miR-142 favors naïve B cell residence in peripheral lymph nodes

B lymphocyte development proceeds through a well-ordered sequence of steps, leading to the formation of a sizeable mature B population recognizing a diversity of antigens. These latter cells are ultimately responsible for the production of antibodies upon immune challenges. The detection of threats to the organism is facilitated by the ability of naïve follicular B cells, the main subset of mature B cells in mice, to circulate between lymphoid tissues in search of their cognate antigens. miRNA-mediated fine-tuning of mRNA stability and translation participates in the optimal expression of genetic programs. This regulatory mechanism has been shown to contribute to B cell biology, although the role of individual miRNAs remains understudied. Here, we selectively inactivated the miR-142 locus in B cells. As a consequence, the mature B compartment was visibly perturbed, in agreement with work in miR-142 knockout mice. However, our strategy allowed us to identify roles for the miR-142 locus in B cell physiology obscured by the complexity of the immune phenotype in the null mutant mice. Thus, these miRNAs are necessary for the proper formation of the pre-B cell compartment during development. More remarkably, naïve follicular B cells demonstrated altered migratory properties upon conditional inactivation of the miR-142 locus. The latter mutant cells expressed reduced levels of the homing molecule CD62L. They also migrated more efficiently towards sphingosine-1-phosphate in vitro and displayed an increased abundance of the sphingosine-1-phosphate receptor 1, compatible with improved lymphocyte egress in vivo. In line with these observations, the ablation of the miR-142 locus in B cells caused a paucity of B cells in the lymph nodes. Mutant B cell accumulation in the latter tissues was also compromised upon transfer into a wild-type environment. These changes coincided with suboptimal levels of FOXO1, a positive regulator of CD62L transcription, in mutant B cells. Overall, our findings indicate contributions for the miR-142 locus in various aspects of the B cell life cycle. Notably, this locus appears to favor the establishment of the migratory behavior required for naïve follicular B cell patrolling activity

A European research agenda for somatic symptom disorders, bodily distress disorders, and functional disorders: Results of an estimate-talk-estimate delphi expert study

Background: Somatic Symptom Disorders (SSD), Bodily Distress Disorders (BDD) and functional disorders (FD) are associated with high medical and societal costs and pose a substantial challenge to the population and health policy of Europe. To meet this challenge, a specific research agenda is needed as one of the cornerstones of sustainable mental health research and health policy for SSD, BDD, and FD in Europe. Aim: To identify the main challenges and research priorities concerning SSD, BDD, and FD from a European perspective. Methods: Delphi study conducted from July 2016 until October 2017 in 3 rounds with 3 workshop meetings and 3 online surveys, involving 75 experts and 21 European countries. EURONET-SOMA and the European Association of Psychosomatic Medicine (EAPM) hosted the meetings. Results: Eight research priorities were identified: (1) Assessment of diagnostic profiles relevant to course and treatment outcome. (2) Development and evaluation of new, effective interventions. (3) Validation studies on questionnaires or semi-structured interviews that assess chronic medical conditions in this context. (4) Research into patients preferences for diagnosis and treatment. (5) Development of new methodologic designs to identify and explore mediators and moderators of clinical course and treatment outcomes (6). Translational research exploring how psychological and somatic symptoms develop from somatic conditions and biological and behavioral pathogenic factors. (7) Development of new, effective interventions to personalize treatment. (8) Implementation studies of treatment interventions in different settings, such as primary care, occupational care, general hospital and specialty mental health settings. The general public and policymakers will benefit from the development of new, effective, personalized interventions for SSD, BDD, and FD, that will be enhanced by translational research, as well as from the outcomes of research into patient involvement, GP-patient communication, consultation-liaison models and implementation. Conclusion: Funding for this research agenda, targeting these challenges in coordinated research networks such as EURONET-SOMA and EAPM, and systematically allocating resources by policymakers to this critical area in mental and physical well-being is urgently needed to improve efficacy and impact for diagnosis and treatment of SSD, BDD, and FD across Europe

Is the stressor criterion dispensable?: a contribution to the criterion A debate from a Swiss sample of survivors of the 2004 tsunami

BACKGROUND: The stressor criterion (criterion A) in the DSM-IV diagnosis of posttraumatic stress disorder (PTSD) is frequently questioned. To explore the clinical and diagnostic usefulness of criterion A, we examined its value in predicting and capturing PTSD symptom clusters (criteria B-D) in a sample of trauma survivors. METHOD: We studied 342 adult German-speaking Swiss tourists affected by the 2004 tsunami. We analyzed sensitivity and specificity, predictive value and variance explanation of criterion A for evoking PTSD criteria B-D. RESULTS: Sensitivity of criterion A for PTSD criteria B-D was 93.2%, while positive predictive value was 23.1%. Criterion A made a small, yet statistically significant contribution of 7.5% for PTSD symptom clusters B-D. CONCLUSION: The assessment of criterion A (A1 and A2) is not necessary for the identification of individuals suffering from PTSD symptoms according to DSM-IV. We suggest therefore that criterion A is a dispensable part of the diagnosis of PTSD

