Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome

Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.     

Evaluation of Regime Switching Models for Real‐Time Business Cycle Analysis of the Euro Area

In this paper, we aim at assessing Markov switching and threshold models in their ability to identify turning points of economic cycles. By using vintage data updated on a monthly basis, we compare their ability to date ex post the occurrence of turning points, evaluate the stability over time of the signal emitted by the models and assess their ability to detect in real‐time recession signals. We show that the competitive use of these models provides a more robust analysis and detection of turning points. To perform the complete analysis, we have built a historical vintage database for the euro area going back to 1970 for two monthly macroeconomic variables of major importance for short‐term economic outlook, namely the industrial production index and the unemployment rate. Copyright © 2013 John Wiley & Sons, Ltd.     

Progress and prospects in rat genetics: a community view

The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research.     

Andalò di Negro’s De compositione astrolabii: a critical edition with English translation and notes

In this article, we publish the critical edition of Andalò di Negro’s De compositione astrolabii, with English translation and commentary. The mathematician and astronomer Andalò di Negro (Genoa ca. 1260–Naples 1334) presumably redacted this treatise on the astrolabe in the 1330s, while residing at the court of King Robert of Naples. The present edition has three purposes: first, to make available a text missing from the previous compilations of works by Andalò di Negro (ed. Bonus Opus preclarissimum astrolabij compositum a domino Andalo de nigro genuensi foeliciter incipit…Explicit tractatus astrolabij excellentissimi mathematici Andalonis genuensis, emendatus per celeberrimum et doctissimum astronomum magistrum Petrum Bonum Avogarium in foelici gymnasio ferrariensi. [Ferrara]: magister Johannes Picardus, 1475; Bertolotto II Trattato sull’Astrolabio di Andalò di Negro, riprodotto dall’edizione ferrarese del 1475, con prefazione del socio G. Bertolotto. Atti della società ligure di storia patria 25, 51–141, 1892; Fornaciari and Faracovi Trattato sull’astrolabio di Andalò di Negro, a cura di P.E. Fornaciari e O.P. Faracovi. Pubblicazione del Comune di Livorno in occasione della “Primavera della Scienza a Livorno” (febbraio-maggio 2005). Ospedaletto: Pacini editore, 2005); second, to revise a privately circulated edition of the text (Cesari L’astrolabio di Andalò di Negro, Parte I, edizione critica. Milano: s.n., 1984a; Practica Astrolabii di Andalò di Negro, Parte I. Edizione critica. Bergamo: Istituto Universitario di Bergamo, 1984b); and third, to help disseminating one of the rare Latin texts presenting the principles of the stereographic projection which underlie the construction of the astrolabe.

     

Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling

A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the basis for establishing central tolerance.     

Brassinosteroid regulates stomatal development by GSK3-mediated inhibition of a MAPK pathway

Plants must coordinate the regulation of biochemistry and anatomy to optimize photosynthesis and water-use efficiency. The formation of stomata, epidermal pores that facilitate gas exchange, is highly coordinated with other aspects of photosynthetic development. The signalling pathways controlling stomata development are not fully understood, although mitogen-activated protein kinase (MAPK) signalling is known to have key roles. Here we demonstrate in Arabidopsis that brassinosteroid regulates stomatal development by activating the MAPK kinase kinase (MAPKKK) YDA (also known as YODA). Genetic analyses indicate that receptor kinase-mediated brassinosteroid signalling inhibits stomatal development through the glycogen synthase kinase 3 (GSK3)-like kinase BIN2, and BIN2 acts upstream of YDA but downstream of the ERECTA family of receptor kinases. Complementary in vitro and in vivo assays show that BIN2 phosphorylates YDA to inhibit YDA phosphorylation of its substrate MKK4, and that activities of downstream MAPKs are reduced in brassinosteroid-deficient mutants but increased by treatment with either brassinosteroid or GSK3-kinase inhibitor. Our results indicate that brassinosteroid inhibits stomatal development by alleviating GSK3-mediated inhibition of this MAPK module, providing two key links; that of a plant MAPKKK to its upstream regulators and of brassinosteroid to a specific developmental output.     

Building the stemma codicum from geometric diagrams

In view of the progress made in recent decades in the fields of stemmatology and the analysis of geometric diagrams, the present article explores the possibility of establishing the stemma codicum of a handwritten tradition from geometric diagrams alone. This exploratory method is tested on Ibn al-Haytham’s Epistle on the Shape of the Eclipse, because this work has not yet been issued in a critical edition. Separate stemmata were constructed on the basis of the diagrams and the text, and a comparison showed no major differences. The greater reliability of a stemma codicum constructed on the basis of the diagrams rather than the text of a mathematical work is discussed, and preliminary conclusions are drawn.     

Ceramide synthase 2 deficiency aggravates AOM-DSS-induced colitis in mice: role of colon barrier integrity

Loss of intestinal barrier functions is a hallmark of inflammatory bowel disease like ulcerative colitis. The molecular mechanisms are not well understood, but likely involve dysregulation of membrane composition, fluidity, and permeability, which are all essentially regulated by sphingolipids, including ceramides of different chain length and saturation. Here, we used a loss-of-function model (CerS2^+/+ and CerS2^?/? mice) to investigate the impact of ceramide synthase 2, a key enzyme in the generation of very long-chain ceramides, in the dextran sodium salt (DSS) evoked model of UC. CerS2^?/? mice developed more severe disease than CerS2^+/+ mice in acute DSS and chronic AOM/DSS colitis. Deletion of CerS2 strongly reduced very long-chain ceramides (Cer24:0, 24:1) but concomitantly increased long-chain ceramides and sphinganine in plasma and colon tissue. In naive CerS2^?/? mice, the expression of tight junction proteins including ZO-1 was almost completely lost in the colon epithelium, leading to increased membrane permeability. This could also be observed in vitro in CerS2 depleted Caco-2 cells. The increase in membrane permeability in CerS2^?/? mice did not manifest with apparent clinical symptoms in naive mice, but with slight inflammatory signs such as an increase in monocytes and IL-10. AOM/DSS and DSS treatment alone led to a further deterioration of membrane integrity and to severe clinical symptoms of the disease. This was associated with stronger upregulation of cytokines in CerS2^?/? mice and increased infiltration of the colon wall by immune cells, particularly monocytes, CD4⁺ and Th17⁺ T-cells, and an increase in tumor burden. In conclusion, CerS2 is crucial for the maintenance of colon barrier function and epithelial integrity. CerS2 knockdown, and associated changes in several sphingolipids such as a drop in very long-chain ceramides/(dh)-ceramides, an increase in long-chain ceramides/(dh)-ceramides, and sphinganine in the colon, may weaken endogenous defense against the endogenous microbiome.     

Local and Global Properties of the World

The essence of the method of physics is inseparably connected with the problem of interplay between local and global properties of the universe. In the present paper we discuss this interplay as it is present in three major departments of contemporary physics: general relativity, quantum mechanics and some attempts at quantizing gravity (especially geometrodynamics and its recent successors in the form of various pregeometry conceptions). It turns out that all big interpretative issues involved in this problem point towards the necessity of changing from the standard space-time geometry to some radically new, most probably non-local, generalization. We argue that the recent noncommutative geometry offers attractive possibilities, and gives us a conceptual insight into its algebraic foundations. Noncommutative spaces are, in general, non-local, and their applications to physics, known at present, seem very promising. One would expect that beneath the Planck threshold there reigns a "noncommutative pregeometry", and only when crossing this threshold does the usual space-time geometry emerges.