In the blink of an eye: Value and novelty drive saccades

Evidence accumulation is an essential component of value-based decisions. Recent human studies suggest that overt attention correlates with evidence accumulation necessary for optimal decisions. However, the influence of covert attention on decision-making remains relatively unexplored. To investigate this issue, two monkeys were trained to perform a decision-making task where they chose between two stimuli, which were either ‘Overtrained’ or learned that day (‘Novel’). Subjects could freely saccade during choice evaluation and indicated their decision by moving a joystick. Saccades were made within 170 ms of stimulus presentation and were strongly driven by both value and novelty, implying covert stimulus evaluation prior to saccade. This effect was strongest for ‘Overtrained’ choices, but rapidly emerged during learning of ‘Novel’ choices. Though novel stimuli attracted initial saccades, final decisions were guided only by value; implying attentional value comparison processes are at least partially dissociable from value comparison processes that govern final decisions. While subjects made highly optimal decisions, they frequently viewed only one stimulus; final choice was thus best explained by assuming covert evidence accumulation. Our results suggest that the primate brain contains multiple value comparison systems for guiding attention toward highly valuable or novel information while simultaneously optimizing final decision value

Combined model-free and model-sensitive reinforcement learning in non-human primates

Contemporary reinforcement learning (RL) theory suggests that potential choices can be evaluated by strategies that may or may not be sensitive to the computational structure of tasks. A paradigmatic model-free (MF) strategy simply repeats actions that have been rewarded in the past; by contrast, modelsensitive (MS) strategies exploit richer information associated with knowledge of task dynamics. MF and MS strategies should typically be combined, because they have complementary statistical and computational strengths; however, this tradeoff between MF/MS RL has mostly only been demonstrated in humans, often with only modest numbers of trials. We trained rhesus monkeys to perform a two-stage decision task designed to elicit and discriminate the use of MF and MS methods. A descriptive analysis of choice behaviour revealed directly that the structure of the task (of MS importance) and the reward history (of MF and MS importance) significantly influenced both choice and response vigour. A detailed, trial-by-trial computational analysis confirmed that choices were made according to a combination of strategies, with a dominant influence of a particular form of model sensitivity that persisted over weeks of testing. The residuals from this model necessitated development of a new combined RL model which incorporates a particular credit assignment weighting procedure. Finally, response vigor exhibited a subtly different collection ofMFand MS influences. These results provide new illumination onto RL behavioural processes in non-human primates

Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection

Citation: Udukala, D. N., Wang, H. W., Wendel, S. O., Malalasekera, A. P., Samarakoon, T. N., Yapa, A. S., . . . Bossmann, S. H. (2016). Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection. Beilstein Journal of Nanotechnology, 7, 364-373. doi:10.3762/bjnano.7.33Additional Authors: Ortega, R.;Toledo, Y.;Bossmann, L.;Robinson, C.;Janik, K. E.;Koper, O. B.;Motamedi, M.;Zhu, G. H.Proteases, including matrix metalloproteinases (MMPs), tissue serine proteases, and cathepsins (CTS) exhibit numerous functions in tumor biology. Solid tumors are characterized by changes in protease expression levels by tumor and surrounding tissue. Therefore, monitoring protease levels in tissue samples and liquid biopsies is a vital strategy for early cancer detection. Water-dispersable Fe/Fe3O4-core/shell based nanoplatforms for protease detection are capable of detecting protease activity down to sub-femtomolar limits of detection. They feature one dye (tetrakis(carboxyphenyl) porphyrin (TCPP)) that is tethered to the central nanoparticle by means of a protease-cleavable consensus sequence and a second dye (Cy 5.5) that is directly linked. Based on the protease activities of urokinase plasminogen activator (uPA), MMPs 1, 2, 3, 7, 9, and 13, as well as CTS B and L, human breast cancer can be detected at stage I by means of a simple serum test. By monitoring CTS B and L stage 0 detection may be achieved. This initial study, comprised of 46 breast cancer patients and 20 apparently healthy human subjects, demonstrates the feasibility of protease-activity-based liquid biopsies for early cancer diagnosis

The role of prefrontal cortex and basal ganglia in model-based and model-free reinforcement learning

Animals can learn to influence their environment either by exploiting stimulus-response associa- tions that have been productive in the past, or by predicting the likely worth of actions in the future based on their causal relationships with outcomes. These respectively model-free (MF) and model-based (MB) strate- gies are supported by structures including midbrain dopaminergic neurons, striatum and prefrontal cortex (PFC), but it is not clear how they interact to realize these two types of reinforcement learning (RL). We trained rhesus monkeys to perform a two-stage Markov decision task that induces a combination of MB and MF behavior. The task starts with a choice between two options. Each of these is more often associated with one of two second-stage states with probabilities that are fixed throughout the experiment. A second two-option choice is required in order to obtain one of three different levels of reward. These second-stage outcomes change independently, according to a random walk, and thus induce exploration. A descriptive analysis of our behavioral data shows that the immediate reward history (of MF and MB importance) and the interaction between reward history and the structure of the task (of MB importance) both significantly influenced stage one choices. On the other hand, only the immediate reward history seemed to influence reaction time. When we performed a trial-by-trial computational analysis on our data using different RL algorithms, we found that in the model that best fit the data, choices were made according to a weighted combination of MF-RL and MB-RL action values (with a weight for MB-RL of 84.3 ± 3.2 %). Our behavioral findings support a more integrated view of MF and MB learning strategies. They also illu- minate the way that the vigor of responding relates to average rate of reward delivery. Neurophysiological recordings are currently being performed in subregions of PFC and the striatum during task performance

