Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

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Students’ Perceptions of Peer-Organized Extra-Curricular Research Course during Medical School: A Qualitative Study

Early integration of research education into medical curricula is crucial for evidence-based practice. Yet, many medical students are graduating with no research experience due to the lack of such integration in their medical school programs. The purpose of this study was to explore the impact of a peer-organized, extra-curricular research methodology course on the attitudes of medical students towards research and future academic careers. Twenty one medical students who participated in a peer-organized research course were enrolled in three focus group discussions to explore their experiences, perceptions and attitudes towards research after the course. Discussions were conducted using a semi-structured interview guide, and were transcribed and thematically analyzed for major and minor themes identification. Our findings indicate that students’ perceptions of research changed after the course from being difficult initially to becoming possible. Participants felt that their research skills and critical thinking were enhanced and that they would develop research proposals and abstracts successfully. Students praised the peer-assisted teaching approach as being successful in enhancing the learning environment and filling the curricular gap. In conclusion, peer-organized extra-curricular research courses may be a useful option to promote research interest and skills of medical students when gaps in research education in medical curricula exist.     

Designing Anti-Influenza Aptamers: Novel Quantitative Structure Activity Relationship Approach Gives Insights into Aptamer – Virus Interaction

This study describes the development of aptamers as a therapy against influenza virus infection. Aptamers are oligonucleotides (like ssDNA or RNA) that are capable of binding to a variety of molecular targets with high affinity and specificity. We have studied the ssDNA aptamer BV02, which was designed to inhibit influenza infection by targeting the hemagglutinin viral protein, a protein that facilitates the first stage of the virus’ infection. While testing other aptamers and during lead optimization, we realized that the dominant characteristics that determine the aptamer’s binding to the influenza virus may not necessarily be sequence-specific, as with other known aptamers, but rather depend on general 2D structural motifs. We adopted QSAR (quantitative structure activity relationship) tool and developed computational algorithm that correlate six calculated structural and physicochemical properties to the aptamers’ binding affinity to the virus. The QSAR study provided us with a predictive tool of the binding potential of an aptamer to the influenza virus. The correlation between the calculated and actual binding was R² = 0.702 for the training set, and R² = 0.66 for the independent test set. Moreover, in the test set the model’s sensitivity was 89%, and the specificity was 87%, in selecting aptamers with enhanced viral binding. The most important properties that positively correlated with the aptamer’s binding were the aptamer length, 2D-loops and repeating sequences of C nucleotides. Based on the structure-activity study, we have managed to produce aptamers having viral affinity that was more than 20 times higher than that of the original BV02 aptamer. Further testing of influenza infection in cell culture and animal models yielded aptamers with 10 to 15 times greater anti-viral activity than the BV02 aptamer. Our insights concerning the mechanism of action and the structural and physicochemical properties that govern the interaction with the influenza virus are discussed.     

The MEK/ERK cascade: from signaling specificity to diverse functions

The ERK signaling cascade is a central MAPK pathway that plays a role in the regulation of various cellular processes such as proliferation, differentiation, development, learning, survival and, under some conditions, also apoptosis. The ability of this cascade to regulate so many distinct, and even opposing, cellular processes, raises the question of signaling specificity determination by this cascade. Here we describe mechanisms that cooperate to direct MEK-ERK signals to their appropriate downstream destinations. These include duration and strength of the signals, interaction with specific scaffolds, changes in subcellular localization, crosstalk with other signaling pathways, and presence of multiple components with distinct functions in each tier of the cascade. Since many of the mechanisms do not function properly in cancer cells, understanding them may shed light not only on the regulation of normal cell proliferation, but also on mechanisms of oncogenic transformation.     

Biochemical and morphological attributes of broiler kidney in response to dietary glucocorticoid,dexamethasone

Glucocorticoids (GCs) initiate oxidative stress and cause renal damage which lead to hypertension, heart failure and ultimately death. The current study aimed to investigate the alterations in serum biochemical parameters i.e. HDL and LDL; gross anatomy, histomorphology and histomorphometry of broiler kidney in response to dietary GC, dexamethasone (DEX). Day old chicks (DOCs) were randomly assigned into four groups: control and three treatment groups (T1, T2 and T3). The control group was fed commercial broiler type ration and the treated groups were fed commercial broiler type ration containing GC (Dexamethasone @ 3, 5 and 7 mg/kg in T1, T2 and T3 group respectively). To measure the biochemical parameters, blood samples were collected on days 7, 14, 21, and 28 of the experiment. For histological investigation, kidney (left) samples were collected from the individual birds after sacrificing on days 7, 14, 21, and 28 of the experiment. Histomorphological alterations of the kidney were assessed by routine hematoxylin and eosin (H&E) staining. Biochemical analysis showed significantly increased serum HDL and LDL level compared to the control. In gross study, dark congested kidney was found with significantly decreased weight, length and width. Treatment with DEX augmented congestion, inflammation and fibrosis in kidney, as evidence by histomorphometric study. Extensively degenerated and atrophied glomeruli, degenerated tubular epithelium with distorted tubules and inter tubular empty spaces were seen. Percentage of atrophied glomeruli increased significantly and maximum percentage of glomerular atrophy was seen at day 28. These changes were found more explicitly in the higher dose group. Histomorphometric study also revealed significant decrease in the diameter of glomerulus. The findings of this study suggest that DEX may alter the serum biochemical parameters as well as kidney gross and histomorphology.     

