Bumpy ride ahead: Anticipated effort as emotional evidence?

Conscious reportable (un)pleasantness feelings were shown to be successfully described by a process in which evidence favoring pleasant and unpleasant feelings accumulates until one response wins the race. This approach is challenged by (a) insufficient specification of "evidence," and (b) incomplete verification that participants report their truly experienced (un)pleasant feelings and not what they expect to feel. In each trial in this preregistered experiment, the (un)pleasant feeling reports regarding emotion evoking pictures was embedded in a period when participants expected a low-effort task (feature visual search) or a high-effort task (feature-conjunction search). Fitting the Linear Ballistic Accumulator model to the feeling report data shows that anticipated effort was associated with a higher rate of unpleasant evidence accumulation, but only when the emotion evoking pictures were normatively unpleasant and not when they were normatively pleasant. These results suggest that anticipated effort may be one source of "evidence," but only given a certain interpretation of the findings, and that genuinely felt emotions contribute to the emotion reports, assuming that participants intended to react to the pictures, as instructed, and not to the anticipated effort.

Numerical cognition: Unitary or diversified system(s)?

Many researchers, including Clarke and Beck, describe the human numerical system as unitary. We offer an alternative view - the coexistence of several systems; namely, multiple systems (general magnitude, parallel individuation, and symbolic) existing in parallel, ready to be activated depending on the task/need. Based on this alternative view, we present an account for the representation of rational numbers.

Discovery and characterization of small molecule inhibitors of cystathionine gamma-synthase with in planta activity.

The synthesis of essential amino acids in plants is pivotal for their viability and growth, and these cellular pathways are therefore targeted for the discovery of new molecules for weed control. Herein, we describe the discovery and design of small molecule inhibitors of cystathionine gamma-synthase, a key enzyme in the biosynthesis of methionine. Based on in silico screening and filtering of a large molecular database followed by the in vitro selection of molecules, we identified small molecules capable of binding the target enzyme. Molecular modelling of the interaction and direct biophysical binding enabled us to explore a focussed chemical expansion set of molecules characterized by an active phenyl-benzamide chemical group. These molecules are bio-active and efficiently inhibit the viability of BY-2 tobacco cells and seedlings growth of Arabidopsis thaliana on agar plates.

Individual Resilience: A Major Protective Factor in Peer Bullying and Victimization of Elementary School Children in Israel.

Peer violence in school has become a major issue for schools around the world. The present study examined the impacts of cultural settings and of protective individual attributes on peer bullying and victimization in school. These protective attributes were self-esteem, sense of autonomy, emotional regulation, and individual resilience. Participants were 112 Jewish and 55 Arab Bedouin pupils 10 to 11 years old. It was hypothesized that Jewish pupils would score lower than Bedouin pupils on bullying and on victimization, and will score higher than them on these protective individual attributes. It was also hypothesized that despite these differences, the investigated attributes would correlate with reduced peer violence in both groups. It was hypothesized further that individual resilience will be the major predictor of both bullying and victimization in both groups. Results have generally supported these hypotheses, suggesting alternative ways for curtailing peer aggression in school.

Correction: Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides.

[This corrects the article DOI: 10.18632/oncotarget.10516.].

Visuospatial processing bias in ADHD: A potential artifact in the Wechsler Adult Intelligence Scale and the Rorschach Inkblots Test.

Global processing bias is the automatic tendency to process the global picture before processing the local details. Recent studies suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) show a lack of global processing bias. In the current study, we examined whether lack of global processing bias affects performance on 2 psychological tests, Wechsler Adult Intelligence Scale IV (WAIS-IV) and the Rorschach inkblots test, which require the use of visuospatial processing while measuring different psychological constructs. Adult participants (30 ADHD and 30 typically developing controls) completed the subtests of the WAIS-IV, which rely on visuospatial components, and the Rorschach inkblots test. We found no indication of differences in general fluid intelligence between the groups. On the WAIS-IV test, ADHD participants consistently exhibited superior performance on tasks that relied on local processing and inferior performance on tasks that relied on global processing when compared with healthy controls. On the Rorschach inkblots test, ADHD participants exhibited more responses that referred to local aspects (part/s) of the stimulus and fewer responses that referred to global aspects (whole) of the stimulus. These findings imply that when patients with ADHD are given psychological tests that require visuospatial processing, a potential confound of visuospatial processing style needs to be considered. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Inhibition of PD1:PD-L1 interaction by an E. coli-derived optimized PD1 variant.

