ALBERT

Description: In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin α M β 2 -mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fib 390-396A ) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the α M β 2 binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/α M β 2 blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-α M β 2 interactions may provide a novel strategy for DMD treatment.

Description: SUMMARY Joint interpretation of models from seismic tomography and inversion of magnetotelluric (MT) data is an efficient approach to determine the lithology of the subsurface. Statistical methods are well established but were developed for only two types of models so far (seismic P velocity and electrical resistivity). We apply self-organizing maps (SOMs), which have no limitations in the number of parameters considered in the joint interpretation. Our SOM method includes (1) generation of data vectors from the seismic and MT images, (2) unsupervised learning, (3) definition of classes by algorithmic segmentation of the SOM using image processing techniques and (4) application of learned knowledge to classify all data vectors and assign a lithological interpretation for each data vector. We apply the workflow to collocated P velocity, vertical P -velocity gradient and resistivity models derived along a 40 km profile around the geothermal site Groß Schönebeck in the Northeast German Basin. The resulting lithological model consists of eight classes covering Cenozoic, Mesozoic and Palaeozoic sediments down to 5 km depth. There is a remarkable agreement between the litho-type distribution from the SOM analysis and regional marker horizons interpolated from sparse 2-D industrial reflection seismic data. The most interesting features include (1) characteristic properties of the Jurassic (low P -velocity gradients, low resistivity values) interpreted as the signature of shales, and (2) a pattern within the Upper Permian Zechstein layer with low resistivity and increased P -velocity values within the salt depressions and increased resistivity and decreased P velocities in the salt pillows. The latter is explained in our interpretation by flow of less dense salt matrix components to form the pillows while denser and more brittle evaporites such as anhydrite remain in place during the salt mobilization.

Description: The EPICOLON consortium was initiated in 1999 by the Gastrointestinal Oncology Group of the Spanish Gastroenterology Association. It recruited consecutive, unselected, population-based colorectal cancer (CRC) cases and control subjects matched by age and gender without personal or familial history of cancer all over Spain with the main goal of gaining knowledge in Lynch syndrome and familial CRC. This epidemiological, prospective and multicentre study collected extensive clinical data and biological samples from ~2000 CRC cases and 2000 controls in Phases 1 and 2 involving 25 and 14 participating hospitals, respectively. Genetic susceptibility projects in EPICOLON have included candidate-gene approaches evaluating single-nucleotide polymorphisms/genes from the historical category (linked to CRC risk by previous studies), from human syntenic CRC susceptibility regions identified in mouse, from the CRC carcinogenesis-related pathways Wnt and BMP, from regions 9q22 and 3q22 with positive linkage in CRC families, and from the mucin gene family. This consortium has also participated actively in the identification 5 of the 16 common, low-penetrance CRC genetic variants identified so far by genome-wide association studies. Finishing their own pangenomic study and performing whole-exome sequencing in selected CRC samples are among EPICOLON future research prospects.

Description: The ability to specifically engineer the genome of living cells at precise locations using rare-cutting designer endonucleases has broad implications for biotechnology and medicine, particularly for functional genomics, transgenics and gene therapy. However, the potential impact of chromosomal context and epigenetics on designer endonuclease-mediated genome editing is poorly understood. To address this question, we conducted a comprehensive analysis on the efficacy of 37 endonucleases derived from the quintessential I-CreI meganuclease that were specifically designed to cleave 39 different genomic targets. The analysis revealed that the efficiency of targeted mutagenesis at a given chromosomal locus is predictive of that of homologous gene targeting. Consequently, a strong genome-wide correlation was apparent between the efficiency of targeted mutagenesis (≤0.1% to ~6%) with that of homologous gene targeting (≤0.1% to ~15%). In contrast, the efficiency of targeted mutagenesis or homologous gene targeting at a given chromosomal locus does not correlate with the activity of individual endonucleases on transiently transfected substrates. Finally, we demonstrate that chromatin accessibility modulates the efficacy of rare-cutting endonucleases, accounting for strong position effects. Thus, chromosomal context and epigenetic mechanisms may play a major role in the efficiency rare-cutting endonuclease-induced genome engineering.

