Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha.

Aldosterone plays a major role in the regulation of salt balance and the pathophysiology of cardiovascular and renal diseases. Many aldosterone-regulated genes--including that encoding the epithelial Na+ channel (ENaC), a key arbiter of Na+ transport in the kidney and other epithelia--have been identified, but the mechanisms by which the hormone modifies chromatin structure and thus transcription remain unknown. We previously described the basal repression of ENaCalpha by a complex containing the histone H3 Lys79 methyltransferase disruptor of telomeric silencing alternative splice variant a (Dot1a) and the putative transcription factor ALL1-fused gene from chromosome 9 (Af9) as well as the release of this repression by aldosterone treatment. Here we provide evidence from renal collecting duct cells and serum- and glucocorticoid-induced kinase-1 (Sgk1) WT and knockout mice that Sgk1 phosphorylated Af9, thereby impairing the Dot1a-Af9 interaction and leading to targeted histone H3 Lys79 hypomethylation at the ENaCalpha promoter and derepression of ENaCalpha transcription. Thus, Af9 is a physiologic target of Sgk1, and Sgk1 negatively regulates the Dot1a-Af9 repressor complex that controls transcription of ENaCalpha and likely other aldosterone-induced genes.

Functional analysis of histones H3 and H4 in Tup1 repression and in GCN5 activation

Tup1 forms a complex with Ssn6 in yeast. Ssn6-Tup1 complex is recruited via direct interactions with specific DNA binding proteins to a specific promoter region and mediates repression of several sets of genes including a-cell specific genes (asg) in $\alpha$ cells. It has been shown that repression of asgs also requires histone H4 and that Tup1 can directly interact with H3 and H4 in vitro. To address whether histone H3 is required for the repression of asgs, I have examined the effect of H3 and H4 mutations on the expression of a $\alpha$2-controlled LacZ reporter. Assay of $\beta$-glactosidase shows that mutations in either H3 or H4 cause a weak derepression of the reporter gene. Some double mutations result in a stronger derepression, while others do not. The H3 N-terminal deletion also leads to a slightly decreased expression of the reporter gene in $\alpha$ cells. Our data suggest that the N-termini of both H3 and H4 are cooperatively involved in the repression of a-cell specific genes in $\alpha$ cells, possibly through their interaction with Tup1.^ GCN5 was originally identified as a transcriptional regulator required to activate a subset of genes in yeast. Recently, it has been shown that GCN5 encodes the catalytic subunit of a nuclear histone acetyltransferase, providing the first direct link between histone acetylation and gene transcription. Recombinant Gcn5p (rGcn5p) exhibits a limited substrate specificity in vitro. However, neither the specificity of this enzyme in vivo nor the importance of particular acetylated residues to transcription or cell growth are well defined. In order to define the sites of histone acetylation mediated by Gcn5p in vivo and assess the significance of histone acetylation, more than 30 yeast strains have been constructed to bear specific H3 and/or H4 mutations in the presence or absence of GCN5 function. Our genetic data suggest that Gcn5p may have additional targets in vivo that are not identified as the targets of rGcn5p by previous studies. Western analysis using antibodies specifically recognizing particular acetylated isoforms of H3 and H4 led us to conclude that Gcn5p is necessary for full acetylation of multiple sites in both H3 and H4 in vivo. Consistent with these observations, rGcn5p still acetylates histones H3 and H4 bearing mutations either in H3 K14 or H4 K8,16, sites previously identified as the targets of acetylation by rGcn5p in H3 and H4. Our data also demonstrated that Gcn5p-mediated acetylation events are important for normal progression of the cell cycle and for transcriptional activation. Furthermore, a critical overall level of acetylation is essential for cell viability. ^

Influence of the background wind on the local soil moisture-precipitation feedback

The importance of soil moisture anomalies on airmass convection over semiarid regions has been recognized in several studies. The underlying mechanisms remain partly unclear. An open question is why wetter soils can result in either an increase or a decrease of precipitation (positive or negative soil moisture–precipitation feedback, respectively). Here an idealized cloud-resolving modeling framework is used to explore the local soil moisture–precipitation feedback. The approach is able to replicate both positive and negative feedback loops, depending on the environmental parameters. The mechanism relies on horizontal soil moisture variations, which may develop and intensify spontaneously. The positive expression of the feedback is associated with the initiation of convection over dry soil patches, but the convective cells then propagate over wet patches where they strengthen and preferentially precipitate. The negative feedback may occur when the wind profile is too weak to support the propagation of convective features from dry to wet areas. Precipitation is then generally weaker and falls preferentially over dry patches. The results highlight the role of the midtropospheric flow in determining the sign of the feedback. A key element of the positive feedback is the exploitation of both low convective inhibition (CIN) over dry patches (for the initiation of convection) and high CAPE over wet patches (for the generation of precipitation).