Immune-checkpoint receptors are a set of signal transduction proteins that can stimulate or inhibit specific anti-tumor responses. It is well established that cancer cells interact with different immune checkpoints to shut down T-cell response, thereby enabling cancer proliferation. Given the importance of immune checkpoint receptors, a structure-function analysis of these systems is imperative. However, recombinant expression and purification of these membrane originated proteins is still a challenge. Therefore, many attempts are being made to improve their expression and solubility while preserving their biological relevance. For this purpose, we designed an E. coli-based optimization system that enables the acquisition of mutations that increases protein solubility and affinity towards its native ligand, while maintaining biological activity. Here we focused on the well-characterized extracellular domain of the 'programmed cell death protein 1' (PD1), an immune checkpoint receptor known to inhibit T-cell proliferation by interacting with its ligands PD-L1 and PD-L2. The simple ELISA-based screening system shown here enabled the identification of high-affinity, highly soluble, functional variants derived from the extracellular domain of human PD1. The system was based on the expression of a GST-tagged variants library in E. coli, which enabled the selection of improved PD1 variants after a single optimization round. Within only two screening rounds, the most active variant showed a 5-fold higher affinity and 2.4-fold enhanced cellular activity as compared to the wild type protein. This scheme can be translated toward other types of challenging receptors toward development of research tools or alternative therapeutics.

A Small Molecule Inhibitor of Bruton's Tyrosine Kinase Involved in B-Cell Signaling.

Protein kinases are fundamental within almost all cellular signal transduction networks. Among these, Bruton's tyrosine kinase (Btk), which belongs to the Tec family of proteins, plays an imperative part in B-cell signaling. Owing to its role, Btk has been established as an important therapeutic target for a vast range of disorders related to B-cell development and function, such as the X-linked agammaglobulinemia, various B-cell malignancies, inflammation, and autoimmune diseases. Herein, using computer-based screening of a library of 20 million small molecules, we identified a small molecule capable of directly binding the Btk kinase domain. On the basis of this hit compound, we conducted a focused structure-similarity search to explore the effect of different chemical modifications on binding toward Btk. This search identified the molecule N2,N6-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9H-purine-2,6-diamine as a potent inhibitor of Btk. The latter small molecule binds Btk with a dissociation constant of 250 nM and inhibits Btk activity both in vitro and in-cell.

Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides.

The p53 tumor suppressor serves as a major barrier against malignant transformation. Over 50% of tumors inactivate p53 by point mutations in its DNA binding domain. Most mutations destabilize p53 protein folding, causing its partial denaturation at physiological temperature. Thus a high proportion of human tumors overexpress a potential potent tumor suppressor in a non-functional, misfolded form. The equilibrium between the properly folded and misfolded states of p53 may be affected by molecules that interact with p53, stabilizing its native folding and restoring wild type p53 activity to cancer cells. To select for mutant p53 (mutp53) reactivating peptides, we adopted the phage display technology, allowing interactions between mutp53 and random peptide libraries presented on phages and enriching for phage that favor the correctly folded p53 conformation. We obtained a large database of potential reactivating peptides. Lead peptides were synthesized and analyzed for their ability to restore proper p53 folding and activity. Remarkably, many enriched peptides corresponded to known p53-binding proteins, including RAD9. Importantly, lead peptides elicited dramatic regression of aggressive tumors in mouse xenograft models. Such peptides might serve as novel agents for human cancer therapy.

Human carotid atherosclerotic plaque protein(s) change HDL protein(s) composition and impair HDL anti-oxidant activity.

High density lipoprotein (HDL) anti-atherogenic functions are closely associated with cardiovascular disease risk factor, and are dictated by its composition, which is often affected by environmental factors. The present study investigates the effects of the human carotid plaque constituents on HDL composition and biological functions. To this end, human carotid plaques were homogenized and incubated with HDL. Results showed that after incubation, most of the apolipoprotein A1 (Apo A1) protein was released from the HDL, and HDL diameter increased by an average of approximately 2 nm. In parallel, HDL antioxidant activity was impaired. In response to homogenate treatment HDL could not prevent the accelerated oxidation of LDL caused by the homogenate. Boiling of the homogenate prior to its incubation with HDL abolished its effects on HDL composition changes. Moreover, tryptophan fluorescence quenching assay revealed an interaction between plaque component(s) and HDL, an interaction that was reduced by 50% upon using pre-boiled homogenate. These results led to hypothesize that plaque protein(s) interacted with HDL-associated Apo A1 and altered the HDL composition. Immuno-precipitation of Apo A1 that was released from the HDL after its incubation with the homogenate revealed a co-precipitation of three isomers of actin. However, beta-actin alone did not significantly affect the HDL composition, and yet the active protein within the plaque was elusive. In conclusion then, protein(s) in the homogenate interact with HDL protein(s), leading to release of Apo A1 from the HDL particle, a process that was associated with an increase in HDL diameter and with impaired HDL anti-oxidant activity.

