Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Stock markets and effective exchange rates in European countries: threshold cointegration findings

© 2015, Eurasia Business and Economics Society. The nexus between stock markets and exchange rates is examined in the case of eight European countries. The sample consists of four economies with national currencies and four that have adopted the euro. Thus, if differences between the two groups in the relationship governing the two markets exist, they will be unveiled. To this effect, a threshold cointegration methodology is adopted that allows for more reliable inferences to be drawn for both the short and long run nexus between the two markets. Monthly data is used covering the period 01/2000–12/2014. The findings reported herein offer support in favor of the portfolio approach thesis over the recent economic crisis period, but this finding is not the case for the entire sample. Bidirectional causality is found for Norway and the UK, pointing to a currency effect on stock markets. In view of the findings reported herein, policies aiming at reducing uncertainty in the stock markets can exert beneficial effects on currency markets

Early adolescent disclosure and parental knowledge regarding online activities: Social anxiety and parental rule-setting as moderators

Early adolescents spend a lot of time online, yet little is currently known about the links between parental rule-setting, adolescent disclosure about online activities, and whether social anxiety may interfere with these processes. Using a longitudinal sample of 526 adolescents (269 girls; Mage = 14.00) and their parents (79% mothers, Mage = 43.66), the results from the current study showed low correspondence between parental knowledge, adolescent disclosure, as well as parents’ and adolescents’ ratings of parental legitimacy to set boundaries about online activities. High social anxiety interacted with high adolescent-rated parental rule-setting in predicting the least disclosure about chatting with strangers and posting online content over time. Also, high social anxiety interacted with low parent-rated control to predict more adolescent disclosure about chatting with strangers and money spent online over time. Thus, social anxiety and parental rule-setting moderated the links between disclosure and knowledge for some early adolescent online activities. Our results conflict with the value typically placed on parental rule-setting in online contexts, at least for socially anxious adolescents

Transcriptional Regulation Is a Major Controller of Cell Cycle Transition Dynamics

DNA replication, mitosis and mitotic exit are critical transitions of the cell cycle which normally occur only once per cycle. A universal control mechanism was proposed for the regulation of mitotic entry in which Cdk helps its own activation through two positive feedback loops. Recent discoveries in various organisms showed the importance of positive feedbacks in other transitions as well. Here we investigate if a universal control system with transcriptional regulation(s) and post-translational positive feedback(s) can be proposed for the regulation of all cell cycle transitions. Through computational modeling, we analyze the transition dynamics in all possible combinations of transcriptional and post-translational regulations. We find that some combinations lead to ‘sloppy’ transitions, while others give very precise control. The periodic transcriptional regulation through the activator or the inhibitor leads to radically different dynamics. Experimental evidence shows that in cell cycle transitions of organisms investigated for cell cycle dependent periodic transcription, only the inhibitor OR the activator is under cyclic control and never both of them. Based on these observations, we propose two transcriptional control modes of cell cycle regulation that either STOP or let the cycle GO in case of a transcriptional failure. We discuss the biological relevance of such differences

Reduction of claustrophobia during magnetic resonance imaging: methods and design of the "CLAUSTRO" randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Magnetic resonance (MR) imaging has been described as the most important medical innovation in the last 25 years. Over 80 million MR procedures are now performed each year and on average 2.3% (95% confidence interval: 2.0 to 2.5%) of all patients scheduled for MR imaging suffer from claustrophobia. Thus, prevention of MR imaging by claustrophobia is a common problem and approximately 2,000,000 MR procedures worldwide cannot be completed due to this situation. Patients with claustrophobic anxiety are more likely to be frightened and experience a feeling of confinement or being closed in during MR imaging. In these patients, conscious sedation and additional sequences (after sedation) may be necessary to complete the examinations. Further improvements in MR design appear to be essential to alleviate this situation and broaden the applicability of MR imaging. A more open scanner configuration might help reduce claustrophobic reactions while maintaining image quality and diagnostic accuracy.</p> <p>Methods/Design</p> <p>We propose to analyze the rate of claustrophobic reactions, clinical utility, image quality, patient acceptance, and cost-effectiveness of an open MR scanner in a randomized comparison with a recently designed short-bore but closed scanner with 97% noise reduction. The primary aim of this study is thus to determine whether an open MR scanner can reduce claustrophobic reactions, thereby enabling more examinations of claustrophobic patients without incurring the safety issues associated with conscious sedation. In this manuscript we detail the methods and design of the prospective "CLAUSTRO" trial.</p> <p>Discussion</p> <p>This randomized controlled trial will be the first direct comparison of open vertical and closed short-bore MR systems in regards to claustrophobia and image quality as well as diagnostic utility.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00715806">NCT00715806</a></p

