Pattern stability and error correction during in-phase and antiphase four-ball juggling

The authors studied pattern stability and error correction during in-phase and antiphase 4-ball fountain juggling. To obtain ball trajectories, they made and digitized high-speed film recordings of 4 highly skilled participants juggling at 3 different heights (and thus different frequencies). From those ball trajectories, the authors determined and analyzed critical events (i.e., toss, zenith, catch, and toss onset) in terms of variability of point estimates of relative phase and temporal correlations. Contrary to common findings on basic instances of rhythmic interlimb coordination, in-phase and antiphase patterns were equally variable (i.e., stable). Consistent with previous findings, however, pattern stability decreased with increasing frequency. In contrast to previous results for 3-ball cascade juggling, negative lag-one correlations for catch-catch intervals were absent, but the authors obtained evidence for error corrections between catches and toss onsets. That finding may have reflected participants' high skill level, which yielded smaller errors that allowed for corrections later in the hand cycle.

Preparation of a molecularly imprinted polymer for the solid-phase extraction of scopolamine with hyoscyamine as a dummy template molecule

Molecularly imprinted polymers (MIPs) selective for scopolamine were produced using hyoscyamine (a close structural analogue) as template molecule. The produced polymers were used as media for solid-phase extraction, exhibiting selective binding properties for the analyte from biological samples. Human and calf urine and serum were processed on the MIP under various extraction protocols. The best performance was observed after loading the analyte in aqueous environment facilitating retention on the MIP by non-selective hydrophobic interactions. The MIPs were subsequently washed using an optimised solvent system to enable selective desorption of the analyte. Other related and non-related compounds were accessed to evaluate molecular recognition properties. Recoveries of up to 79% were achieved for the analyte of interest from biological samples.

Delineation of a quick clay zone at Smørgrav, Norway, with electromagnetic methods under geotechnical constraints

In many coastal areas of North America and Scandinavia, post-glacial clay sediments have emerged above sea level due to iso-static uplift. These clays are often destabilised by fresh water leaching and transformed to so-called quick clays as at the investigated area at Smørgrav, Norway. Slight mechanical disturbances of these materials may trigger landslides. Since the leaching increases the electrical resistivity of quick clay as compared to normal marine clay, the application of electromagnetic (EM) methods is of particular interest in the study of quick clay structures.

For the first time, single and joint inversions of direct-current resistivity (DCR), radiomagnetotelluric (RMT) and controlled-source audiomagnetotelluric (CSAMT) data were applied to delineate a zone of quick clay. The resulting 2-D models of electrical resistivity correlate excellently with previously published data from a ground conductivity metre and resistivity logs from two resistivity cone penetration tests (RCPT) into marine clay and quick clay. The RCPT log into the central part of the quick clay identifies the electrical resistivity of the quick clay structure to lie between 10 and 80 O m. In combination with the 2-D inversion models, it becomes possible to delineate the vertical and horizontal extent of the quick clay zone. As compared to the inversions of single data sets, the joint inversion model exhibits sharper resistivity contrasts and its resistivity values are more characteristic of the expected geology. In our preferred joint inversion model, there is a clear demarcation between dry soil, marine clay, quick clay and bedrock, which consists of alum shale and limestone.

Laser - Ion Acceleration in the Laser Transparency Regime

Experiments on laser-induced ion acceleration from ultra-thin (nm) foil targets reveal a dramatic increase in the conversion efficiency and the acceleration of C6$+$ions in a phase stable way by the laser radiation pressure.

The Interlaboratory Robustness Of Next-Generation Sequencing (IRON) Study Phase II: Deep-Sequencing Analyses Of Hematological Malignancies Performed In 8,867 Cases By An International Network Involving 27 Laboratories

Introduction: Amplicon deep-sequencing using second-generation sequencing technology is an innovative molecular diagnostic technique and enables a highly-sensitive detection of mutations. As an international consortium we had investigated previously the robustness, precision, and reproducibility of 454 amplicon next-generation sequencing (NGS) across 10 laboratories from 8 countries (Leukemia, 2011;25:1840-8).

Aims: In Phase II of the study, we established distinct working groups for various hematological malignancies, i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and multiple myeloma. Currently, 27 laboratories from 13 countries are part of this research consortium. In total, 74 gene targets were selected by the working groups and amplicons were developed for a NGS deep-sequencing assay (454 Life Sciences, Branford, CT). A data analysis pipeline was developed to standardize mutation interpretation both for accessing raw data (Roche Amplicon Variant Analyzer, 454 Life Sciences) and variant interpretation (Sequence Pilot, JSI Medical Systems, Kippenheim, Germany).

