Cathodal Transcranial Direct Current Stimulation Over Left Dorsolateral Prefrontal Cortex Area Promotes Implicit Motor Learning in a Golf Putting Task.

© 2015 Elsevier Inc. All rights reserved. Background Implicit motor learning is characterized by low dependence on working memory and stable performance despite stress, fatigue, or multi-tasking. However, current paradigms for implicit motor learning are based on behavioral interventions that are often task-specific and limited when applied in practice. Objective To investigate whether cathodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) area during motor learning suppressed working memory activity and reduced explicit verbal-analytical involvement in movement control, thereby promoting implicit motor learning. Methods Twenty-seven healthy individuals practiced a golf putting task during a Training Phase while receiving either real cathodal tDCS stimulation over the left DLPFC area or sham stimulation. Their performance was assessed during a Test phase on another day. Verbal working memory capacity was assessed before and after the Training Phase, and before the Test Phase. Results Compared to sham stimulation, real stimulation suppressed verbal working memory activity after the Training Phase, but enhanced golf putting performance during the Training Phase and the Test Phase, especially when participants were required to multi-task. Conclusion Cathodal tDCS over the left DLPFC may foster implicit motor learning and performance in complex real-life motor tasks that occur during sports, surgery or motor rehabilitation

Predicting the response to sorafenib in hepatocellular carcinoma: where is the evidence for phosphorylated extracellular signaling-regulated kinase (pERK)?

The approval of sorafenib and active development of many other molecularly targeted agents in hepatocellular carcinoma (HCC) have presented a challenge to understand the mechanism of action of sorafenib and identify predictive biomarkers to select patients more likely to benefit from sorafenib. The preclinical study by Zhang and celleagues published this month in BMC Medicine provides preliminary evidence that baseline phosphorylated extracellular signaling-regulated kinase (pERK) may be a relevant marker to reflect the level of constitutive activation of the RAF/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway and has the potential value in predicting response to sorafenib. The clinical data from the initial single arm phase II study and preliminary report from the randomized phase III study also suggest the correlation of baseline archived tumor pERK levels and time to tumor progression in HCC patients. Whether baseline pERK will prove to be a useful predictive biomarker of response and clinical benefits for sorafenib in HCC will need to be validated in future large prospective studies

Weaker land–climate feedbacks from nutrient uptake during photosynthesis-inactive periods

Terrestrial carbon–climate feedbacks depend on two large and opposing fluxes—soil organic matter decomposition and photosynthesis—that are tightly regulated by nutrients . Earth system models (ESMs) participating in the Coupled Model Intercomparison Project Phase 5 represented nutrient dynamics poorly , rendering predictions of twenty-first century carbon–climate feedbacks highly uncertain. Here, we use a new land model to quantify the effects of observed plant nutrient uptake mechanisms missing in most other ESMs. In particular, we estimate the global role of root nutrient competition with microbes and abiotic processes during periods without photosynthesis. Nitrogen and phosphorus uptake during these periods account for 45 and 43%, respectively, of annual uptake, with large latitudinal variation. Globally, night-time nutrient uptake dominates this signal. Simulations show that ignoring this plant uptake, as is done when applying an instantaneous relative demand approach, leads to large positive biases in annual nitrogen leaching (96%) and N O emissions (44%). This N O emission bias has a GWP equivalent of ~2.4 PgCO yr , which is substantial compared to the current terrestrial CO sink. Such large biases will lead to predictions of overly open terrestrial nutrient cycles and lower carbon sequestration capacity. Both factors imply over-prediction of positive terrestrial feedbacks with climate in current ESMs. 1,2 1,3 −1 2 2 2

Results of the MAJORANA DEMONSTRATOR's Search for Double-Beta Decay of 76Ge to Excited States of 76Se

