanus cornutus, R. nasutus and Calanoides carinatus formed three separate clusters with species-specific lipid profiles, high lipid contents (>=41% DM), mainly accumulated as WE (>=79% TL). C. carinatus and R. nasutus were primarily herbivorous with almost no bacterial input. Despite deviating feeding strategies, R. nasutus clustered with deep-dwelling, carnivorous species, which had high amounts of lipids (>=37% DM) and WE (>=54% TL). Tropical and subtropical calanoid copepods exhibited a wide variety of life strategies, characterized by specialized feeding. This allows them, together with vertical habitat partitioning, to maintain high abundance and diversity in tropical oligotrophic open oceans, where they play an essential role in the energy flux and carbon cycling.

Paleomagnetic analysed of two sediment cores off Cape Ghir

Holocene records documenting variations in direction and intensity of the geomagnetic field during the last about seven and a half millennia are presented for Northwest Africa. High resolution paleomagnetic analyses of two marine sediment sequences recovered from around 900 meter water depth on the upper continental slope off Cape Ghir (30°51'N, 10°16'W) were supplemented by magnetic measurements characterizing composition, concentration, grain size and coercivity of the magnetic mineral assemblage. Age control for the high sedimentation rate deposits (~60 cm/kyr) was established by AMS radiocarbon dates. The natural remanent magnetization (NRM) is very predominantly carried by a fine grained, mostly single domain (titano-)magnetite fraction allowing the reliable definition of stable NRM inclinations and declinations from alternating field demagnetization and principal component analysis. Predictions of the Korte and Constable (2005) geomagnetic field model CALS7K.2 for the study area are in fair agreement with the Holocene directional records for the most parts, yet noticeable differences exist in some intervals. The magnetic mineral inventory of the sediments reveals various climate controlled variations, specifically in concentration and grain size. A very strong impact had the mid-Holocene environmental change from humid to arid conditions on the African continent which also clearly affects relative paleointensity (RPI) estimates based on different remanence normalizers. To overcome this problem the pseudo-Thellier RPI technique has been applied. The results represent the first Holocene record of Earth's magnetic field intensity variations in the NW Africa region. It displays long term trends similar to those of model predictions, but also conspicuous millennium scale differences.

A practical approach to the global analysis of CLP programs

This paper presents and illustrates with an example a practical approach to the dataflow analysis of programs written in constraint logic programming (CLP) languages using abstract interpretation. It is first argued that, from the framework point of view, it sufnces to propose relatively simple extensions of traditional analysis methods which have already been proved useful and practical and for which efncient fixpoint algorithms have been developed. This is shown by proposing a simple but quite general extensión of Bruynooghe's traditional framework to the analysis of CLP programs. In this extensión constraints are viewed not as "suspended goals" but rather as new information in the store, following the traditional view of CLP. Using this approach, and as an example of its use, a complete, constraint system independent, abstract analysis is presented for approximating definiteness information. The analysis is in fact of quite general applicability. It has been implemented and used in the analysis of CLP(R) and Prolog-III applications. Results from the implementation of this analysis are also presented.

Latest developments in data analysis tools for disruption prediction and for the exploration of multimachine operational spaces.

In the last years significant efforts have been devoted to the development of advanced data analysis tools to both predict the occurrence of disruptions and to investigate the operational spaces of devices, with the long term goal of advancing the understanding of the physics of these events and to prepare for ITER. On JET the latest generation of the disruption predictor called APODIS has been deployed in the real time network during the last campaigns with the new metallic wall. Even if it was trained only with discharges with the carbon wall, it has reached very good performance, with both missed alarms and false alarms in the order of a few percent (and strategies to improve the performance have already been identified). Since for the optimisation of the mitigation measures, predicting also the type of disruption is considered to be also very important, a new clustering method, based on the geodesic distance on a probabilistic manifold, has been developed. This technique allows automatic classification of an incoming disruption with a success rate of better than 85%. Various other manifold learning tools, particularly Principal Component Analysis and Self Organised Maps, are also producing very interesting results in the comparative analysis of JET and ASDEX Upgrade (AUG) operational spaces, on the route to developing predictors capable of extrapolating from one device to another.