Saccadic latency in hepatic encephalopathy: a pilot study

Hepatic encephalopathy is a common complication of cirrhosis. The degree of neuro-psychiatric impairment is highly variable and its clinical staging subjective. We investigated whether eye movement response times—saccadic latencies—could serve as an indicator of encephalopathy. We studied the association between saccadic latency, liver function and paper- and pencil tests in 70 patients with cirrhosis and 31 patients after liver transplantation. The tests included the porto-systemic encephalopathy (PSE-) test, critical flicker frequency, MELD score and ammonia concentration. A normal range for saccades was established in 31 control subjects. Clinical and biochemical parameters of liver, blood, and kidney function were also determined. Median saccadic latencies were significantly longer in patients with liver cirrhosis when compared to patients after liver transplantation (244 ms vs. 278 ms p < 0.001). Both patient groups had prolonged saccadic latency when compared to an age matched control group (175 ms). The reciprocal of median saccadic latency (μ) correlated with PSE tests, MELD score and critical flicker frequency. A significant correlation between the saccadic latency parameter early slope (σE) that represents the prevalence of early saccades and partial pressure of ammonia was also noted. Psychometric test performance, but not saccadic latency, correlated with blood urea and sodium concentrations. Saccadic latency represents an objective and quantitative parameter of hepatic encephalopathy. Unlike psychometric test performance, these ocular responses were unaffected by renal function and can be obtained clinically within a matter of minutes by non-trained personnel

Paradoxical Evidence Integration in Rapid Decision Processes

Decisions about noisy stimuli require evidence integration over time. Traditionally, evidence integration and decision making are described as a one-stage process: a decision is made when evidence for the presence of a stimulus crosses a threshold. Here, we show that one-stage models cannot explain psychophysical experiments on feature fusion, where two visual stimuli are presented in rapid succession. Paradoxically, the second stimulus biases decisions more strongly than the first one, contrary to predictions of one-stage models and intuition. We present a two-stage model where sensory information is integrated and buffered before it is fed into a drift diffusion process. The model is tested in a series of psychophysical experiments and explains both accuracy and reaction time distributions

Apoptosis Inducing Effect of Plumbagin on Colonic Cancer Cells Depends on Expression of COX-2

Plumbagin, a quinonoid found in the plants of the Plumbaginaceae, possesses medicinal properties. In this study we investigated the anti-proliferative and apoptotic activity of plumbagin by using two human colonic cancer cell lines, HT29 and HCT15. IC50 of Plumbagin for HCT15 and HT29 cells (22.5 µM and 62.5 µM, respectively) were significantly different. To study the response of cancer cells during treatment strategies, cells were treated with two different concentrations, 15 µM, 30 µM for HCT15 and 50 µM, 75 µM for HT29 cells. Though activation of NFκB, Caspases-3, elevated levels of TNF-α, cytosolic Cytochrome C were seen in both HCT15 cells HT29 treated with plumbagin, aberrant apoptosis with decreased level of pEGFR, pAkt, pGsk-3β, PCNA and Cyclin D1was observed only in 15 µM and 30 µM plumbagin treated HCT15 and 75 µM plumbagin treated HT29 cells. This suggests that plumbagin induces apoptosis in both HCT15 cells and HT29 treated, whereas, proliferation was inhibited only in 15 µM and 30 µM plumbagin treated HCT15 and 75 µM plumbagin treated HT29 cells, but not in 50 µM plumbagin treated HT29 cells. Expression of COX-2 was decreased in 75 µM plumbagin treated HT29 cells when compared to 50 µM plumbagin treated HT29 cells, whereas HCT15 cells lack COX. Hence the observed resistance to induction of apoptosis in 50 µM plumbagin treated HT29 cells are attributed to the expression of COX-2. In conclusion, plumbagin induces apoptosis in colonic cancer cells through TNF-α mediated pathway depending on expression of COX-2 expression

Prediction of binding hot spot residues by using structural and evolutionary parameters

In this work, we present a method for predicting hot spot residues by using a set of structural and evolutionary parameters. Unlike previous studies, we use a set of parameters which do not depend on the structure of the protein in complex, so that the predictor can also be used when the interface region is unknown. Despite the fact that no information concerning proteins in complex is used for prediction, the application of the method to a compiled dataset described in the literature achieved a performance of 60.4%, as measured by F-Measure, corresponding to a recall of 78.1% and a precision of 49.5%. This result is higher than those reported by previous studies using the same data set

Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on growth and osteogenic differentiation of human mesenchymal stem cells

Mesenchymal stem cell differentiation of osteoblasts is triggered by a series of signaling processes including integrin and bone morphogenetic protein (BMP), which therefore act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in an artificial poly-(l)-lactide acid (PLLA) based nanofiber scaffold. Matrices composed of PLLA-collagen type I or BMP-2 incorporated PLLA-collagen type I were seeded with human mesenchymal stem cells (hMSC) and cultivated over a period of 22 days, either under growth or osteoinductive conditions. During the course of culture, gene expression of alkaline phosphatase (ALP), osteocalcin (OC) and collagen I (COL-I) as well as Smad5 and focal adhesion kinase (FAK), two signal transduction molecules involved in BMP-2 or integrin signaling were analyzed. Furthermore, calcium and collagen I deposition, as well as cell densities and proliferation, were determined using fluorescence microscopy. The incorporation of BMP-2 into PLLA-collagen type I nanofibers resulted in a decrease in diameter as well as pore sizes of the scaffold. Mesenchymal stem cells showed better adherence and a reduced proliferation on BMP-containing scaffolds. This was accompanied by an increase in gene expression of ALP, OC and COL-I. Furthermore the presence of BMP-2 resulted in an upregulation of FAK, while collagen had an impact on the gene expression of Smad5. Therefore these different strategies can be combined in order to enhance the osteoblast differentiation of hMSC on PLLA based nanofiber scaffold. By doing this, different signal transduction pathways seem to be up regulated

Integration of Sensory and Reward Information during Perceptual Decision-Making in Lateral Intraparietal Cortex (LIP) of the Macaque Monkey

Single neurons in cortical area LIP are known to carry information relevant to both sensory and value-based decisions that are reported by eye movements. It is not known, however, how sensory and value information are combined in LIP when individual decisions must be based on a combination of these variables. To investigate this issue, we conducted behavioral and electrophysiological experiments in rhesus monkeys during performance of a two-alternative, forced-choice discrimination of motion direction (sensory component). Monkeys reported each decision by making an eye movement to one of two visual targets associated with the two possible directions of motion. We introduced choice biases to the monkeys' decision process (value component) by randomly interleaving balanced reward conditions (equal reward value for the two choices) with unbalanced conditions (one alternative worth twice as much as the other). The monkeys' behavior, as well as that of most LIP neurons, reflected the influence of all relevant variables: the strength of the sensory information, the value of the target in the neuron's response field, and the value of the target outside the response field. Overall, detailed analysis and computer simulation reveal that our data are consistent with a two-stage drift diffusion model proposed by Diederich and Bussmeyer [1] for the effect of payoffs in the context of sensory discrimination tasks. Initial processing of payoff information strongly influences the starting point for the accumulation of sensory evidence, while exerting little if any effect on the rate of accumulation of sensory evidence

Dynamic excitatory and inhibitory gain modulation can produce flexible, robust and optimal decision-making

<div><p>Behavioural and neurophysiological studies in primates have increasingly shown the involvement of urgency signals during the temporal integration of sensory evidence in perceptual decision-making. Neuronal correlates of such signals have been found in the parietal cortex, and in separate studies, demonstrated attention-induced gain modulation of both excitatory and inhibitory neurons. Although previous computational models of decision-making have incorporated gain modulation, their abstract forms do not permit an understanding of the contribution of inhibitory gain modulation. Thus, the effects of co-modulating both excitatory and inhibitory neuronal gains on decision-making dynamics and behavioural performance remain unclear. In this work, we incorporate time-dependent co-modulation of the gains of both excitatory and inhibitory neurons into our previous biologically based decision circuit model. We base our computational study in the context of two classic motion-discrimination tasks performed in animals. Our model shows that by simultaneously increasing the gains of both excitatory and inhibitory neurons, a variety of the observed dynamic neuronal firing activities can be replicated. In particular, the model can exhibit winner-take-all decision-making behaviour with higher firing rates and within a significantly more robust model parameter range. It also exhibits short-tailed reaction time distributions even when operating near a dynamical bifurcation point. The model further shows that neuronal gain modulation can compensate for weaker recurrent excitation in a decision neural circuit, and support decision formation and storage. Higher neuronal gain is also suggested in the more cognitively demanding reaction time than in the fixed delay version of the task. Using the exact temporal delays from the animal experiments, fast recruitment of gain co-modulation is shown to maximize reward rate, with a timescale that is surprisingly near the experimentally fitted value. Our work provides insights into the simultaneous and rapid modulation of excitatory and inhibitory neuronal gains, which enables flexible, robust, and optimal decision-making.</p></div

