Decisional role of the dorsolateral prefrontal cortex in ocular motor behaviour

Three patients with a unilateral cortical lesion affecting the dorsolateral prefrontal cortex (DLPFC), i.e. Brodmann area 46, were tested using different paradigms of reflexive saccades (gap and overlap tasks), intentional saccades (antisaccades, memory‐guided and predictive saccades) and smooth pursuit movements. Visually guided saccades with gap and overlap, latency of correct antisaccades and memory‐guided saccades and the gain of smooth pursuit were normal, compared with controls. These results confirm our anatomical data showing that the adjacent frontal eye field (FEF) was unimpaired in these patients. The specific pattern of abnormalities after a unilateral DLPFC lesion, compared with that of the FEF lesions previously reported, consists mainly of: (i) a bilateral increase in the percentage of errors in the antisaccade task (misdirected reflexive saccades); (ii) a bilateral increase in the variable error in amplitude, without significant decrease in the gain, in the memory‐guided saccade task; and (iii) a bilateral decrease in the percentage of anticipatory saccades in the predictive task. Taken together, these results suggest that the DLPFC plays a crucial role in the decisional processes, preparing saccades by inhibiting unwanted reflexive saccades (inhibition), maintaining memorized information for ongoing intentional saccades (short‐term spatial memory) or facilitating anticipatory saccades (prediction), depending upon current external environmental and internal circumstance

Space-Time Distribution of G-Band and Ca II H-Line Intensity Oscillations in Hinode/SOT-FG Observations

We study the space-time distributions of intensity fluctuations in 2 - 3 hour sequences of multi-spectral, high-resolution, high-cadence broad-band filtergram images (BFI) made by the SOT-FG system aboard the Hinode spacecraft. In the frequency range 5.5 < f < 8.0 mHz both G-band and Ca II H-line oscillations are suppressed in the presence of magnetic fields, but the suppression disappears for f > 10 mHz. By looking at G-band frequencies above 10 mHz we find that the oscillatory power, both at these frequencies and at lower frequencies too, lies in a mesh pattern with cell scale 2 - 3 Mm, clearly larger than normal granulation, and with correlation times on the order of hours. The mesh pattern lies in the dark lanes between stable cells found in time-integrated G-band intensity images. It also underlies part of the bright pattern in time-integrated H-line emission. This discovery may reflect dynamical constraints on the sizes of rising granular convection cells together with the turbulence created in strong intercellular downflows.Comment: 24 pages, 15 figure

Establishing a major cause of discrepancy in the calibration of Affymetrix GeneChips

<p>Abstract</p> <p>Background</p> <p>Affymetrix GeneChips are a popular platform for performing whole-genome experiments on the transcriptome. There are a range of different calibration steps, and users are presented with choices of different background subtractions, normalisations and expression measures. We wished to establish which of the calibration steps resulted in the biggest uncertainty in the sets of genes reported to be differentially expressed.</p> <p>Results</p> <p>Our results indicate that the sets of genes identified as being most significantly differentially expressed, as estimated by the z-score of fold change, is relatively insensitive to the choice of background subtraction and normalisation. However, the contents of the gene list are most sensitive to the choice of expression measure. This is irrespective of whether the experiment uses a rat, mouse or human chip and whether the chip definition is made using probe mappings from Unigene, RefSeq, Entrez Gene or the original Affymetrix definitions. It is also irrespective of whether both Present and Absent, or just Present, Calls from the MAS5 algorithm are used to filter genelists, and this conclusion holds for genes of differing intensities. We also reach the same conclusion after assigning genes to be differentially expressed using t-statistics, although this approach results in a large amount of false positives in the sets of genes identified due to the small numbers of replicates typically used in microarray experiments.</p> <p>Conclusion</p> <p>The major calibration uncertainty that biologists need to consider when analysing Affymetrix data is how their multiple probe values are condensed into one expression measure.</p

Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer

Despite increasing options for treatment of castration-resistant prostate cancer, development of drug resistance is inevitable. The glucocorticoid receptor (GR) is a prime suspect for acquired therapy resistance, as prostate cancer (PCa) cells are able to increase GR signaling during anti-androgen therapy and thereby circumvent androgen receptor (AR)-blockade and cell death. As standard AR-directed therapies fail to block the GR and GR inhibitors might result in intolerable side effects, the identification of GR signature genes, which are better suited for a targeted approach, is of clinical importance. Therefore, the specific epithelial and stromal GR signature was determined in cancer-associated fibroblasts as well as in abiraterone and enzalutamide-resistant cells after glucocorticoid (GC) treatment. Microarray and ChIP analysis identified MAO-A as a directly up-regulated mutual epithelial and stromal GR target, which is induced after GC treatment and during PCa progression. Elevated MAO-A levels were confirmed in in vitro cell models, in primary tissue cultures after GC treatment, and in patients after neoadjuvant chemotherapy with GCs. MAO-A expression correlates with GR/AR activity as well as with a reduced progression-free survival. Pharmacological MAO-A inhibition combined with 2(nd) generation AR signaling inhibitors or chemotherapeutics results in impaired growth of androgen-dependent, androgen-independent, and long-term anti-androgen-treated cells. In summary, these findings demonstrate that targeting MAO-A represents an innovative therapeutic strategy to synergistically block GR and AR dependent PCa cell growth and thereby overcome therapy resistance.Prostatic carcinom

GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy

Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). The BCL-2 family has an essential role in regulating GC-induced cell death. Here we show that downregulation of antiapoptotic BCL-2 family proteins, especially MCL-1, enhances GC-induced cell death. Thus we target MCL-1 by using GX15-070 (obatoclax) in ALL cells. Treatment with GX15-070 in both dexamethasone (Dex)-sensitive and -resistant ALL cells shows effective growth inhibition and cell death. GX15-070 induces caspase-3 cleavage and increases the Annexin V-positive population, which is indicative of apoptosis. Before the onset of apoptosis, GX15-070 induces LC3 conversion as well as p62 degradation, both of which are autophagic cell death markers. A pro-apoptotic molecule BAK is released from the BAK/MCL-1 complex following GX15-070 treatment. Consistently, downregulation of BAK reduces caspase-3 cleavage and cell death, but does not alter LC3 conversion. In contrast, downregulation of ATG5, an autophagy regulator, decreases LC3 conversion and cell death, but does not alter caspase-3 cleavage, suggesting that apoptosis and autophagy induced by GX15-070 are independently regulated. Downregulation of Beclin-1, which is capable of crosstalk between apoptosis and autophagy, affects GX15-070-induced cell death through apoptosis but not autophagy. Taken together, GX15-070 treatment in ALL could be an alternative regimen to overcome glucocorticoid resistance by inducing BAK-dependent apoptosis and ATG5-dependent autophagy

Impaired Representation of Geometric Relationships in Humans with Damage to the Hippocampal Formation

The pivotal role of the hippocampus for spatial memory is well-established. However, while neurophysiological and imaging studies suggest a specialization of the hippocampus for viewpoint-independent or allocentric memory, results from human lesion studies have been less conclusive. It is currently unclear whether disproportionate impairment in allocentric memory tasks reflects impairment of cognitive functions that are not sufficiently supported by regions outside the medial temporal lobe or whether the deficits observed in some studies are due to experimental factors. Here, we have investigated whether hippocampal contributions to spatial memory depend on the spatial references that are available in a certain behavioral context. Patients with medial temporal lobe lesions affecting systematically the right hippocampal formation performed a series of three oculomotor tasks that required memory of a spatial cue either in retinal coordinates or relative to a single environmental reference across a delay of 5000 ms. Stimulus displays varied the availability of spatial references and contained no complex visuo-spatial associations. Patients showed a selective impairment in a condition that critically depended on memory of the geometric relationship between spatial cue and environmental reference. We infer that regions of the medial temporal lobe, most likely the hippocampal formation, contribute to behavior in conditions that exceed the potential of viewpoint-dependent or egocentric representations. Apparently, this already applies to short-term memory of simple geometric relationships and does not necessarily depend on task difficulty or integration of landmarks into more complex representations. Deficient memory of basic geometric relationships may represent a core deficit that contributes to impaired performance in allocentric spatial memory tasks

Community projects: an experimental analysis of a fair implementation process

We define and experimentally test a public provision mechanism that meets three basic ethical requirements and allows community members to influence, via monetary bids, which of several projects is implemented. For each project, participants are assigned personal values, which can be positive or negative. We provide either public or private information about personal values. This produces two distinct public provision games, which are experimentally implemented and analyzed for various projects. In spite of the complex experimental task, participants do not rely on bidding their own personal values as an obvious simple heuristic whose general acceptance would result in fair and efficient outcomes. Rather, they rely on strategic underbidding. Although underbidding is affected by projects’ characteristics, the provision mechanism mostly leads to the implementation of the most efficient project

Mapping patterns of complementary and alternative medicine use in cancer: An explorative cross-sectional study of individuals with reported positive "exceptional" experiences

<p>Abstract</p> <p>Background</p> <p>While the use of complementary and alternative medicine (CAM) among cancer patients is common and widespread, levels of commitment to CAM vary. "Committed" CAM use is important to investigate, as it may be associated with elevated risks and benefits, and may affect use of biomedically-oriented health care (BHC). Multiple methodological approaches were used to explore and map patterns of CAM use among individuals postulated to be committed users, voluntarily reporting exceptional experiences associated with CAM use after cancer diagnosis.</p> <p>Method</p> <p>The verbatim transcripts of thirty-eight unstructured interviews were analyzed in two steps. First, manifest content analysis was used to elucidate and map participants' use of CAM, based on the National Center for Complementary Medicine (NCCAM)'s classification system. Second, patterns of CAM use were explored statistically using principal component analysis.</p> <p>Findings</p> <p>The 38 participants reported using a total of 274 specific CAM (median = 4) consisting of 148 different therapeutic modalities. Most reported therapies could be categorized using the NCCAM taxonomy (n = 224). However, a significant number of CAM therapies were not consistent with this categorization (n = 50); consequently, we introduced two additional categories: <it>Spiritual/health literature </it>and <it>Treatment centers</it>. The two factors explaining the largest proportion of variation in CAM usage patterns were a) number of CAM modalities used and b) a category preference for <it>Energy therapies </it>over the categories <it>Alternative Medical Systems </it>and <it>Treatment centers </it>or vice versa.</p> <p>Discussion</p> <p>We found considerable heterogeneity in patterns of CAM use. By analyzing users' own descriptions of CAM in relation to the most commonly used predefined professional taxonomy, this study highlights discrepancies between user and professional conceptualizations of CAM not previously addressed. Beyond variations in users' reports of CAM, our findings indicate some patterns in CAM usage related to number of therapies used and preference for different CAM categories.</p

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.Peer reviewe