The Role of Informative and Ambiguous Feedback in Avoidance Behavior: Empirical and Computational Findings

Avoidance behavior is a critical component of many psychiatric disorders, and as such, it is important to understand how avoidance behavior arises, and whether it can be modified. In this study, we used empirical and computational methods to assess the role of informational feedback and ambiguous outcome in avoidance behavior. We adapted a computer-based probabilistic classification learning task, which includes positive, negative and no-feedback outcomes; the latter outcome is ambiguous as it might signal either a successful outcome (missed punishment) or a failure (missed reward). Prior work with this task suggested that most healthy subjects viewed the no-feedback outcome as strongly positive. Interestingly, in a later version of the classification task, when healthy subjects were allowed to opt out of (i.e. avoid) responding, some subjects (“avoiders”) reliably avoided trials where there was a risk of punishment, but other subjects (“non-avoiders”) never made any avoidance responses at all. One possible interpretation is that the “non-avoiders” valued the no-feedback outcome so positively on punishment-based trials that they had little incentive to avoid. Another possible interpretation is that the outcome of an avoided trial is unspecified and that lack of information is aversive, decreasing subjects’ tendency to avoid. To examine these ideas, we here tested healthy young adults on versions of the task where avoidance responses either did or did not generate informational feedback about the optimal response. Results showed that provision of informational feedback decreased avoidance responses and also decreased categorization performance, without significantly affecting the percentage of subjects classified as “avoiders.” To better understand these results, we used a modified Q-learning model to fit individual subject data. Simulation results suggest that subjects in the feedback condition adjusted their behavior faster following better-than-expected outcomes, compared to subjects in the no-feedback condition. Additionally, in both task conditions, “avoiders” adjusted their behavior faster following worse-than-expected outcomes, and treated the ambiguous no-feedback outcome as less rewarding, compared to non-avoiders. Together, results shed light on the important role of ambiguous and informative feedback in avoidance behavior.     

Evaluating the effect of silver nanoparticles on testes of adult albino rats (histological,immunohistochemical and biochemical study)

Silver nanoparticles (AgNPs) are widely used in medicine, however, they have toxic impacts on different organs. AgNPs distribution to the testes was reported, so, we aimed to study the effect of intraperitoneal injection of AgNPs, at different concentrations and different time durations, on adult rat testes. Sixty healthy adult male Wistar albino rats were divided into three groups; control group (Group I) and two experimental groups (Groups II & III), each of which were subdivided into two subgroups. Rats in group II were exposed for 7 days to low and high doses of AgNPs, respectively. Rats in group III were exposed for 28 days to low and high doses of AgNPs, respectively. Testicular sections were stained with H&E, Toluidine blue, Immunohistochemical staining for Ki-67 and CD68 and Electron microscope examination were performed. Serum testosterone level and Quantitative Real-Time PCR for spermatogenesis genes were measured. Group IIa & IIb showed thickened capsule studded with nanoparticles, congested blood vessels, disorganized seminiferous tubules (Sts) and detached germinal epithelium. Group IIIa & IIIb showed marked reduction in the germinal epithelium, and shrunken Sts with the absence of sperms in most of them, which was more evident with higher doses of AgNPs. Significant decrease in cell proliferation and increase in interstitial tissue macrophages were more detected in groups II & III than in the control group. Decreased serum testosterone and decreased expression levels of spermatogenesis genes in groups IIa, IIb & IIIa, IIIb than in the control group were observed. In conclusion: intraperitoneal injection of AgNPs adversely affected the structure of adult rat testes. The tissue damage was more manifested with increased dose and duration of exposure.     

Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism

The chemical synthesis of new compounds designed as inhibitors of Mycobacterium tuberculosis TMP kinase (TMPK) is reported. The synthesis concerns TMP analogues modified at the 5-position of the thymine ring as well as a novel compound with a six-membered sugar ring. The binding properties of the analogues are compared with the known inhibitor azido-TMP, which is postulated here to work by excluding the TMP-bound Mg(2+) ion. The crystallographic structure of the complex of one of the compounds, 5-CH(2)OH-dUMP, with TMPK has been determined at 2.0 A. It reveals a major conformation for the hydroxyl group in contact with a water molecule and a minor conformation pointing toward Ser(99). Looking for a role for Ser(99), we have identified an unusual catalytic triad, or a proton wire, made of strictly conserved residues (including Glu(6), Ser(99), Arg(95), and Asp(9)) that probably serves to protonate the transferred PO(3) group. The crystallographic structure of the commercially available bisubstrate analogue P(1)-(adenosine-5')-P(5)-(thymidine-5')-pentaphosphate bound to TMPK is also reported at 2.45 A and reveals an alternative binding pocket for the adenine moiety of the molecule compared with what is observed either in the Escherichia coli or in the yeast enzyme structures. This alternative binding pocket opens a way for the design of a new family of specific inhibitors.     