Human carotid atherosclerotic lesion protein components decrease cholesterol biosynthesis rate in macrophages through 3-hydroxy-3-methylglutaryl-CoA reductase regulation.

Atherosclerosis is characterized by the formation of cholesterol-loaded macrophages, which are turned into foam cells, the hallmark of early atherogenesis. As part of ongoing research on the interactions among human carotid lesion components and blood elements, the effect of plaque homogenate on macrophage cholesterol biosynthesis rate was examined. Human carotid plaques were ground, extracted with phosphate-buffered saline (homogenate), and then added to the macrophage medium. This extract decreased macrophage cholesterol biosynthesis rate up to 50% in a dose-dependent manner. Cholesterol or lipoproteins were separated from the homogenate and added to the MQ medium. Unlike the homogenate, neither free cholesterol nor the lipoproteins were able to inhibit cholesterol biosynthesis rate under the above experimental concentration, suggesting that the homogenate-induced cholesterol biosynthesis inhibition in our experimental system was not owing to the feedback inhibition of cholesterol. Furthermore, the homogenate remaining after lipoprotein removal (lipoprotein-deficient homogenate) also decreased cholesterol biosynthesis rate, whereas boiled homogenate or phospholipids extracted from the homogenate decreased macrophage cholesterol biosynthesis rate only partially. Finally, cholesterol biosynthesis inhibition was achieved only upon using the precursor [(3)H]acetate, but not [(14)C]mevalonate, suggesting that 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA Reductase), the rate-limiting enzyme in the cholesterol biosynthesis pathway, is involved in the above antiatherogenic effect of the homogenate, whereas the treatment with homogenate decreased HMGCoA Reductase mRNA. Proteins and phospholipids from human carotid lesion homogenate decrease cholesterol biosynthesis rate in macrophages secondary to HMGCoA Reductase feedback regulation. Such an effect may delay foam cell formation and atherosclerosis progression.

Human carotid plaque phosphatidylcholine specifically interacts with paraoxonase 1, increases its activity, and enhances its uptake by macrophage at the expense of its binding to HDL.

Human carotid atherosclerotic plaque is in direct contact with circulatory blood components. Thus, plaque and blood components may affect each other. The current study presents the effects of plaque chloroform:methanol (C:M) extract on the HDL-associated enzyme paraoxnase 1 (PON1). This study is part of our investigation on the mutual effects of the interactions between atherosclerotic lesions and blood components. Recombinant PON1 (rePON1) was incubated with the human carotid plaques C:M extract and PON1 activities were analyzed. Lactonase and paraoxonase activities were elevated due to C:M treatment, by 140 and by 69%, respectively. Analytical chemistry analyses revealed specific phosphatidylcholines (PCs) as the plaque active components. Tryptophan fluorescence quenching assay, together with molecular docking, shows that PON1 activity is enhanced in correlation with the level of PC affinity to PON1. Molecular docking revealed that PCs interact specifically with H2-PON1 α-helix, which together with H1 enzyme α-helix links the protein to the HDL surface. These findings are supported by additional results from the PON1 ∆20 mutant that lack its H1-α-helix. Incubation of this mutant with the plaque C:M extract increased PON1 activity by only 20%, much less than the wild-type PON1 that elevated PON1 activity at the same concentration by as much as 95%. Furthermore, as much as the affinity of the enzyme to the PC was augmented, the ability of PON1 to bind to the HDL particle decreased. Finally, PON1 interaction with PC enhance its uptake into the macrophage cytoplasm. In conclusions, Specific lesion phosphatidylcholines (PCs) present in the human carotid plaque significantly enhance PON1 catalytic activities due to their interaction with the enzyme. Such a lesion׳s PC-PON1 interaction, in turn, competes with HDL PCs and enhances PON1 uptake by macrophage at the expense of PON1 binding to the HDL.

Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner.

Cells encountering hypoxic stress conserve resources and energy by downregulating the protein synthesis. Here we demonstrate that one mechanism in this response is the translational repression of TOP mRNAs that encode components of the translational apparatus. This mode of regulation involves TSC and Rheb, as knockout of TSC1 or TSC2 or overexpression of Rheb rescued TOP mRNA translation in oxygen-deprived cells. Stress-induced translational repression of these mRNAs closely correlates with the hypophosphorylated state of 4E-BP, a translational repressor. However, a series of 4E-BP loss- and gain-of-function experiments disprove a cause-and-effect relationship between the phosphorylation status of 4E-BP and the translational repression of TOP mRNAs under oxygen or growth factor deprivation. Furthermore, the repressive effect of anoxia is similar to that attained by the very efficient inhibition of mTOR activity by Torin 1, but much more pronounced than raptor or rictor knockout. Likewise, deficiency of raptor or rictor, even though it mildly downregulated basal translation efficiency of TOP mRNAs, failed to suppress the oxygen-mediated translational activation of TOP mRNAs. Finally, co-knockdown of TIA-1 and TIAR, two RNA-binding proteins previously implicated in translational repression of TOP mRNAs in amino acid-starved cells, failed to relieve TOP mRNA translation under other stress conditions. Thus, the nature of the proximal translational regulator of TOP mRNAs remains elusive.