Feedback von Schülerinnen und Schülern als Quelle des Lernprozesses im Praktikum von Lehramtsstudierenden

Rückmeldungen von Schülerinnen und Schülern zum Unterricht nehmen eine wichtige Rolle zur Verbesserung der Unterrichtsqualität ein. Während der Ausbildung von Lehrpersonen wird dieses Potenzial bisher aber selten genutzt. Der Beitrag stellt Ergebnisse aus dem Forschungsprojekt "Lernen im Praktikum" vor. Befragt wurden 150 Studierende des Lehramts für 7.-9. Klassen (Sekundarstufe 1) zur Bedeutung von Schülerrückmeldungen im Praktikum sowie 1331 Schülerinnen und Schüler aus Praktikumsklassen zum Praktikum und zum Lernprozess der Praktikantinnen und Praktikanten. Die Ergebnisse unterstützen einerseits die Relevanz systematischer Schülerrückmeldungen für das Lernen im Praktikum. Andererseits machen sie auf die Notwendigkeit aufmerksam, die Kriterien, die Schülerbeurteilungen zugrunde liegen, weiter zu erforschen.

FAIR_OSCE – Feedback structure for assessment of interactive roleplay in Objective Structured Clinical Exams

Introduction Since the quality of patient portrayal of standardized patients (SPs) during an Objective Structured Clinical Exam (OSCE) has a major impact on the reliability and validity of the exam, quality control should be initiated. Literature about quality control of SPs’ performance focuses on feedback [1, 2] or completion of checklists [3, 4]. Since we did not find a published instrument meeting our needs for the assessment of patient portrayal, we developed such an instrument after being inspired by others [5] and used it in our high-stakes exam. Project description SP trainers from five medical faculties collected and prioritized quality criteria for patient portrayal. Items were revised twice, based on experiences during OSCEs. The final instrument contains 14 criteria for acting (i.e. adequate verbal and non-verbal expression) and standardization (i.e. verbatim delivery of the first sentence). All partners used the instrument during a high-stakes OSCE. SPs and trainers were introduced to the instrument. The tool was used in training (more than 100 observations) and during the exam (more than 250 observations). Outcome High quality of SPs’ patient portrayal during the exam was documented. More than 90% of SP performances were rated to be completely correct or sufficient. An increase in quality of performance between training and exam was noted. For example, the rate of completely correct reaction in medical tests increased from 88% to 95%. Together with 4% of sufficient performances these 95% add up to 99% of the reactions in medical tests meeting the standards of the exam. SP educators using the instrument reported an augmentation of SPs’ performance induced by the use of the instrument. Disadvantages mentioned were the high concentration needed to observe all criteria and the cumbersome handling of the paper-based forms. Discussion We were able to document a very high quality of SP performance in our exam. The data also indicates that our training is effective. We believe that the high concentration needed using the instrument is well invested, considering the observed enhancement of performance. The development of an iPad-based application for the form is planned to address the cumbersome handling of the paper.

Quality assurance of simulated patient feedback in communication training for fourth-year medical students