Results: We will report on the design, standardization, quality control aspects, landscape of mutations, as well as the prognostic and predictive utility of this assay in a cohort of 8,867 cases. Overall, 1,146 primer sequences were designed and tested. In detail, for example in AML, 924 cases had been screened for CEBPA mutations. RUNX1 mutations were analyzed in 1,888 cases applying the deep-sequencing read counts to study the stability of such mutations at relapse and their utility as a biomarker to detect residual disease. Analyses of DNMT3A (n=1,041) were focused to perform landscape investigations and to address the prognostic relevance. Additionally, this working group is focusing on TET2, ASXL1, and TP53 analyses. A novel prognostic model is being developed allowing stratification of AML into prognostic subgroups based on molecular markers only. In ALL, 1,124 pediatric and adult cases have been screened, including 763 assays for TP53 mutations both at diagnosis and relapse of ALL. Pediatric and adult leukemia expert labs developed additional content to study the mutation incidence of other B and T lineage markers such as IKZF1, JAK2, IL7R, PAX5, EP300, LEF1, CRLF2, PHF6, WT1, JAK1, PTEN, AKT1, IL7R, NOTCH1, CREBBP, or FBXW7. Further, the molecular landscape of CLL is changing rapidly. As such, a separate working group focused on analyses including NOTCH1, SF3B1, MYD88, XPO1, FBXW7 and BIRC3. Currently, 922 cases were screened to investigate the range of mutational burden of NOTCH1 mutations for their prognostic relevance. In MDS, RUNX1 mutation analyses were performed in 977 cases. The prognostic relevance of TP53 mutations in MDS was assessed in additional 327 cases, including isolated deletions of chromosome 5q. Next, content was developed targeting genes of the cellular splicing component, e.g. SF3B1, SRSF2, U2AF1, and ZRSR2. In BCR-ABL1-negative MPN, nine genes of interest (JAK2, MPL, TET2, CBL, KRAS, EZH2, IDH1, IDH2, ASXL1) have been analyzed in a cohort of 155 primary myelofibrosis cases searching for novel somatic mutations and addressing their relevance for disease progression and leukemia transformation. Moreover, an assay was developed and applied to CMML cases allowing the simultaneous analysis of 25 leukemia-associated target genes in a single sequencing run using just 20 ng of starting DNA. Finally, nine laboratories are studying CML, applying ultra-deep sequencing of the BCR-ABL1 tyrosine kinase domain. Analyses were performed on 615 cases investigating the dynamics of expansion of mutated clones under various tyrosine kinase inhibitor therapies.

Conclusion: Molecular characterization of hematological malignancies today requires high diagnostic sensitivity and specificity. As part of the IRON-II study, a network of laboratories analyzed a variety of disease entities applying amplicon-based NGS assays. Importantly, the consortium not only standardized assay design for disease-specific panels, but also achieved consensus on a common data analysis pipeline for mutation interpretation. Distinct working groups have been forged to address scientific tasks and in total 8,867 cases had been analyzed thus far.

Influence of the Pacific Decadal Oscillation, El Niño-Southern Oscillation and solar forcing on climate and primary productivity changes in the northeast Pacific

Evidence of 11-year Schwabe solar sunspot cycles, El Niño-Southern Oscillation (ENSO) and the Pacific Decadal Oscillation (PDO) were detected in an annual record of diatomaceous laminated sediments from anoxic Effingham Inlet, Vancouver Island, British Columbia. Radiometric dating and counting of annual varves dates the sediments from AD 1947-1993. Intact sediment slabs were X-rayed for sediment structure (lamina thickness and composition based on gray-scale), and subsamples were examined for diatom abundances and for grain size. Wavelet analysis reveals the presence of ~2-3, ~4.5, ~7 and ~9-12-year cycles in the diatom record and an w11e13 year record in the sedimentary varve thickness record. These cycle lengths suggest that both ENSO and the sunspot cycle had an influence on primary productivity and sedimentation patterns. Sediment grain size could not be correlated to the sunspot cycle although a peak in the grain size data centered around the mid-1970s may be related to the 1976-1977 Pacific climate shift, which occurred when the PDO index shifted from negative (cool conditions) to positive (warm conditions). Additional evidence of the PDO regime shift is found in wavelet and cross-wavelet results for Skeletonema costatum, a weakly silicified variant of S. costatum, annual precipitation and April to June precipitation. Higher spring (April/May) values of the North Pacific High pressure index during sunspot minima suggest that during this time, increased cloud cover and concomitant suppression of the Aleutian Low (AL) pressure system led to strengthened coastal upwelling and enhanced diatom production earlier in the year. These results suggest that the 11-year solar cycle, amplified by cloud cover and upwelling changes, as well as ENSO, exert significant influence on marine primary productivity in the northeast Pacific. The expression of these cyclic phenomena in the sedimentary record were in turn modulated by the phase of PDO, as indicated by the change in period of ENSO and suppression of the solar signal in the record after the 1976-1977 regime shift. © 2013 Elsevier Ltd and INQUA. All rights reserved.

