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.     

BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy. Although nine BBS genes have been cloned, they explain only 40-50% of the total mutational load. Here we report a major new BBS locus, BBS10, that encodes a previously unknown, rapidly evolving vertebrate-specific chaperonin-like protein. We found BBS10 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.     

GSK3 and β-catenin determines functional expression of sodium channels at the axon initial segment

Neuronal action potentials are generated through voltage-gated sodium channels, which are tethered by ankyrinG at the membrane of the axon initial segment (AIS). Despite the importance of the AIS in the control of neuronal excitability, the cellular and molecular mechanisms regulating sodium channel expression at the AIS remain elusive. Our results show that GSK3α/β and β-catenin phosphorylated by GSK3 (S33/37/T41) are localized at the AIS and are new components of this essential neuronal domain. Pharmacological inhibition of GSK3 or β-catenin knockdown with shRNAs decreased the levels of phosphorylated-β-catenin, ankyrinG, and voltage-gated sodium channels at the AIS, both “in vitro” and “in vivo”, therefore diminishing neuronal excitability as evaluated via sodium current amplitude and action potential number. Thus, our results suggest a mechanism for the modulation of neuronal excitability through the control of sodium channel density by GSK3 and β-catenin at the AIS.     

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.