Liberation of platelet histamine by the alkaline tissue extract and oleic acid

Zusammenfassung Durch In-vitro-Inkubation mit alkalischen Gewebsextrakten oder mit Oleinsäure wurde Histamin aus den Blutplättchen von Kaninchen freigesetzt.     

Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex

Sliding clamps are ring-shaped proteins that encircle DNA and confer high processivity on DNA polymerases. Here we report the crystal structure of the five-protein clamp loader complex (replication factor-C, RFC) of the yeast Saccharomyces cerevisiae, bound to the sliding clamp (proliferating cell nuclear antigen, PCNA). Tight interfacial coordination of the ATP analogue ATP-gammaS by RFC results in a spiral arrangement of the ATPase domains of the clamp loader above the PCNA ring. Placement of a model for primed DNA within the central hole of PCNA reveals a striking correspondence between the RFC spiral and the grooves of the DNA double helix. This model, in which the clamp loader complex locks onto primed DNA in a screw-cap-like arrangement, provides a simple explanation for the process by which the engagement of primer-template junctions by the RFC:PCNA complex results in ATP hydrolysis and release of the sliding clamp on DNA.     

A large-scale RNAi screen in human cells identifies new components of the p53 pathway

RNA interference (RNAi) is a powerful new tool with which to perform loss-of-function genetic screens in lower organisms and can greatly facilitate the identification of components of cellular signalling pathways. In mammalian cells, such screens have been hampered by a lack of suitable tools that can be used on a large scale. We and others have recently developed expression vectors to direct the synthesis of short hairpin RNAs (shRNAs) that act as short interfering RNA (siRNA)-like molecules to stably suppress gene expression. Here we report the construction of a set of retroviral vectors encoding 23,742 distinct shRNAs, which target 7,914 different human genes for suppression. We use this RNAi library in human cells to identify one known and five new modulators of p53-dependent proliferation arrest. Suppression of these genes confers resistance to both p53-dependent and p19ARF-dependent proliferation arrest, and abolishes a DNA-damage-induced G1 cell-cycle arrest. Furthermore, we describe siRNA bar-code screens to rapidly identify individual siRNA vectors associated with a specific phenotype. These new tools will greatly facilitate large-scale loss-of-function genetic screens in mammalian cells.     

Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.     

Problem Conceptualisation Using Idea Networks

The social act of conceptualising a situation as problematic is thought to determine what will later be seen as a satisfactory solution. Pierce argues that conceptualising something (or an event) is a process of thinking about it through a set of conceptual frames. This paper presents a method for emerging those conceptual frames from preliminary discussions with participants. It draws on the work of Christopher Alexander and the Small Worlds phenomenon. Alexander suggests that participants’ statements can be thought of as being networked. The Small Worlds phenomenon then suggests that this network will not be uniform but rather be made up of a number of clusters (small worlds). These can be used to identify the conceptual frames in the participants’ statements. Therefore, the argument of this paper is that this method can be used to conceptualise problems. Having an explicit method is thought preferable to calling for unspecified creativity. The creativity comes from the method taking Dewey’s advice to switch between analysis and synthesis. The paper’s argument will be supported by explaining how the method can be practiced, while explaining why (theorising) the steps advised might be creative.

Revealing forecaster's preferences: A Bayesian multivariate loss function approach

Revealing the underlying preferences of a forecaster has always been at the core of much controversy. Herein, we build on the multivariate loss function concept and propose a flexible and multivariate family of likelihoods. This allows examining whether a vector of forecast errors, along with control variables, shapes a forecaster's preferences and, therefore, the underlying multivariate, nonseparable, loss function. We estimate the likelihood function using Bayesian exponentially tilted empirical likelihood, which reveals the shape of the parameter and the power of the multivariate loss function. In the empirical section, the reported evidence reveals that the EU Commission forecasts are predominantly asymmetric, leaning towards optimism in the year ahead, while a correction towards pessimism occurs in the current year forecast. There is some variability of this asymmetry across member states, with forecasts, i.e. gross domestic product growth, for large Member States exhibiting more optimism