Molecular- and pollen-based vegetation analysis in lake sediments from central Scandinavia

Plant and animal biodiversity can be studied by obtaining DNA directly from the environment. This new approach in combination with the use of generic barcoding primers (metabarcoding) has been suggested as complementary or alternative to traditional biodiversity monitoring in ancient soil sediments. However, the extent to which metabarcoding truly reflects plant composition remains unclear, as does its power to identify species with no pollen or macrofossil evidence. Here, we compared pollen-based and metabarcoding approaches to explore the Holocene plant composition around two lakes in central Scandinavia. At one site, we also compared barcoding results with those obtained in earlier studies with species-specific primers. The pollen analyses revealed a larger number of taxa (46), of which the majority (78%) was not identified by metabarcoding. The metabarcoding identified 14 taxa (MTUs), but allowed identification to a lower taxonomical level. The combined analyses identified 52 taxa. The barcoding primers may favour amplification of certain taxa, as they did not detect taxa previously identified with species-specific primers. Taphonomy and selectiveness of the primers are likely the major factors influencing these results. We conclude that metabarcoding from lake sediments provides a complementary, but not an alternative, tool to pollen analysis for investigating past flora. In the absence of other fossil evidence, metabarcoding gives a local and important signal from the vegetation, but the resulting assemblages show limited capacity to detect all taxa, regardless of their abundance around the lake. We suggest that metabarcoding is followed by pollen analysis and the use of species-specific primers to provide the most comprehensive signal from the environment. © 2013 Blackwell Publishing Ltd.

A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

Energy Efficiency through Significance-Based Computing

An extension of approximate computing, significance-based computing exploits applications' inherent error resiliency and offers a new structural paradigm that strategically relaxes full computational precision to provide significant energy savings with minimal performance degradation.

Antimicrobial peptides and proinflammatory cytokines in periprosthetic joint infection

Background: Differentiation between septic and aseptic loosening of joint replacements is essential for successful revision surgery, but reliable markers for the diagnosis of low-grade infection are lacking. The present study was performed to assess intra-articular and systemic levels of antimicrobial peptides and proinflammatory cytokines as diagnostic markers for periprosthetic joint infection. Methods: Fifteen consecutive patients with staphylococcal periprosthetic joint infections and twenty control patients with aseptic loosening of total hip and knee replacements were included in this prospective, single-center, controlled clinical trial. Expression of the antimicrobial peptides human β-defensin-2 (HBD-2), human β-defensin-3 (HBD-3), and cathelicidin LL-37 (LL-37) was determined by ELISA (enzyme-linked immunosorbent assay) in serum and joint aspirates. Proinflammatory cytokines were assessed in serum and joint aspirates with use of cytometric bead arrays. C-reactive protein in serum, microbiology, and histopathology of periprosthetic tissue served as the “gold standard” for the diagnosis of infection. Results: The antimicrobial peptides HBD-3 and LL-37 were significantly elevated in joint aspirates from patients with periprosthetic joint infection compared with patients with aseptic loosening, and the area under the curve (AUC) in a receiver operating characteristic curve analysis was equal to 0.745 and 0.875, respectively. Additionally, significant local increases in the proinflammatory cytokines interleukin (IL)-1β, IL-4, IL-6, IL-17A, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were observed to be associated with infection. Logistic regression analysis indicated that the combination of an antimicrobial peptide with another synovial fluid biomarker improved diagnostic accuracy; the AUC value was 0.916 for LL-37 and IL-4, 0.895 for LL-37 and IL-6, 0.972 for HBD-3 and IL-4, and 0.849 for HBD-3 and IL-6. In contrast, the only antimicrobial peptides and cytokines in serum that showed a significant systemic increase in association with infection were HBD-2, IL-4, and IL-6 (all of which had an AUC value of <0.75). Conclusions: The present study showed promising results for the use of antimicrobial peptides and other biomarkers in synovial fluid for the diagnosis of periprosthetic joint infection, and analysis of the levels in synovial fluid was more accurate than analysis of serum.