Long-term incubation with mifepristone (MLTI) increases the spine density in developing Purkinje cells: new insights into progesterone receptor mechanisms

Cerebellar Purkinje cells (PC) physiologically reveal an age-dependent expression of progesterone with high endogenous concentrations during the neonatal period. Even if progesterone has been previously shown to induce spinogenesis, dendritogenesis and synaptogenesis in immature PC, data about the effects of progesterone on mature PC are missing, even though they could be of significant therapeutic interest. The current study demonstrates for the first time a progesterone effect, depending on the developmental age of PC. Comparable with the physiological course of the progesterone concentration, experimental treatment with progesterone for 24 h achieves the highest effects on the dendritic tree during the early neonate, inducing an highly significant increase in dendritic length, spine number and spine area, while spine density in mature PC could not be further stimulated by progesterone incubation. Observed progesterone effects are certainly mediated by classical progesterone receptors, as spine area and number were comparable to controls when progesterone incubation was combined with mifepristone (incubation for 24 h), an antagonist of progesterone receptors A and B (PR-A/PR-B). In contrast, an increase in the spine number and area of both immature and mature PC was detected when slice cultures were incubated with mifepristone for more than 72 h (mifepristone long-time incubation, MLTI). By including time-lapse microscopy, electron microscopic techniques, PCR, western blot, and MALDI IMS receptor analysis, as well as specific antagonists like trilostane and AG 205, we were able to detect the underlying mechanism of this diverging mifepristone effect. Thus, our results provide new insights into the function and signaling mechanisms of the recently described progesterone receptor membrane component 1 (PGRMC1) in PC. It is highly suitable that progesterone does not just induce effects by the well-known genomic mechanisms of the classical progesterone receptors but also acts through PGRMC1 mediated non-genomic mechanisms. Thus, our results provide first proofs for a previously discussed progesterone-dependent induction of neurosteroidogenesis in PC by interaction with PGRMC1. But while genomic progesterone effects mediated through classical PR-A and PR-B seem to be restricted to the neonatal period of PC, PGRMC1 also transmits signals by non-genomic mechanisms like regulation of the neurosteroidogenesis in mature PC. Thus, PGRMC1 might be an interesting target for future clinical studies and therapeutic interventions.     

Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis

Dysfunction of the intestinal epithelium is believed to result in the excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease, an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria adjacent to the epithelium. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn's disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death.     

Beethoven, a mouse model for dominant, progressive hearing loss DFNA36

Despite recent progress in identifying genes underlying deafness, there are still relatively few mouse models of specific forms of human deafness. Here we describe the phenotype of the Beethoven (Bth) mouse mutant and a missense mutation in Tmc1 (transmembrane cochlear-expressed gene 1). Progressive hearing loss (DFNA36) and profound congenital deafness (DFNB7/B11) are caused by dominant and recessive mutations of the human ortholog, TMC1 (ref. 1), for which Bth and deafness (dn) are mouse models, respectively.     

Adaptive forecasting of the EURIBOR swap term structure

In this paper we adopt a principal components analysis (PCA) to reduce the dimensionality of the term structure and employ autoregressive (AR) models to forecast principal components which, in turn, are used to forecast swap rates. Arguing in favour of structural variation, we propose data‐driven, adaptive model selection strategies based on the PCA/AR model. To evaluate ex ante forecasting performance for particular rates, distinct forecast features, such as mean squared errors, directional accuracy and directional forecast value, are considered. It turns out that, relative to benchmark models, the adaptive approach offers additional forecast accuracy in terms of directional accuracy and directional forecast value. Copyright © 2009 John Wiley & Sons, Ltd.     

Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer

PALB2 was recently identified as a nuclear binding partner of BRCA2. Biallelic BRCA2 mutations cause Fanconi anemia subtype FA-D1 and predispose to childhood malignancies. We identified pathogenic mutations in PALB2 (also known as FANCN) in seven families affected with Fanconi anemia and cancer in early childhood, demonstrating that biallelic PALB2 mutations cause a new subtype of Fanconi anemia, FA-N, and, similar to biallelic BRCA2 mutations, confer a high risk of childhood cancer.     

Formalised and Non-Formalised Methods in Resource Management—Knowledge and Social Learning in Participatory Processes: An Introduction

The participation of non-state actors in public decision-making and transdisciplinary research is increasingly regarded as an effective means to cope with growing uncertainties and complexities in human–nature interactions. The management of natural resources is expected to profit from a broader knowledge base and processes of social learning, thus allowing for potentially more informed and creative decision-making. Communication is a key element of transmitting knowledge and fostering social learning. This article introduces the special issue, which assembles contributions that discuss different methods, instruments, tools, and models that have been developed in order to facilitate the transmission of information as well its selection and aggregation. Each of the contributions is briefly reviewed. The approaches discussed here and in the individual papers aim to foster learning in participatory processes. We argue that a key aspect is the degree to which methods are formalised. Formalisation refers to the extent to which information is channelled in a certain way, leaving more or less scope for open communication. Depending on the goals and context, more or less formalised methods can be employed. We conclude by highlighting the context-dependency of participatory processes in natural resource management and indicate some directions for future research.

The Role of Formalisation, Participation and Context in the Success of Public Involvement Mechanisms in Resource Management

In the face of complex and uncertain issues, one important goal of public participation in resource management and research is to foster communication and the inclusion of non-expert knowledge—thus the effective flow of information between project organisers and stakeholders. We compare different methods (instruments, tools) that were employed in the German–Austrian ‘PartizipA’ project to structure information flows in participatory processes. Depending on their goals and context, more or less ‘formalised’ and ‘participatory’ methods were applied, the most important being guided interviews, focus groups, agent-based modelling, nutrient modelling, cognitive mapping and group model building as well as the development of a common document. Two regional case studies, both concerned with European-induced institutional change, are portrayed in which the specific participatory methods were embedded. The Austrian case study involved the analysis and modelling of agricultural land use in the region of St. Pölten against the background of the reform of the Common Agricultural Policy, while the implementation of recent European water policy was the issue in the German agricultural region north of Osnabrück. Presenting both cases in their regional context, the applied methods are first described according to the logic of the entire respective process. Subsequently, the specific methods are systematically analysed and compared according to their objective, context and degrees of participation and formalisation. Finally, we evaluate all methods regarding their effectiveness in terms of goal attainment and their potential generalisation, seeking to respond to the question of when a particular method might best be used.