Effects of Acacia seyal and biochar on soil properties and sorghum yield in agroforestry systems in South Sudan

We studied the effects of Acacia seyal Del. intercropping and biochar soil amendment on soil physico-chemical properties and sorghum (Sorghum bicolor L.) yields in a two-year field experiment conducted on a silt loam site near Renk in South Sudan. A split-plot design with three replications was used. The main factor was tree-cropping system (dense acacia + sorghum, scattered acacia + sorghum, and sole sorghum) and biochar (0 and 10 Mg ha(-1)) was the subplot factor. The two acacia systems had lower soil pH, N and higher C/N ratios compared to the sole sorghum system. Biochar significantly increased soil C, exchangeable K+ contents, field capacity and available water content, but reduced soil exchangeable Ca2+ and effective CEC, and had no effect on soil pH. Acacia intercropping significantly reduced sorghum grain yields while biochar had no significant effect on sorghum yields. The land equivalent ratio (LER) for sorghum yield was 0.3 for both acacia systems in 2011, with or without biochar, but increased in 2012 to 0.6 for the scattered acacia system when combined with biochar. The reduction in sorghum yields by the A. seyal trees was probably due to a combination of competition for water and nutrients and shading. The lack of a yield response to biochar maybe due to insufficient time or too low a dosage. Further research is needed to test for the effects of tree intercropping and biochar and their interactions on soil properties and crop yields in drylands.Peer reviewe

Embryonic Diapause Is Conserved across Mammals

Embryonic diapause (ED) is a temporary arrest of embryo development and is characterized by delayed implantation in the uterus. ED occurs in blastocysts of less than 2% of mammalian species, including the mouse (Mus musculus). If ED were an evolutionarily conserved phenomenon, then it should be inducible in blastocysts of normally non-diapausing mammals, such as domestic species. To prove this hypothesis, we examined whether blastocysts from domestic sheep (Ovis aries) could enter into diapause following their transfer into mouse uteri in which diapause conditions were induced. Sheep blastocysts entered into diapause, as demonstrated by growth arrest, viability maintenance and their ED-specific pattern of gene expression. Seven days after transfer, diapausing ovine blastocysts were able to resume growth in vitro and, after transfer to surrogate ewe recipients, to develop into normal lambs. The finding that non-diapausing ovine embryos can enter into diapause implies that this phenomenon is phylogenetically conserved and not secondarily acquired by embryos of diapausing species. Our study questions the current model of independent evolution of ED in different mammalian orders

Is organizational justice climate at the workplace associated with individual-level quality of care and organizational affective commitment?:A multi-level, cross-sectional study on dentistry in Sweden

Purpose The aim of this study is to investigate whether organizational justice climate at the workplace level is associated with individual staff members’ perceptions of carequality and affective commitment to the workplace.Methods The study adopts a cross-sectional multi-level design. Data were collected using an electronic survey and a response rate of 75% was obtained. Organizational justice climate and affective commitment to the workplace were measured by items from Copenhagen Psychosocial Questionnaire and quality of care by three self-developed items. Non-managerial staff working at dental clinics with at least five respondents (n = 900 from 68 units) was included in analyses. A set of Level-2 random intercept models were built to predict individual-level organizational affective commitment and perceived quality of care from unit-level organizational justice climate, controlling for potential confoundingby group size, gender, age, and occupation.Results The results of the empty model showed substantial between-unit variation for both affective commitment (ICC-1 = 0.17) and quality of care (ICC-1 = 0.12). The overall results showed that the shared perception of organizational justice climate at the clinical unit level was significantly associated with perceived quality of care and affective commitment to the organization (p < 0.001).Conclusions Organizational justice climate at work unit level explained all variation in affective commitment among dental clinics and was associated with both the individualstaff members’ affective commitment and perceived quality of care. These findings suggest a potential for that addressing organizational justice climate may be a way to promote quality of care and enhancing affective commitment. However, longitudinal studies are needed to support causality in the examined relationships. Intervention research is also recommended to probe the effectiveness of actions increasingunit-level organizational justice climate and test their impact on quality of care and affective commitment