Introduction In our program, simulated patients (SPs) give feedback to medical students in the course of communication skills training. To ensure effective training, quality control of the SPs’ feedback should be implemented. At other institutions, medical students evaluate the SPs’ feedback for quality control (Bouter et al., 2012). Thinking about implementing quality control for SPs’ feedback in our program, we wondered whether the evaluation by students would result in the same scores as evaluation by experts. Methods Consultations simulated by 4th-year medical students with SPs were video taped including the SP’s feedback to the students (n=85). At the end of the training sessions students rated the SPs’ performance using a rating instrument called Bernese Assessment for Role-play and Feedback (BARF) containing 11 items concerning feedback quality. Additionally the videos were evaluated by 3 trained experts using the BARF. Results The experts showed a high interrater agreement when rating identical feedbacks (ICCunjust=0.953). Comparing the rating of students and experts, high agreement was found with regard to the following items: 1. The SP invited the student to reflect on the consultation first, Amin (= minimal agreement) 97% 2. The SP asked the student what he/she liked about the consultation, Amin = 88%. 3. The SP started with positive feedback, Amin = 91%. 4. The SP was comparing the student with other students, Amin = 92%. In contrast the following items showed differences between the rating of experts and students: 1. The SP used precise situations for feedback, Amax (=maximal agreement) 55%, Students rated 67 of SPs’ feedbacks to be perfect with regard to this item (highest rating on a 5 point Likert scale), while only 29 feedbacks were rated this way by the experts. 2. The SP gave precise suggestions for improvement, Amax 75%, 62 of SPs’ feedbacks obtained the highest rating from students, while only 44 of SPs’ feedbacks achieved the highest rating in the view of the experts. 3. The SP speaks about his/her role in the third person, Amax 60%. Students rated 77 feedbacks with the highest score, while experts judged only 43 feedbacks this way. Conclusion Although evaluation by the students was in agreement with that of experts concerning some items, students rated the SPs’ feedback more often with the optimal score than experts did. Moreover it seems difficult for students to notice when SPs talk about the role in the first instead of the third person. Since precision and talking about the role in the third person are important quality criteria of feedback, this result should be taken into account when thinking about students’ evaluation of SPs’ feedback for quality control. Bouter, S., E. van Weel-Baumgarten, and S. Bolhuis. 2012. Construction and Validation of the Nijmegen Evaluation of the Simulated Patient (NESP): Assessing Simulated Patients’ Ability to Role-Play and Provide Feedback to Students. Academic Medicine: Journal of the Association of American Medical Colleges

Functional lateralization of the anterior insula during feedback processing

Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self-attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self- and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence × attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self-attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self-attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello-thalamic-cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations.

Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement.

Abstract Background: Aromatase deficiency may result in a complete block of estrogen synthesis because of the failure to convert androgens to estrogens. In females, this results in virilisation at birth, ovarian cysts in prepuberty and lack of pubertal development but virilisation, thereafter. Objective and methods: We studied the impact of oral 17β-estradiol treatment on ovarian and uterine development, and on LH/FSH and inhibin B during the long-term follow-up of a girl harboring compound heterozygote point mutations in the CYP19A1 gene. Results: In early childhood, low doses of oral 17β-estradiol were needed. During prepuberty treatment with slowly increasing doses of E2 resulted in normal uterine and almost normal development of ovarian volume, as well as number and size of follicles. Regarding hormonal feedback mechanisms, inhibin B levels were in the upper normal range during childhood and puberty. Low doses of estradiol did not suffice to achieve physiological gonadotropin levels in late prepuberty and puberty. However, when estradiol doses were further increased in late puberty levels of both FSH and LH declined with estradiol levels within normal range. Conclusion: Complete aromatase deficiency provides an excellent model of how ovarian and uterine development in relation to E2, LH, FSH and inhibin B feedback progresses from infancy to adolescence.

BDNF Val66Met polymorphism influence on striatal blood-level-dependent response to monetary feedback depends on valence and agency

Animal work implicates the brain-derived neurotrophic factor (BDNF) in function of the ventral striatum (VS), a region known for its role in processing valenced feedback. Recent evidence in humans shows that BDNF Val66Met polymorphism modulates VS activity in anticipation of monetary feedback. However, it remains unclear whether the polymorphism impacts the processing of self-attributed feedback differently from feedback attributed to an external agent. In this study, we emphasize the importance of the feedback attribution because agency is central to computational accounts of the striatum and cognitive accounts of valence processing. We used functional magnetic resonance imaging and a task, in which financial gains/losses are either attributable to performance (self-attributed, SA) or chance (externally-attributed, EA) to ask whether BDNF Val66Met polymorphism predicts VS activity. We found that BDNF Val66Met polymorphism influenced how feedback valence and agency information were combined in the VS and in the right inferior frontal junction (IFJ). Specifically, Met carriers' VS response to valenced feedback depended on agency information, while Val/Val carriers' VS response did not. This context-specific modulation of valence effectively amplified VS responses to SA losses in Met carriers. The IFJ response to SA losses also differentiated Val/Val from Met carriers. These results may point to a reduced allocation of attention and altered motivational salience to SA losses in Val/Val compared to Met carriers. Implications for major depressive disorder are discussed.