The effect of atomoxetine on directed and random exploration in humans

The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity

Active caspase-3 is removed from cells by release of caspase-3-enriched vesicles

AbstractCleavage of Rho associated Coiled Coil kinase I (ROCK I) by caspase-3 contributes to membrane blebbing. Whether caspase-3 and ROCK I also play a role in the release of membrane vesicles is unknown. Therefore, we transfected a human breast cancer cell line (MCF-7) that is caspase-3 deficient, lacks membrane blebbing, and does not release membrane vesicles, with caspase-3. Cells expressing caspase-3 demonstrate both ROCK I-mediated membrane blebbing, and release of small (400–600nm) membrane vesicles in a ROCK I-independent manner. These membrane vesicles contain caspase-3, and are enriched in caspase-3 activity compared to the releasing cells. Caspase-3-containing vesicles are taken up by untransfected cells but the cells do not show any sign of apoptosis. In conclusion, we show that the release of caspase-3-enriched membrane vesicles and membrane blebbing are two differentially regulated processes. Furthermore, we hypothesize that packaging of caspase-3 into membrane vesicles contributes to cellular homeostasis by the removal of caspase-3, and concurrently, protects the cells' environment from direct exposure to caspase-3 activity

Catecholamine-mediated increases in neural gain improve the precision of cortical representations

Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations

SPAD array camera for localization based super resolution microscopy

Super resolution microscopy by localization is a stochastic based approach, where the resolution is determined by the localization accuracy [1] [2] [3]. The accuracy of localization heavily depends on the statistics of the data obtained with a camera during imaging. Current state of the art EMCCD (electron multiplying charge coupled device) cameras have frame rates up to 200 fps and hence a limited temporal resolution between frames. This can lead to ambiguities in localization. For example, a single fluorescent spot appearing at the same location in two successive frames is not considered for localization, because it is not clear, whether the spot arises from a single fluorophore in ON state for a long time or from two adjacent fluorophores, which switches ON and OFF. In this work, we explore for the first time the use of a single-photon counting SPAD (single photon avalanche diodes) array camera for super resolution microscopy. These cameras can provide high frame rates (up to 375000 fps), with improved temporal resolution between the frames, enabling a more accurate view of events that can be precisely tracked over time. The rich information obtained from such large number of frames leads to more accurate statistical estimations for overcoming the current ambiguities in localization. Also, SPAD array cameras are capable of reading frames having pixels depth of 1-bit. [4]. Such, a fine granularity enables the user to add any number of frames for identifying and localizing individual events with a very high accuracy. SPADs have been success fully used in performing time-resolved imaging measurements like FLIM (fluorescence life time imaging measurements). This allows us to extend the possibility of performing FLIM and super resolution imaging simultaneously. As a result, two different fluorophores can be separated based on their unique life times, enabling multi-channel operations using a single camera. An example of a preliminary image captured using a SPAD array camera is depicted in Figure

Mutational profiling of kinases in glioblastoma

Background: Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.Methods: Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced. Results: Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway. Conclusions: The knowledge that at least 50% of glioblastoma tumors display mutational activation of the PI3K-AKT pathway should offer new opportunities for the rational development of therapeutic approaches for glioblastomas. However, due to the development of resistance mechanisms, kinase inhibition studies targeting the PI3K-AKT pathway for relapsing glioblastoma have mostly failed thus far. Other therapies should be investigated, targeting early events in gliomagenesis that involve both kinases and non-kinases

Indirect measurement of pinch and pull forces at the shaft of laparoscopic graspers

The grasping instruments used in minimally invasive surgery reduce the ability of the surgeon to feel the forces applied on the tissue, thereby complicating the handling of the tissue and increasing the risk of tissue damage. Force sensors implemented in the forceps of the instruments enable accurate measurements of applied forces, but also complicate the design of the instrument. Alternatively, indirect estimations of tissue interaction forces from measurements of the forces applied on the handle are prone to errors due to friction in the linkages. Further, the force transmission from handle to forceps exhibits large nonlinearities, so that extensive calibration procedures are needed. The kinematic analysis of the grasping mechanism and experimental results presented in this paper show that an intermediate solution, force measurements at the shaft and rod of the grasper, enables accurate measurements of the pinch and pull forces on tissue with only a limited number of calibration measurements. We further show that the force propagation from the shaft and rod to the forceps can be approximated by a linear two-dimensional function of the opening angle of the grasper and the force on the rod

Flipping Journals to Open: Rethinking Publishing Infrastructure

The resignation of the editorial board of an Elsevier-owned linguistics journal and its open access reorganization could get the ball rolling for other journals to follow suit. This case is a reminder that open access means more than just providing access to an article; it means rethinking the whole process of publishing. Open access also raises important questions about who owns the critical information infrastructure for online publishing