The programming of sequences of saccades

Saccadic eye movements move the high-resolution fovea to point at regions of interest. Saccades can only be generated serially (i.e., one at a time). However, what remains unclear is the extent to which saccades are programmed in parallel (i.e., a series of such moments can be planned together) and how far ahead such planning occurs. In the current experiment, we investigate this issue with a saccade contingent preview paradigm. Participants were asked to execute saccadic eye movements in response to seven small circles presented on a screen. The extent to which participants were given prior information about target locations was varied on a trial-by-trial basis: participants were aware of the location of the next target only, the next three, five, or all seven targets. The addition of new targets to the display was made during the saccade to the next target in the sequence. The overall time taken to complete the sequence was decreased as more targets were available up to all seven targets. This was a result of a reduction in the number of saccades being executed and a reduction in their saccade latencies. Surprisingly, these results suggest that, when faced with a demand to saccade to a large number of target locations, saccade preparation about all target locations is carried out in paralle

The concurrent programming of saccades

Sequences of saccades have been shown to be prepared concurrently however it remains unclear exactly what aspects of those saccades are programmed in parallel. To examine this participants were asked to make one or two target-driven saccades: a reflexive saccade; a voluntary saccade; a reflexive then a voluntary saccade; or vice versa. During the first response the position of a second target was manipulated. The new location of the second saccade target was found to impact on second saccade latencies and second saccade accuracy showing that some aspects of the second saccade program are prepared in parallel with the first. However, differences were found in the specific pattern of effects for each sequence type. These differences fit well within a general framework for saccade control in which a common priority map for saccade control is computed and the influence of saccade programs on one another depends not so much on the types of saccade being produced but rather on the rate at which their programs develop

Minimizing early relapse and maximizing treatment outcomes in hormone-sensitive postmenopausal breast cancer: efficacy review of AI trials

Breast cancer is one of the leading causes of cancer-related deaths in women. Regardless of prognosis, all women with breast cancer are at risk for early recurrence. Nearly 50% of early recurrences occur within 5 years of surgery, and they peak at 2 years after surgery in women treated with adjuvant tamoxifen. Most early recurrences are distant metastases, which strongly correlate with increased mortality. Treatments that mitigate the risk of early distant metastases (DM) are, therefore, likely to improve overall survival in women with early breast cancer (EBC). Aromatase inhibitors (AIs)—anastrozole, letrozole, and exemestane—have been investigated as alternatives to tamoxifen for adjuvant treatment of hormone receptor-positive (HR+) EBC in postmenopausal women (PMW). AIs are better at minimizing risk of early relapse compared with tamoxifen. However, it is not clear if preferential use of AIs over tamoxifen will benefit all PMW with HR+ EBC. The ability to subtype HR+ breast cancer on the basis of biomarkers predictive of response to AIs and tamoxifen would likely be key to determining the most beneficial hormonal treatment within patient subpopulations, but this process requires thorough investigation. Until then, adjuvant therapies that provide the greatest reduction in risk of DM should be considered for all PMW with HR+ EBC. This article reviews the clinical trials of AI adjuvant therapies for hormone-sensitive breast cancer, particularly in the context of how they compare with tamoxifen in minimizing the risk of relapse, occurrence of DM, and breast cancer-related deaths

Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57

Endoplasmic reticulum (ER) malfunction, leading to ER stress, can be a consequence of genome instability and hypoxic tissue environments. Cancer cells survive by acquiring or enhancing survival mechanisms to counter the effects of ER stress and these homeostatic responses may be new therapeutic targets. Understanding the links between ER stress and apoptosis may be approached using drugs specifically to target ER stress responses in cancer cells. The retinoid analogue fenretinide [N-(4-hydroxyphenyl) retinamide] is a new cancer preventive and chemotherapeutic drug, that induces apoptosis of some cancer cell types via oxidative stress, accompanied by induction of an ER stress-related transcription factor, GADD153. The aim of this study was to test the hypothesis that fenretinide induces ER stress in neuroectodermal tumour cells, and to elucidate the role of ER stress responses in fenretinide-induced apoptosis. The ER stress genes ERdj5, ERp57, GRP78, calreticulin and calnexin were induced in neuroectodermal tumour cells by fenretinide. In contrast to the apoptosis-inducing chemotherapeutic drugs vincristine and temozolomide, fenretinide induced the phosphorylation of eIF2α, expression of ATF4 and splicing of XBP-1 mRNA, events that define ER stress. In these respects, fenretinide displayed properties similar to the ER stress inducer thapsigargin. ER stress responses were inhibited by antioxidant treatment. Knockdown of ERp57 or ERdj5 by RNA interference in these cells increased the apoptotic response to fenretinide. These data suggest that downregulating homeostatic ER stress responses may enhance apoptosis induced by oxidative stress-inducing drugs acting through the ER stress pathway. Therefore, ER-resident proteins such as ERdj5 and ERp57 may represent novel chemotherapeutic targets

Macrorheology of cystic fibrosis, chronic obstructive pulmonary disease & normal sputum

<p>Abstract</p> <p>Background</p> <p>Prior microrheologic assessments of selected, microlitre plugs of cystic fibrosis (CF) sputum suggest no intrinsic rheologic abnormality. However, such analyses may not be representative of CF sputum as a whole. We therefore reassessed this question using whole sputum macrorheology. Additionally, we wished to further explore the relationships between sputum rheology, inflammation and infection.</p> <p>Methods</p> <p>Dynamic oscillatory macrorheometry was performed on whole expectorated sputum from stable adults with CF (n = 18) and COPD (n = 12) and induced sputum from normal controls (n = 7). Concomitant sputum inflammatory mediator levels were measured in CF and COPD samples. Sputum collected from CF subjects (n = 6) at commencement and completion of intravenous antibiotic therapy for an infective exacerbation was also assessed.</p> <p>Results</p> <p>CF sputum neutrophil elastase activity (NE) was significantly related to degree of sputum purulence (p = 0.049) and correlated significantly with measures of sputum viscoelasticity (r = 0.696, p = 0.008 for storage modulus G' at 9 Hz). There were significant differences in viscoelasticity between subject groups when samples were compared irrespective of appearance/degree of sputum purulence. However, the macrorheology of mucoid CF sputum did not differ from normal sputum (eg median (range) G' at 9 Hz 2.25 (0.79, 3.26) vs 2.04 (1.4,4.6) Pa, p = 1). In contrast, mucoid COPD samples demonstrated significantly greater viscoelasticity (G' at 9 Hz 4.5 (2.4, 23) Pa) than sputum from both CF (p = 0.048) & normal subjects (p = 0.009). Antibiotic therapy during exacerbations was associated with significant reductions in CF sputum viscoelasticity, with mean (SD) G' at 9 Hz decreasing from 28.5 (11.5) Pa at commencement to 6.4 (4.6) Pa on day 7 (p = 0.01).</p> <p>Conclusion</p> <p>The macrorheologic properties of whole, mucoid CF sputum are not different from normal, confirming the results of prior microrheologic studies. Instead, CF sputum viscoelasticity is related to secondary infection, decreases with intravenous antibiotic therapy and correlates with inflammation. In contrast, COPD sputum demonstrates inherently greater viscoelasticity, providing a novel target for potential therapeutic interventions.</p

Bidirectional lipid droplet velocities are controlled by differential binding strengths of HCV Core DII protein