Description: We present a dual tableau system, $$\mathcal{R}$$ $$\mathcal{L}$$ $$\mathcal{K}$$ , which is itself a deterministic decision procedure verifying validity of K -formulas. The system is constructed in the framework of the original methodology of relational proof systems, determined only by axioms and inference rules, without any external techniques. Furthermore, we describe an implementation of the system $$\mathcal{R}$$ $$\mathcal{L}$$ $$\mathcal{K}$$ in Prolog, and we show some of its advantages.

Description: Vitamin D deficiency is associated with the high risk of colon cancer and a variety of other diseases. The active vitamin D metabolite 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) regulates gene transcription via its nuclear receptor (VDR), and posttranscriptional regulatory mechanisms of gene expression have also been proposed. We have identified microRNA-22 (miR-22) and several other miRNA species as 1,25(OH) 2 D 3 targets in human colon cancer cells. Remarkably, miR-22 is induced by 1,25(OH) 2 D 3 in a time-, dose- and VDR-dependent manner. In SW480-ADH and HCT116 cells, miR-22 loss-of-function by transfection of a miR-22 inhibitor suppresses the antiproliferative effect of 1,25(OH) 2 D 3 . Additionally, miR-22 inhibition increases cell migration per se and decreases the antimigratory effect of 1,25(OH) 2 D 3 in both cell types. In silico analysis shows a significant overlap between genes suppressed by 1,25(OH) 2 D 3 and miR-22 putative target genes. Consistently, miR-22 inhibition abrogates the 1,25(OH) 2 D 3 -mediated suppression of NELL2 , OGN, HNRPH1, RERE and NFAT5 genes. In 39 out of 50 (78%) human colon cancer patients, miR-22 expression was found lower in the tumour than in the matched normal tissue and correlated directly with that of VDR. Our results indicate that miR-22 is induced by 1,25(OH) 2 D 3 in human colon cancer cells and it may contribute to its antitumour action against this neoplasia.

Description: SUMMARY Joint interpretation of models from seismic tomography and inversion of magnetotelluric (MT) data is an efficient approach to determine the lithology of the subsurface. Statistical methods are well established but were developed for only two types of models so far (seismic P velocity and electrical resistivity). We apply self-organizing maps (SOMs), which have no limitations in the number of parameters considered in the joint interpretation. Our SOM method includes (1) generation of data vectors from the seismic and MT images, (2) unsupervised learning, (3) definition of classes by algorithmic segmentation of the SOM using image processing techniques and (4) application of learned knowledge to classify all data vectors and assign a lithological interpretation for each data vector. We apply the workflow to collocated P velocity, vertical P -velocity gradient and resistivity models derived along a 40 km profile around the geothermal site Groß Schönebeck in the Northeast German Basin. The resulting lithological model consists of eight classes covering Cenozoic, Mesozoic and Palaeozoic sediments down to 5 km depth. There is a remarkable agreement between the litho-type distribution from the SOM analysis and regional marker horizons interpolated from sparse 2-D industrial reflection seismic data. The most interesting features include (1) characteristic properties of the Jurassic (low P -velocity gradients, low resistivity values) interpreted as the signature of shales, and (2) a pattern within the Upper Permian Zechstein layer with low resistivity and increased P -velocity values within the salt depressions and increased resistivity and decreased P velocities in the salt pillows. The latter is explained in our interpretation by flow of less dense salt matrix components to form the pillows while denser and more brittle evaporites such as anhydrite remain in place during the salt mobilization.

