Expression of zebrafish pax6b in pancreas is regulated by two enhancers containing highly conserved cis-elements bound by PDX1, PBX and PREP factors

BACKGROUND: PAX6 is a transcription factor playing a crucial role in the development of the eye and in the differentiation of the pancreatic endocrine cells as well as of enteroendocrine cells. Studies on the mouse Pax6 gene have shown that sequences upstream from the P0 promoter are required for expression in the lens and the pancreas; but there remain discrepancies regarding the precise location of the pancreatic regulatory elements. RESULTS: Due to genome duplication in the evolution of ray-finned fishes, zebrafish has two pax6 genes, pax6a and pax6b. While both zebrafish pax6 genes are expressed in the developing eye and nervous system, only pax6b is expressed in the endocrine cells of the pancreas. To investigate the cause of this differential expression, we used a combination of in silico, in vivo and in vitro approaches. We show that the pax6b P0 promoter targets expression to endocrine pancreatic cells and also to enteroendocrine cells, retinal neurons and the telencephalon of transgenic zebrafish. Deletion analyses indicate that strong pancreatic expression of the pax6b gene relies on the combined action of two conserved regulatory enhancers, called regions A and C. By means of gel shift assays, we detected binding of the homeoproteins PDX1, PBX and PREP to several cis-elements of these regions. In constrast, regions A and C of the zebrafish pax6a gene are not active in the pancreas, this difference being attributable to sequence divergences within two cis-elements binding the pancreatic homeoprotein PDX1. CONCLUSION: Our data indicate a conserved role of enhancers A and C in the pancreatic expression of pax6b and emphasize the importance of the homeoproteins PBX and PREP cooperating with PDX1, in activating pax6b expression in endocrine pancreatic cells. This study also provides a striking example of how adaptative evolution of gene regulatory sequences upon gene duplication progressively leads to subfunctionalization of the paralogous gene pair

Attentional control theory in childhood: enhanced attentional capture by non-emotional and emotional distractors in anxiety and depression

Attentional control theory (ACT) proposes that anxiety is associated with executive functioning deficits. The theory has been widely investigated in adults. The current study tested whether symptoms of childhood anxiety and depression were associated with experimentally measured attentional control in the context of non-emotional and emotional stimuli. Sixty-one children (mean age = 9.23 years, range = 8.39 - 10.41) reported their trait anxiety and depression symptoms and completed three visual search tasks. The tasks used a variant of an irrelevant singleton paradigm and measured attentional capture by task-irrelevant non-emotional (color) and emotional (facial expressions) distractors. Significant attentional capture by both non-emotional and emotional distractors was observed, and was significantly correlated with trait anxiety and symptoms of depression. The strength of relationship between attentional capture and the symptoms did not differ significantly for non-emotional and emotional distractors. The results suggest that symptoms of childhood anxiety and depression are associated with poorer attentional control both in the presence of emotional and non-emotional stimuli, supporting ACT in younger populations. This attentional deficit in the context of non-emotional information might be as central to childhood internalizing symptoms as attentional biases often observed on tasks investigating processing of emotional stimuli

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control

Cognitive training in stroke; a proof of concept study.

This pilot study was carried out to examine whether 1 month of on-line cognitive training could be beneficial in improving cognitive function and reducing disability in patients with chronic strokes that affected areas of the brain most likely to impact on their attentional functioning. Full details of the methods can be obtained from the open access paper by following this link. https://doi.org/10.1080/09602011.2018.1554534 6 files are available in this repository. These are as follows: Trainingdata.xls - a file containing summary measures of training functions for the online training. PilotFinalSPSSdata.xls - a file containing all pre and post training assessment measures for each individual. Kvariabilitydataf.xls- a file containing the calculations used to derive variability in the K paprameter of the TVA task using mean and SD data pre and post training. CompletePilotDataSept14.sav- SPSS data file containing pre and post data for each individual CompletePilotTrainingDataonly.sav- SPSS data file including pre and post assessment measures and summary measures of the training functions for each individual. Trainingoutputsapril15.spy – results of analyses completed

The effects of time-on-task and concurrent cognitive load on normal visuospatial bias.

Research suggests that the severity of left spatial neglect can be modulated by changes in general alertness. Analogous effects in healthy volunteers now suggest that this may reflect an amplified form of a normal pattern. Recent neuropsychological studies also suggest that concurrent cognitive load may exacerbate rightward bias. In this study, for the first time, the authors examined the effect of both factors on spatial bias in healthy volunteers. Participants performed a task in which as many letters as possible needed to be reported from a briefly presented visual array under three conditions (alone, with a syllable-discrimination secondary task and with a pitch-discrimination secondary task). The results confirmed a significant rightward shift associated with time-on-task across all conditions--the first demonstration of such an effect within a fixation controlled, brief presentation task. While the secondary tasks influenced overall visual performance, there was no discernable effect on bias

Attentional functions of parietal and frontal cortex

A model of normal attentional function, based on the concept of competitive parallel processing, is used to compare attentional deficits following parietal and frontal lobe lesions. Measurements are obtained for visual processing speed, capacity of visual short-term memory (VSTM), spatial bias (bias to left or right hemifield) and top-down control (selective attention based on task relevance). The results show important differences, but also surprising similarities, in parietal and frontal lobe patients. For processing speed and VSTM, deficits are selectively associated with parietal lesions, in particular lesions of the temporoparietal junction. We discuss explanations based on either grey matter or white matter lesions. In striking contrast, measures of attentional weighting (spatial bias and top-down control) are predicted by simple lesion volume. We suggest that attentional weights reflect competition between broadly distributed object representations. Parietal and frontal mechanisms work together, both in weighting by location and weighting by task context