Hydroxychloroquine in rheumatic autoimmune disorders and beyond

Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases. Due to its cost-effectiveness, safety and efficacy, HCQ is especially used in rheumatic autoimmune disorders (RADs), such as systemic lupus erythematosus, primary Sjögren's syndrome and rheumatoid arthritis. Despite this widespread use in the clinic, HCQ molecular modes of action are still not completely understood. By influencing several cellular pathways through different mechanisms, CQ and HCQ inhibit multiple endolysosomal functions, including autophagy, as well as endosomal Toll-like receptor activation and calcium signalling. These effects alter several aspects of the immune system with the synergistic consequence of reducing pro-inflammatory cytokine production and release, one of the most marked symptoms of RADs. Here, we review the current knowledge on the molecular modes of action of these drugs and the circumstances under which they trigger side effects. This is of particular importance as the therapeutic use of HCQ is expanding beyond the treatment of malaria and RADs

Affective responses as guides to category-based inferences

Initial nonconscious affective reactions to a target individual may influence a perceiver's selection from among descriptively plausible categories with which to organize his impression of the target. Specifically, a perceiver may be more likely to employ a category that is consistent, in affective tone, with the tone of his affective reaction. Subjects in two studies were exposed to photographs of faces of target individuals. Degree of preference for the faces was manipulated, outside of subjects' awareness, by varying the state of pupillary dilation. Participants in Study One reported that verbal descriptions that characterized positively (compared to negatively) evaluated category prototypes were more likely to be descriptive of targets with dilated pupils. Similarly, participants judged descriptions that characterized negatively (compared to positively) evaluated prototypes as more likely to be descriptive of targets with constricted pupils. In Study Two, subjects' recall of personality descriptions that were (evaluatively) inconsistent with their initial affective response to the target was superior to their recall of descriptions that were (evaluatively) consistent with the tone of their initial response. The data are interpreted as evidence for the importance of nonconscious affective reactions in guiding the process of impression formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45360/1/11031_2004_Article_BF00992317.pd

Why Robots Should Be Social: Enhancing Machine Learning through Social Human-Robot Interaction.

Social learning is a powerful method for cultural propagation of knowledge and skills relying on a complex interplay of learning strategies, social ecology and the human propensity for both learning and tutoring. Social learning has the potential to be an equally potent learning strategy for artificial systems and robots in specific. However, given the complexity and unstructured nature of social learning, implementing social machine learning proves to be a challenging problem. We study one particular aspect of social machine learning: that of offering social cues during the learning interaction. Specifically, we study whether people are sensitive to social cues offered by a learning robot, in a similar way to children's social bids for tutoring. We use a child-like social robot and a task in which the robot has to learn the meaning of words. For this a simple turn-based interaction is used, based on language games. Two conditions are tested: one in which the robot uses social means to invite a human teacher to provide information based on what the robot requires to fill gaps in its knowledge (i.e. expression of a learning preference); the other in which the robot does not provide social cues to communicate a learning preference. We observe that conveying a learning preference through the use of social cues results in better and faster learning by the robot. People also seem to form a "mental model" of the robot, tailoring the tutoring to the robot's performance as opposed to using simply random teaching. In addition, the social learning shows a clear gender effect with female participants being responsive to the robot's bids, while male teachers appear to be less receptive. This work shows how additional social cues in social machine learning can result in people offering better quality learning input to artificial systems, resulting in improved learning performance

Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase

The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive. Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the discovery of regulators against GCN5 enzymes and related HAT family enzymes

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)