Description: Intrusive rocks related to porphyry copper mineralization are part of the wide diversity of subduction-related, mantle-derived, igneous rocks generated in convergent margin settings. What differentiates them from barren igneous rocks results ultimately from the multi-component and multi-stage processes that condition magma composition in these settings. Unfortunately, the petrogenetic history is largely obscured by the pervasive alteration that affects rocks in these deposits. We address this issue through the study of zircon grains from El Teniente, one of the largest known porphyry Cu–Mo deposits in the world. El Teniente belongs to the Miocene–Pliocene Cu–Mo belt of the Central Chilean Andes, which formed in a short timespan during the Cenozoic constructive period of the orogen. Previously U–Pb dated zircon grains were selected for re-examination of their morphological characteristics and in situ analysis of chemical (rare earth element, Hf, Y and Ti contents) and isotopic (Hf, O) composition. They are from six intermediate to felsic syn- to late-mineralization, intrusive units covering a timespan of ~1·6 Myr. The El Teniente zircons have compositional and morphological characteristics indicating crystallization from a series of cogenetic melts. However, a minor hydrothermal imprint is documented in the presence of crystals with mottled surfaces that correspond to thin high U–Th overgrowth rims (low-luminescent features in cathodoluminescence images). In terms of any other chemical and isotopic characteristic, these are indistinguishable from the main mineral populations. Zircons define morphological and chemical trends reflecting an evolution towards more differentiated magma compositions, lower crystallization temperatures and increased cooling rates with decreasing age of intrusion. Hf and O isotopic compositions are remarkably uniform at grain, sample and deposit scale. This, together with the general absence of older inherited zircon components, the lack of correlations between isotopic signature and whole-rock composition and high initial Hf values (total average 7·4 ± 1·2; 2), rules out involvement of any significant crustal contamination in the genesis of the El Teniente magmas. The Hf isotopic composition indicates a relatively juvenile source, but with some crustal residence time. The 18 O Zrc weighted mean of 4·76 ± 0·12 (2; 61 analyses) is at the lower limit of the normal mantle zircon range of 5·3 ± 0·6 (2), and might reflect crystallization from low- 18 O magmas. Hf isotopic compositions have a restricted range in initial Hf values between +6 and +10, identical to preceding Cenozoic barren magmatic activity in Central Chile. These igneous rocks are the product of nearly 25 Myr of subduction-related magmatic activity, developed under contrasting tectonic regimes and margin configurations. This suggests a primary control of the isotopic signature by a stable long-lived MASH-type (melting, assimilation, storage and homogenization) reservoir in the deep lithosphere. In the context of the Cenozoic evolution of Central Chile we argue that dehydration melting in the enriched MASH reservoir occurred as a consequence of increasing crustal thickness, and was prompted by a high-temperature thermal regime resulting from long-lasting preceding magmatism. This process can also fractionate O to generate low- 18 O magmas. At the time of El Teniente formation, dehydration melting occurred coevally with arc migration, which probably influenced the fertility of the magmas by increasing the melt component derived from this process relative to the component derived from primary basalt differentiation. At a regional scale, such reactions are expected to occur as a consequence of progressive crustal thickening during the constructive period of the Andes, and can explain the simultaneous generation of porphyry deposits in the Miocene–Pliocene Cu–Mo belt of Central Chile.

Description: In this paper, we study the set of periods of (chaotic) strongly continuous semigroups. We prove a relationship between eigenvalues on the imaginary axis of the generator of a strongly continuous semigroup and the set of periods of the semigroup itself. This relationship in turn is used to obtain information about the structure of the set of periods and to construct (chaotic) semigroups with prescribed periods.

Description: Security is considered one of the crucial issues for the widespread adoption of cloud computing. Despite all research done in preventive security for cloud computing, the high complexity and the interdependence of many software layers and infrastructures mean that in practice there are always chances for something going wrong. For this reason, there is a need to complement preventive security measures with reactive measures. Among these, monitoring is the most relevant approach. In this paper, we introduce a new and robust architecture for dynamic security monitoring and enforcement specially designed for cloud computing scenarios. Our solution is therefore a complete one including a three-layered architecture, a new language for expressing monitoring rules and a strategy based on the generation of a finite-state machine to improve the performance of the monitoring engine.