Serotonin, inhibition, and negative mood

Pavlovian predictions of future aversive outcomes lead to behavioral inhibition, suppression, and withdrawal. There is considerable evidence for the involvement of serotonin in both the learning of these predictions and the inhibitory consequences that ensue, although less for a causal relationship between the two. In the context of a highly simplified model of chains of affectively charged thoughts, we interpret the combined effects of serotonin in terms of pruning a tree of possible decisions, (i.e., eliminating those choices that have low or negative expected outcomes). We show how a drop in behavioral inhibition, putatively resulting from an experimentally or psychiatrically influenced drop in serotonin, could result in unexpectedly large negative prediction errors and a significant aversive shift in reinforcement statistics. We suggest an interpretation of this finding that helps dissolve the apparent contradiction between the fact that inhibition of serotonin reuptake is the first-line treatment of depression, although serotonin itself is most strongly linked with aversive rather than appetitive outcomes and predictions.     

Explaining distortions in metacognition with an attractor network model of decision uncertainty

Metacognition is the ability to reflect on, and evaluate, our cognition and behaviour. Distortions in metacognition are common in mental health disorders, though the neural underpinnings of such dysfunction are unknown. One reason for this is that models of key components of metacognition, such as decision confidence, are generally specified at an algorithmic or process level. While such models can be used to relate brain function to psychopathology, they are difficult to map to a neurobiological mechanism. Here, we develop a biologically-plausible model of decision uncertainty in an attempt to bridge this gap. We first relate the model’s uncertainty in perceptual decisions to standard metrics of metacognition, namely mean confidence level (bias) and the accuracy of metacognitive judgments (sensitivity). We show that dissociable shifts in metacognition are associated with isolated disturbances at higher-order levels of a circuit associated with self-monitoring, akin to neuropsychological findings that highlight the detrimental effect of prefrontal brain lesions on metacognitive performance. Notably, we are able to account for empirical confidence judgements by fitting the parameters of our biophysical model to first-order performance data, specifically choice and response times. Lastly, in a reanalysis of existing data we show that self-reported mental health symptoms relate to disturbances in an uncertainty-monitoring component of the network. By bridging a gap between a biologically-plausible model of confidence formation and observed disturbances of metacognition in mental health disorders we provide a first step towards mapping theoretical constructs of metacognition onto dynamical models of decision uncertainty. In doing so, we provide a computational framework for modelling metacognitive performance in settings where access to explicit confidence reports is not possible.     

Characterization and isolation of a T-DNA tagged banana promoter active during in vitro culture and low temperature stress

Background  

Next-generation transgenic plants will require a more precise regulation of transgene expression, preferably under the control of native promoters. A genome-wide T-DNA tagging strategy was therefore performed for the identification and characterization of novel banana promoters. Embryogenic cell suspensions of a plantain-type banana were transformed with a promoterless, codon-optimized luciferase (luc ⁺) gene and low temperature-responsive luciferase activation was monitored in real time.     

Vimentin binding to phosphorylated Erk sterically hinders enzymatic dephosphorylation of the kinase

Cleavage fragments of de novo synthesized vimentin were recently reported to interact with phosphorylated Erk1 and Erk2 MAP kinases (pErk) in injured sciatic nerve, thus linking pErk to a signaling complex retrogradely transported on importins and dynein. Here we clarify the structural basis for this interaction, which explains how pErk is protected from dephosphorylation while bound to vimentin. Pull-down and ELISA experiments revealed robust calcium-dependent binding of pErk to the second coiled-coil domain of vimentin, with observed affinities of binding increasing from 180 nM at 0.1 microM calcium to 15 nM at 10 microM calcium. In contrast there was little or no binding of non-phosphorylated Erk to vimentin under these conditions. Geometric and electrostatic complementarity docking generated a number of solutions wherein vimentin binding to pErk occludes the lip containing the phosphorylated residues in the kinase. Binding competition experiments with Erk peptides confirmed a solution in which vimentin covers the phosphorylation lip in pErk, interacting with residues above and below the lip. The same peptides inhibited pErk binding to the dynein complex in sciatic nerve axoplasm, and interfered with protection from phosphatases by vimentin. Thus, a soluble intermediate filament fragment interacts with a signaling kinase and protects it from dephosphorylation by calcium-dependent steric hindrance.