Bone Morphogenetic Protein (BMP)-4 and BMP-7 regulate differentially Transforming Growth Factor (TGF)-beta 1 in normal human lung fibroblasts (NHLF)

<p>Abstract</p> <p>Background</p> <p>Airway remodelling is thought to be under the control of a complex group of molecules belonging to the Transforming Growth Factor <b>(</b>TGF)-superfamily. The Bone Morphogenetic Proteins <b>(</b>BMPs) belong to this family and have been shown to regulate fibrosis in kidney and liver diseases. However, the role of BMPs in lung remodelling remains unclear. BMPs may regulate tissue remodelling in asthma by controlling TGF-β-induced profibrotic functions in lung fibroblasts.</p> <p>Methods</p> <p>Cell cultures were exposed to TGF-β1 alone or in the presence of BMP-4 or BMP-7; control cultures were exposed to medium only. Cell proliferation was assessed by quantification of the incorporation of [3H]-thymidine. The expression of the mRNA encoding collagen type I and IV, tenascin C and fibronectin in normal human lung fibroblasts (NHLF) was determined by real-time quantitative PCR and the main results were confirmed by ELISA. Cell differentiation was determined by the analysis of the expression of α-smooth muscle actin (α-SMA) by western blot and immunohistochemistry. The effect on matrix metalloproteinase (MMP) activity was assessed by zymography.</p> <p>Results</p> <p>We have demonstrated TGF-β1 induced upregulation of mRNAs encoding the extracellular matrix proteins, tenascin C, fibronectin and collagen type I and IV when compared to unstimulated NHLF, and confirmed these results at the protein level. BMP-4, but not BMP-7, reduced TGF-β1-induced extracellular matrix protein production. TGF-β1 induced an increase in the activity of the pro-form of MMP-2 which was inhibited by BMP-7 but not BMP-4. Both BMP-4 and BMP-7 downregulated TGF-β1-induced MMP-13 release compared to untreated and TGF-β1-treated cells. TGF-β1 also induced a myofibroblast-like transformation which was partially inhibited by BMP-7 but not BMP-4.</p> <p>Conclusions</p> <p>Our study suggests that some regulatory properties of BMP-7 may be tissue or cell type specific and unveil a potential regulatory role for BMP-4 in the regulation of lung fibroblast function.</p

Deciding not to decide : computational and neural evidence for hidden behavior in sequential choice

Understanding the cognitive and neural processes that underlie human decision making requires the successful prediction of how, but also of when, people choose. Sequential sampling models (SSMs) have greatly advanced the decision sciences by assuming decisions to emerge from a bounded evidence accumulation process so that response times (RTs) become predictable. Here, we demonstrate a difficulty of SSMs that occurs when people are not forced to respond at once but are allowed to sample information sequentially: The decision maker might decide to delay the choice and terminate the accumulation process temporarily, a scenario not accounted for by the standard SSM approach. We developed several SSMs for predicting RTs from two independent samples of an electroencephalography (EEG) and a functional magnetic resonance imaging (fMRI) study. In these studies, participants bought or rejected fictitious stocks based on sequentially presented cues and were free to respond at any time. Standard SSM implementations did not describe RT distributions adequately. However, by adding a mechanism for postponing decisions to the model we obtained an accurate fit to the data. Time-frequency analysis of EEG data revealed alternating states of de- and increasing oscillatory power in beta-band frequencies (14-30 Hz), indicating that responses were repeatedly prepared and inhibited and thus lending further support for the existence of a decision not to decide. Finally, the extended model accounted for the results of an adapted version of our paradigm in which participants had to press a button for sampling more information. Our results show how computational modeling of decisions and RTs support a deeper understanding of the hidden dynamics in cognition