Host cell lipid droplets (LD) are essential in the hepatitis C virus (HCV) life cycle and are targeted by the viral capsid core protein. Core-coated LDs accumulate in the perinuclear region and facilitate viral particle assembly, but it is unclear how mobility of these LDs is directed by core. Herein we used two-photon fluorescence, differential interference contrast imaging, and coherent anti-Stokes Raman scattering microscopies, to reveal novel core-mediated changes to LD dynamics. Expression of core protein’s lipid binding domain II (DII-core) induced slower LD speeds, but did not affect directionality of movement on microtubules. Modulating the LD binding strength of DII-core further impacted LD mobility, revealing the temporal effects of LD-bound DII-core. These results for DII-core coated LDs support a model for core-mediated LD localization that involves core slowing down the rate of movement of LDs until localization at the perinuclear region is accomplished where LD movement ceases. The guided localization of LDs by HCV core protein not only is essential to the viral life cycle but also poses an interesting target for the development of antiviral strategies against HCV

Neurogenesis Drives Stimulus Decorrelation in a Model of the Olfactory Bulb

The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb -- the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells -- are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures

Drought-Adaptation Potential in Fagus sylvatica: Linking Moisture Availability with Genetic Diversity and Dendrochronology

<div><h3>Background</h3><p>Microevolution is essential for species persistence especially under anticipated climate change scenarios. Species distribution projection models suggested that the dominant tree species of lowland forests in Switzerland, European beech (<em>Fagus sylvatica</em> L.), might disappear from most areas due to expected longer dry periods. However, if genotypes at the moisture boundary of the species climatic envelope are adapted to lower moisture availability, they can serve as seed source for the continuation of beech forests under changing climates.</p> <h3>Methodology/Principal Findings</h3><p>With an AFLP genome scan approach, we studied neutral and potentially adaptive genetic variation in <em>Fagus sylvatica</em> in three regions containing a dry and a mesic site each (<em>n</em>_ind. = 241, <em>n</em>_markers = 517). We linked this dataset with dendrochronological growth measures and local moisture availabilities based on precipitation and soil characteristics. Genetic diversity decreased slightly at dry sites. Overall genetic differentiation was low (<em>F</em>_st = 0.028) and Bayesian cluster analysis grouped all populations together suggesting high (historical) gene flow. The Bayesian outlier analyses indicated 13 markers with three markers differing between all dry and mesic sites and the others between the contrasting sites within individual regions. A total of 41 markers, including seven outlier loci, changed their frequency with local moisture availability. Tree height and median basal growth increments were reduced at dry sites, but marker presence/absence was not related to dendrochronological characteristics.</p> <h3>Conclusion and Their Significance</h3><p>The outlier alleles and the makers with changing frequencies in relation to moisture availability indicate microevolutionary processes occurring within short geographic distances. The general genetic similarity among sites suggests that ‘preadaptive’ genes can easily spread across the landscape. Yet, due to the long live span of trees, fostering saplings originating from dry sites and grown within mesic sites might increase resistance of beech forests during the anticipated longer dry periods.</p> </div

Consistency Analysis of Redundant Probe Sets on Affymetrix Three-Prime Expression Arrays and Applications to Differential mRNA Processing

Affymetrix three-prime expression microarrays contain thousands of redundant probe sets that interrogate different regions of the same gene. Differential expression analysis methods rarely consider probe redundancy, which can lead to inaccurate inference about overall gene expression or cause investigators to overlook potentially valuable information about differential regulation of variant mRNA products. We investigated the behaviour and consistency of redundant probe sets in a publicly-available data set containing samples from mouse brain amygdala and hippocampus and asked how applying filtering methods to the data affected consistency of results obtained from redundant probe sets. A genome-based filter that screens and groups probe sets according to their overlapping genomic alignments significantly improved redundant probe set consistency. Screening based on qualitative Present-Absent calls from MAS5 also improved consistency. However, even after applying these filters, many redundant probe sets showed significant fold-change differences relative to each other, suggesting differential regulation of alternative transcript production. Visual inspection of these loci using an interactive genome visualization tool (igb.bioviz.org) exposed thirty putative examples of differential regulation of alternative splicing or polyadenylation across brain regions in mouse. This work demonstrates how P/A-call and genome-based filtering can improve consistency among redundant probe sets while at the same time exposing possible differential regulation of RNA processing pathways across sample types