Erdheim-Chester disease : from palliative care to targeted treatment

Erdheim-Chester disease (ECD) is a life-threatening multi-systemic non-Langerhans histiocytosis with cardiovascular complications as the leading cause of death. ECD affects the kidneys in up to 30% of cases, with fibrotic tissue deposition in the perirenal fat and renal hilum. Diagnosis is usually based on histological analysis of the pathologic tissue, which typically shows xanthogranulomatous infiltrates of foamy CD68+/CD1a-histiocytes surrounded by fibrosis. A consistent percentage of patients affected by ECD develop renal failure and hypertension as a consequence of renal artery stenosis and hydronephrosis. These conditions have been generally treated with the placement of stents and nephrostomies that frequently led to disappointing outcomes. Before the introduction of interferon-alpha (IFN\u3b1) treatment, the mortality rate was as high as 57% in the long term. Recent studies have granted new insights into the pathogenesis of ECD, which seems to bear a dual component of clonal and inflammatory disease. These advances led to use specific therapies targeting either the oncogenes (BRAFV600E) or the effectors of the immune response implicated in ECD (IL-1, TNF\u3b1). Drugs such as anakinra (recombinant human IL-1 receptor antagonist), infliximab (monoclonal antibody against TNF\u3b1) and vemurafenib (inhibitor of mutant BRAF) showed promising results in small single-centre series. Although larger trials will be needed to address the impact of these drugs on ECD prognosis and to select the most effective treatment, targeted therapies hold the premises to drastically change the outcome of this condition. \ua9 2014 The Author

The Incorporation of Ribonucleotides Induces Structural and Conformational Changes in DNA

Ribonucleotide incorporation is the most common error occurring during DNA replication. Cells have hence developed mechanisms to remove ribonucleotides from the genome and restore its integrity. Indeed, the persistence of ribonucleotides into DNA leads to severe consequences, such as genome instability and replication stress. Thus, it becomes important to understand the effects of ribonucleotides incorporation, starting from their impact on DNA structure and conformation. Here we present a systematic study of the effects of ribonucleotide incorporation into DNA molecules. We have developed, to our knowledge, a new method to efficiently synthesize long DNA molecules (hundreds of basepairs) containing ribonucleotides, which is based on a modified protocol for the polymerase chain reaction. By means of atomic force microscopy, we could therefore investigate the changes, upon ribonucleotide incorporation, of the structural and conformational properties of numerous DNA populations at the single-molecule level. Specifically, we characterized the scaling of the contour length with the number of basepairs and the scaling of the end-to-end distance with the curvilinear distance, the bending angle distribution, and the persistence length. Our results revealed that ribonucleotides affect DNA structure and conformation on scales that go well beyond the typical dimension of the single ribonucleotide. In particular, the presence of ribonucleotides induces a systematic shortening of the molecules, together with a decrease of the persistence length. Such structural changes are also likely to occur in vivo, where they could directly affect the downstream DNA transactions, as well as interfere with protein binding and recognition

Multidisciplinary studies on a sick-leader syndrome-associated mass stranding of sperm whales (Physeter macrocephalus) along the Adriatic coast of Italy

Mass strandings of sperm whales (Physeter macrocephalus) are rare in the Mediterranean Sea. Nevertheless, in 2014 a pod of 7 specimens stranded alive along the Italian coast of the Central Adriatic Sea: 3 individuals died on the beach after a few hours due to internal damages induced by prolonged recumbency; the remaining 4 whales were refloated after great efforts. All the dead animals were genetically related females; one was pregnant. All the animals were infected by dolphin morbillivirus (DMV) and the pregnant whale was also affected by a severe nephropathy due to a large kidney stone. Other analyses ruled out other possible relevant factors related to weather conditions or human activities. The results of multidisciplinary post-mortem analyses revealed that the 7 sperm whales entered the Adriatic Sea encountering adverse weather conditions and then kept heading northward following the pregnant but sick leader of the pod, thereby reaching the stranding site. DMV infection most likely played a crucial role in impairing the health condition and orientation abilities of the whales. They did not steer back towards deeper waters, but eventually stranded along the Central Adriatic Sea coastline, a real trap for sperm whales

Convergence Without Hard Criteria: Does EU Soft Law Affect Domestic Unemployment Protection Schemes?

(VLID)177126

Symplectically Asystatic actions of compact Lie Groups

In the present paper we introduce the notion of symplectically asystatic Hamiltonian action on a K\"ahler manifold. In the algebraic setting we prove that if a complex linear group $G$ acts in a symplectically asystatic fashion on a K\"ahler manifold then the $G$-orbits are spherical. Finally we give the complete classification of symplectically asystatic irreducible representations

Growth Mechanism of Cluster-Assembled Surfaces : From Submonolayer to Thin-Film Regime

Nanostructured films obtained by assembling preformed atomic clusters are of strategic importance for a wide variety of applications. The deposition of clusters produced in the gas phase onto a substrate offers the possibility to control and engineer the structural and functional properties of the cluster-assembled films. To date, the microscopic mechanisms underlying the growth and structuring of cluster-assembled films are poorly understood, and, in particular, the transition from the submonolayer to the thin-film regime is experimentally unexplored. Here we report the systematic characterization by atomic force microscopy of the evolution of the structural properties of cluster-assembled films deposited by supersonic cluster beam deposition. As a paradigm of nanostructured systems, we focus our attention on cluster-assembled zirconia films, investigating the influence of the building block dimensions on the growth mechanisms and roughening of the thin films, following the growth process from the early stages of the submonolayer to the thin-film regime. Our results demonstrate that the growth dynamics in the submonolayer regime determines different morphological properties of the cluster-assembled thin film. The evolution of the roughness with the number of deposited clusters reproduces the growth exponent of the ballistic deposition in the 2 thorn 1 model from the submonolayer to the thin-film regime

Progetto di restauro, consolidamento e miglioramento sismico del Duomo di Pienza

Il presente articolo \ue8 volto a descrivere il processo progettuale che ha portato alla definizione dell\u2019intervento di restauro, consolidamento e miglioramento sismico del Duomo di Pienza (SI), redatto su incarico del Ministero dei Beni e delle Attivit\ue0 Culturali e del Turismo - Direzione Regionale per i Beni Culturali e Paesaggistici della Toscana. Per una corretta definizione degli interventi di miglioramento sismico di un edificio esistente, assume particolare importanza il percorso di conoscenza del manufatto: per il Duomo di Pienza tale percorso inizia con la sua costruzione nel 1459 in quanto, gi\ue0 durante le fasi di realizzazione, iniziarono a manifestarsi i primi effetti dei dissesti che ancora oggi sono presenti nella zona absidale. Contestualmente al manifestarsi delle prime lesioni iniziarono, infatti, studi approfonditi per determinare le cause e definire interventi di ripristino e consolidamento. L\u2019intervento progettato, che riguarda la copertura della zona absidale, \ue8 stato definito tenendo in considerazione le criticit\ue0 strutturali che caratterizzano il Duomo ed in particolare il dissesto legato al cedimento gravitativo profondo della zona absidale. La filosofia progettuale adottata individua tre distinte aree di intervento, ciascuna caratterizzata da un diverso criterio di definizione delle opere e di controllo del dissesto in atto