The MAJORANA DEMONSTRATOR is searching for double-beta decay of 76Ge to excited states (E.S.) in 76Se using a modular array of high purity Germanium detectors. 76Ge can decay into three E.S.s of 76Se. The E.S. decays have a clear event signature consisting of a ββ-decay with the prompt emission of one or two γ-rays, resulting in with high probability in a multi-site event. The granularity of the DEMONSTRATOR detector array enables powerful discrimination of this event signature from backgrounds. Using 21.3 kg-y of isotopic exposure, the DEMONSTRATOR has set world leading limits for each E.S. decay, with 90% CL lower half-life limits in the range of (0.56 2.1) ⋅ 1024 y. In particular, for the 2v transition to the first 0+ E.S. of 76Se, a lower half-life limit of 0.68 ⋅ 1024 at 90% CL was achieved

ADC Nonlinearity Correction for the Majorana Demonstrator

Imperfections in analog-to-digital conversion (ADC) cannot be ignored when signal digitization requirements demand both wide dynamic range and high resolution, as is the case for the Majorana Demonstrator 76Ge neutrinoless double-beta decay search. Enabling the experiment's high-resolution spectral analysis and efficient pulse shape discrimination required careful measurement and correction of ADC nonlinearities. A simple measurement protocol was developed that did not require sophisticated equipment or lengthy data-taking campaigns. A slope-dependent hysteresis was observed and characterized. A correction applied to digitized waveforms prior to signal processing reduced the differential and integral nonlinearities by an order of magnitude, eliminating these as dominant contributions to the systematic energy uncertainty at the double-beta decay Q value

Synthesis of Starch-Stabilized Ag Nanoparticles and Hg2+Recognition in Aqueous Media

The starch-stabilized Ag nanoparticles were successfully synthesized via a reduction approach and characterized with SPR UV/Vis spectroscopy, TEM, and HRTEM. By utilizing the redox reaction between Ag nanoparticles and Hg2+, and the resulted decrease in UV/Vis signal, we develop a colorimetric method for detection of Hg2+ion. A linear relationship stands between the absorbance intensity of the Ag nanoparticles and the concentration of Hg2+ion over the range from 10 ppb to 1 ppm at the absorption of 390 nm. The detection limit for Hg2+ions in homogeneous aqueous solutions is estimated to be ~5 ppb. This system shows excellent selectivity for Hg2+over other metal ions including Na+, K+, Ba2+, Mg2+, Ca2+, Fe3+, and Cd2+. The results shown herein have potential implications in the development of new colorimetric sensors for easy and selective detection and monitoring of mercuric ions in aqueous solutions

Pregnancy in multiple system atrophy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Multiple system atrophy is a late, adult-onset α-synucleinopathy with no data on the effect of pregnancy on the disease course. Early stage multiple system atrophy can be difficult to distinguish from Parkinson's disease.</p> <p>Case presentation</p> <p>We describe the case of an Irish woman with parkinsonism starting at age 31, initially diagnosed as having dopa-responsive, idiopathic Parkinson's disease, who successfully delivered a full-term child at age 35. Her pregnancy was complicated by severe orthostatic hypotension and motor fluctuations. Two years post-partum, she underwent bilateral subthalamic nuclei deep brain stimulation for intractable motor fluctuations and disabling dyskinesia. After this treatment course she experienced deterioration of motor symptoms and death eight years after disease onset. Post-mortem neuropathological examination revealed striatonigral degeneration and α-synuclein-positive glial cytoplasmic inclusions in brain stem nuclei, basal ganglia and white matter tracts, consistent with a neuropathological diagnosis of multiple system atrophy.</p> <p>Conclusions</p> <p>Multiple system atrophy can affect women of child-bearing age and pregnancy may be associated with marked disease progression.</p

Roles for Treg expansion and HMGB1 signaling through the TLR1-2-6 axis in determining the magnitude of the antigen-specific immune response to MVA85A

© 2013 Matsumiya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedA better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2Rα two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans.This work was funded by the Wellcome Trust. MM has a Wellcome Trust PhD studentship and HM is a Wellcome Trust Senior Fello

Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitro study

<p>Abstract</p> <p>Background</p> <p>Sorafenib is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma (HCC), setting a new standard for first-line treatment. However, no one has yet been able to predict sensitivity to sorafenib. Pre-treatment pERK level has been shown to be associated with favorable response to such therapy in a phase II clinical study, indicating that pERK may be a potential biomarker for treatment of HCC with sorafenib.</p> <p>Methods</p> <p>The effects of sorafenib and 5-fluorouracil (5-FU) on cell proliferation were evaluated by cell viability assays in four HCC cell lines (SMMC-7721, MHCC97-L, MHCC97-H and HCCLM6) with different metastatic potential and basal pERK expression levels. Expression levels of pERK were determined by immunocytochemical quantification together with western blot analysis, and pERK density values were also calculated. Correlation analyses were then carried out between the IC₅₀values of drugs and pERK density values. After basal ERK phosphorylation was down-regulated with U0126 in MHCC97-H cells, cellular responsiveness to sorafenib was assessed by cell viability assay.</p> <p>Results</p> <p>Basal pERK levels increased stepwise in cell lines in accordance with their metastatic potential. Sorafenib inhibited ERK phosphorylation in a dose-dependent manner in all four cell lines at a concentration between 5 and 20 μM, but the degree of inhibition was significantly different according to their basal pERK expression level (<it>P </it>< 0.0001). In contrast, no significant change was observed after 5-FU treatment. Correlation analyses between the IC₅₀values and pERK densities revealed that the effects of sorafenib on cell proliferation were significantly correlated with basal pERK levels (Spearman r = -0.8671, <it>P </it>= 0.0003). Resistance to 5-FU was also significantly associated with basal pERK expression in these HCC cell lines (Spearman r = 0.7832, <it>P </it>= 0.0026). After the basal ERK phosphorylation level in MHCC97-H cells was reduced with U0126, they were significantly less sensitive to sorafenib-mediated growth inhibition, with an IC₅₀of 17.31 ± 1.62 μM versus 10.81 ± 1.24 μM (<it>P </it>= 0.0281).</p> <p>Conclusion</p> <p>In this <it>in vitro </it>study, pERK was confirmed to be a potential biomarker predictive of sensitivity to sorafenib in treating HCC. The RAF/MEK/ERK pathway may be involved in drug resistance to traditional chemotherapy in HCC.</p

EzArray: A web-based highly automated Affymetrix expression array data management and analysis system

<p>Abstract</p> <p>Background</p> <p>Though microarray experiments are very popular in life science research, managing and analyzing microarray data are still challenging tasks for many biologists. Most microarray programs require users to have sophisticated knowledge of mathematics, statistics and computer skills for usage. With accumulating microarray data deposited in public databases, easy-to-use programs to re-analyze previously published microarray data are in high demand.</p> <p>Results</p> <p>EzArray is a web-based Affymetrix expression array data management and analysis system for researchers who need to organize microarray data efficiently and get data analyzed instantly. EzArray organizes microarray data into projects that can be analyzed online with predefined or custom procedures. EzArray performs data preprocessing and detection of differentially expressed genes with statistical methods. All analysis procedures are optimized and highly automated so that even novice users with limited pre-knowledge of microarray data analysis can complete initial analysis quickly. Since all input files, analysis parameters, and executed scripts can be downloaded, EzArray provides maximum reproducibility for each analysis. In addition, EzArray integrates with Gene Expression Omnibus (GEO) and allows instantaneous re-analysis of published array data.</p> <p>Conclusion</p> <p>EzArray is a novel Affymetrix expression array data analysis and sharing system. EzArray provides easy-to-use tools for re-analyzing published microarray data and will help both novice and experienced users perform initial analysis of their microarray data from the location of data storage. We believe EzArray will be a useful system for facilities with microarray services and laboratories with multiple members involved in microarray data analysis. EzArray is freely available from <url>http://www.ezarray.com/</url>.</p