The role of caveolae and caveolin 1 in calcium handling in pacing and contraction of mouse intestine

In mouse intestine, caveolae and caveolin‐1 (Cav‐1) are present in smooth muscle (responsible for executing contractions) and in interstitial cells of Cajal (ICC; responsible for pacing contractions). We found that a number of calcium handling/dependent molecules are associated with caveolae, including L‐type Ca²⁺ channels, Na⁺‐Ca²⁺ exchanger type 1 (NCX1), plasma membrane Ca²⁺ pumps and neural nitric oxide synthase (nNOS), and that caveolae are close to the peripheral endo‐sarcoplasmic reticulum (ER‐SR). Also we found that this assemblage may account for recycling of calcium from caveolar domains to SR through L‐type Ca ⁺ channels to sustain pacing and contractions. Here we test this hypothesis further comparing pacing and contractions under various conditions in longitudinal muscle of Cav‐1 knockout mice (lacking caveolae) and in their genetic controls. We used a procedure in which pacing frequencies (indicative of functioning of ICC) and contraction amplitudes (indicative of functioning of smooth muscle) were studied in calcium‐free media with 100 mM ethylene glycol tetra‐acetic acid (EGTA). The absence of caveolae in ICC inhibited the ability of ICC to maintain frequencies of contraction in the calcium‐free medium by reducing recycling of calcium from caveolar plasma membrane to SR when the calcium stores were initially full. This recycling to ICC involved primarily L‐type Ca²⁺ channels; i.e. pacing frequencies were enhanced by opening and inhibited by closing these channels. However, when these stores were depleted by block of the sarco/endoplasmic reticulum Ca²⁺‐ATPase (SERCA) pump or calcium release was activated by carbachol, the absence of Cav‐1 or caveolae had little or no effect. The absence of caveolae had little impact on contraction amplitudes, indicative of recycling of calcium to SR in smooth muscle. However, the absence of caveolae slowed the rate of loss of calcium from SR under some conditions in both ICC and smooth muscle, which may reflect the loss of proximity to store operated Ca channels. We found evidence that these channels were associated with Cav‐1. These changes were all consistent with the hypothesis that a reduction of the extracellular calcium associated with caveolae in ICC of the myenteric plexus, the state of L‐type Ca²⁺ channels or an increase in the distance between caveolae and SR affected calcium handling.     

Digitalis receptor sugar binding site characteristics: A model based upon studies of Na+, K+-ATPase preparations with differing digitalis sensitivities

The structure-activity relationships of the genin moieties of digitalis glycosides are commonly elucidated by determining the inhibitory potency of a variety of genins toward the plasma membrane Na⁺, K⁺-ATPase; qualitatively these relationships appear to be fairly independent of the specific Na⁺, K⁺-ATPase preparation utilized for the analysis. To determine whether this is the case with regard to the sugar moieties of glycosides, the inhibitory effects of 12 monoglycosides of digitoxigenin toward four Na⁺, K⁺-ATPase preparations of different origin were measured. It was found that while recognition of the major structural determinants of sugar activity appeared to be independent of enzyme source, recognition of the minor structural determinants of activity showed some source dependence. It was also observed that the intrinsic sensitivity to sugar potentiation may be source dependent and unrelated to intrinsic sensitivity to inhibition by digitoxigenin. These observations are compatible with a model of the Na⁺, K⁺-ATPase sugar binding site(s) in which intrinsic sensitivity to sugar attachment as well as recognition characteristics (for sugar structural features) both determine the extent to which a sugar moiety may contribute to the activity of monoglycosides. Further, in these studies one of the Na⁺, K⁺-ATPase preparations employed was obtained from rat brain, a tissue known to contain a mixture of ouabain sensitive and insensitive isoforms. We have observed that the rigorous purification techniques employed appear to have selectively removed from or denatured the less ouabain sensitive al isoform found in this enzyme preparation.