Phase transition in crowd synchrony of delay-coupled multilayer laser networks.

An analogy between crowd synchrony and multi-layer neural network architectures is proposed. It indicates that many non-identical dynamical elements (oscillators) communicating indirectly via a few mediators (hubs) can synchronize when the number of delayed couplings to the hubs or the strength of the couplings is large enough. This phenomenon is modeled using a system of semiconductor lasers optically delay-coupled in either a fully connected or a diluted manner to a fixed number of non-identical central hub lasers. A universal phase transition to crowd synchrony with hysteresis is observed, where the time to achieve synchronization diverges near the critical coupling independent of the number of hubs.

Seed concentration control of metal nanowire diameter.

Gold/silver nanowires (NWs) of controlled diameters were synthesized from catalytic metal seed particles at the substrate/solution interface. Small seed nanoparticles of three different sizes: ~1 nm (11 gold atoms), ~1.4 nm (~55 gold atoms), and homemade nanoparticles of ~2 nm were used. By varying a single type of seed particle concentration in the growth solution, the NW diameters and morphology could be controlled, between bundles of ultrathin NWs of ~2-3 nm diameter to thicker isolated single NWs with a mean diameter of ~16 nm. In addition, the catalytic reduction rate leading to NW growth was found to be seed size dependent at small seed sizes (<2 nm). The two types of metallic NW films were tested for their performance as transparent electrodes after additional metal deposition for their stabilization and conductivity enhancement. The thin NW bundles exhibit superior transparent conductor properties.

Increased Levels of Human Carotid Lesion Linoleic Acid Hydroperoxide in Symptomatic and Asymptomatic Patients Is Inversely Correlated with Serum HDL and Paraoxonase 1 Activity.

Human carotid plaque components interact directly with circulating blood elements and thus they might affect each other. We determined plaque paraoxonase1 (PON1) hydrolytic-catalytic activity and compared plaque and blood levels of lipids, HDL, PON1, and HbA1c, as well as plaque-oxidized lipids in symptomatic and asymptomatic patients. Human carotid plaques were obtained from symptomatic and asymptomatic patients undergoing routine endarterectomy, and the lesions were ground and extracted for PON activity and lipid content determinations. Plaque PONs preserved paraoxonase, arylesterase, and lactonase activities. The PON1-specific inhibitor 2-hydroxyquinoline almost completely inhibited paraoxonase and lactonase activities, while only moderately inhibiting arylesterase activity. Oxysterol and triglyceride levels in plaques from symptomatic and asymptomatic patients did not differ significantly, but plaques from symptomatic patients had significantly higher (135%) linoleic acid hydroperoxide (LA-13OOH) levels. Their serum PON1 activity, cholesterol and triglyceride levels did not differ significantly, but symptomatic patients had significantly lower (28%) serum HDL levels and higher (18%) HbA1c levels. Thus LA-13OOH, a major atherogenic plaque element, showed significant negative correlations with serum PON1 activity and HDL levels, and a positive correlation with the prodiabetic atherogenic HbA1c. Plaque PON1 retains its activity and may decrease plaque atherogenicity by reducing specific oxidized lipids (e.g., LA-13OOH). The inverse correlation between plaque LA-13OOH level and serum HDL level and PON1 activity suggests a role for serum HDL and PON1 in LA-13OOH accumulation.

Spiking optical patterns and synchronization.

We analyze the time resolved spike statistics of a solitary and two mutually interacting chaotic semiconductor lasers whose chaos is characterized by apparently random, short intensity spikes. Repulsion between two successive spikes is observed, resulting in a refractory period, which is largest at laser threshold. For time intervals between spikes greater than the refractory period, the distribution of the intervals follows a Poisson distribution. The spiking pattern is highly periodic over time windows corresponding to the optical length of the external cavity, with a slow change of the spiking pattern as time increases. When zero-lag synchronization between two lasers is established, the statistics of the nearly perfectly matched spikes are not altered. The similarity of these features to those found in complex interacting neural networks, suggests the use of laser systems as simpler physical models for neural networks.