Varicose Veins : Aspects on Diagnosis and Surgical Treatment

Treatment for varicose veins (VV) is insufficiently evidence based and recurrence rates are high. The aim of this thesis was to study the long-term results after VV surgery, risk factors for recurrences and the effect of preoperative duplex scanning on recurrence rate, quality of life (QoL) and costs. In a follow-up study 89 patients with 100 legs operated on for VV 6–10 years earlier were re-examined with duplex, in 13 cases also with varicography. 57% had incompetent vessels in the groin visible with duplex, equally well defined by varicography. Residual branches could not be differentiated from new vessel formation. The recurrence rate did not correlate to the surgeon’s level of experience or perioperative difficulties at primary surgery. In a prospective randomized study 293 patients (343 legs) were operated on for primary VV with or without preoperative duplex. Duplex was done postoperatively, at 2 months and 2 years. QoL was measured with SF-36 preoperatively, at 1 month, 1 year and 2 years. After 2 years the number of reoperations were 2 in the group with preoperative duplex and 14 in the group without (p=0.002). Incompetent veins were seen in the saphenofemoral or saphenopopliteal junction in 19 and 53 legs respectively (p<0.001). Preoperative QoL was worse in the VV patients compared to a reference population, and was normalised 2 years postoperatively. The improved surgical result in the duplex group was not reflected in a significantly higher QoL. The lower costs for redo surgery in the duplex group did not offset the costs for duplex, partly due to more extensive primary surgery. A significant proportion of recurrences after 2 years was new vessel formation and progression of disease. Preoperative perforating vein incompetence did not influence recurrence rate, and was abolished without specific interruption in 60% at 2 years postoperatively

A nanobiosensor for the detection of arginase activity

A nanobiosensor for arginase detection was designed and synthesized. It features a central dopamine-coated iron/iron oxide nanoparticle to which sulfonated cyanine 7.0 is tethered via a stable amide bond. Cyanine 5.5 is linked to the N-terminal of the peptide sequence GRRRRRRRG. Arginine (R) reacts to ornithine (O) in the presence of arginase. Based on calibration with commercially obtained arginase II, the limit of detection (LOD) is picomolar. It is noteworthy that the nanobiosensor for arginase detection does not show a fluorescence increase when incubated with the enzyme NO-reductase, which also uses arginase as substrate, but is indicative of an inflammatory response by the host to cancer and infections. Arginase activity was determined in a syngeneic mouse model for aggressive breast cancer (4 T1 tumors in BALB/c mice). It was found that the arginase activity is systemically enhanced, but especially pronounced in the active tumor regions. (C) 2016 Elsevier Inc. All rights reserved

Impingement characteristics of an early injection gasoline direct injection engine: A numerical study

This paper describes the use of a Lagrangian discrete droplet model to evaluate the liquid fuel impingement characteristics on the internal surfaces of an early injection gasoline direct injection (GDI) engine. The study focuses on fuel impingement on the intake valve and cylinder liner between start of injection (SOI) and 20° after SOI using both a single- and multi-component fuel. The single-component fuel used was iso-octane and the multi-component fuel contained fractions of iso-pentane, iso-octane and n-decane to represent the light, medium and heavy fuel fractions of gasoline, respectively. A detailed description of the impingement and liquid film modelling approach is also provided Fuel properties, wall surface temperature and droplet Weber number and Laplace number were used to quantify the impingement regime for different fuel fractions and correlated well with the predicted onset of liquid film formation. Evidence of film stripping was seen from the liquid film formed on the side of the intake valve head with subsequent ejected droplets being a likely source of unburned hydrocarbons and particulate matter emissions. Differences in impingement location and subsequent location of liquid film formation were also observed between single- and multi-component fuels. A qualitative comparison with experimental cylinder liner impingement data showed the model to well predict the timing and positioning of the liner fuel impingement

Unsteady flamelet/progress variable approach for non-premixed turbulent lifted flames

This article was accepted for publication in the journal, Химическая физика / Khimicheskaya Fizika / Russian Journal of Physical Chemistry. The final publication is available at www.springerlink.com.The unsteady flamelet/progress variable approach has been developed for the prediction of a lifted flame to capture the extinction and re-ignition physics. In this work inclusion of the time variant behavior in the flamelet generation embedded in the large eddy simulation technique, allows better understanding of partially premixed flame dynamics. In the process sufficient simulations to generate unsteady laminar flamelets are performed, which are a function of time. These flamelets are used for the generation of the look-up table and the flamelet library is produced. This library is used for the calculation of temperature and other species in the computational domain as the solution progresses. The library constitutes filtered quantities of all the scalars as a function of mean mixture fraction, mixture fraction variance and mean progress variable. Mixture fraction and progress variable distributions are assumed to be β-PDF and -PDF respectively. The technique used here is known as the unsteady flamelet progress variable (UFPV) approach. One of the well known lifted flames is considered for the present modeling which shows flame lift-off. The results are compared with the experimental data for the mixture fraction and temperature. Lift off height is predicted from the numerical calculations and compared with the experimentally given value. Comparisons show a reasonably good agreement and the UFPV combustion model appear to be a promising technique for the prediction of lifted and partially premixed flames