The psychological outcome of religious coping with stressful life events in a Swiss sample of church attendees

BACKGROUND: Recent research suggested that religious coping, based on dispositional religiousness and spirituality (R/S), is an important modulating factor in the process of dealing with adversity. In contrast to the United States, the effect of R/S on psychological adjustment to stress is a widely unexplored area in Europe. METHODS: We examined a Swiss sample of 328 church attendees in the aftermath of stressful life events to explore associations of positive or negative religious coping with the psychological outcome. Applying a cross-sectional design, we used Huber's Centrality Scale to specify religiousness and Pargament's measure of religious coping (RCOPE) for the assessment of positive and negative religious coping. Depressive symptoms and anxiety as outcome variables were examined by the Brief Symptom Inventory. The Stress-Related Growth Scale and the Marburg questionnaire for the assessment of well-being were used to assess positive outcome aspects. We conducted Mann-Whitney tests for group comparisons and cumulative logit analysis for the assessment of associations of religious coping with our outcome variables. RESULTS: Both forms of religious coping were positively associated with stress-related growth (p > 0.01). However, negative religious coping additionally reduced well-being (p = 0.05, beta = 0.52, 95% CI = 0.27-0.99) and increased anxiety (p = 0.02, beta = 1.94, 95% CI = 1.10-3.39) and depressive symptoms (p = 0.01, beta = 2.27, 95% CI = 1.27-4.06). CONCLUSIONS: The effects of religious coping on the psychological adjustment to stressful life events seem relevant. These findings should be confirmed in prospective studie

Growth and decomposition of aligned and ordered PdO nanoparticles

The formation, thermal decomposition, and reduction of small PdO particles were studied by high-resolution transmission electron microscopy and selected area electron diffraction. Well-defined Pd particles (mean size of 5–7 nm) were grown epitaxially on NaCl (001) surfaces and subsequently covered by a layer of amorphous SiO2 (25 nm), prepared by reactive deposition of SiO in 10–2 Pa O2. The resulting films were exposed to molecular O2 in the temperature range of 373–673 K, and the growth of PdO was studied. The formation of a PdO phase starts at 623 K and is almost completed at 673 K. The high-resolution experiments suggest a topotactic growth of PdO crystallites on top of the original Pd particles. Subsequent reaction of the PdO in 10 mbar CO for 15 min and thermal decomposition in 1 bar He for 1 h were also investigated in the temperature range from 373 to 573 K. Reductive treatments in CO up to 493 K do not cause a significant change in the PdO structure. The reduction of PdO starts at 503 K and is completed at 523 K. In contrast, PdO decomposes in 1 bar He at around 573 K. The mechanism of PdO growth and decay is discussed and compared to results of previous studies on other metals, e.g., on rhodium

Water-mediated protein-fluorophore interactions modulate the affinity of an ABC-ATPase/TNP-ADP complex

TNP-modified nucleotides have been used extensively to study protein-nucleotide interactions. In the case of ABC-ATPases, application of these powerful tools has been greatly restricted due to the significantly higher affinity of the TNP-nucleotide for the corresponding ABC-ATPase in comparison to the non-modified nucleotides. To understand the molecular changes occurring upon binding of the TNP-nucleotide to an ABC-ATPase, we have determined the crystal structure of the TNP-ADP/HlyB-NBD complex at 1.6A resolution. Despite the higher affinity of TNP-ADP, no direct fluorophore-protein interactions were observed. Unexpectedly, only water-mediated interactions were detected between the TNP moiety and Tyr(477), that is engaged in pi-pi stacking with the adenine ring, as well as with two serine residues (Ser(504) and Ser(509)) of the Walker A motif. Interestingly, the side chains of these two serine residues adopt novel conformations that are not observed in the corresponding ADP structure. However, in the crystal structure of the S504A mutant, which binds TNP-ADP with similar affinity to the wild type enzyme, a novel TNP-water interaction compensates for the missing serine side chain. Since this water molecule is not present in the wild type enzyme, these results suggest that only water-mediated interactions provide a structural explanation for the increased affinity of TNP-nucleotides towards ABC-ATPases. However, our results also imply that in silico approaches such as docking or modeling cannot directly be applied to generate 'affinity-adopted' ADP- or ATP-analogs for ABC-ATPases