Duchenne muscular dystrophy: From diagnosis to therapy

Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options

The stress shadow induced by the 1975-1984 Krafla rifting episode

It has been posited that the 1975\u20131984 Krafla rifting episode in northern Iceland was responsible for a significant drop in the rate of earthquakes along the H\ufasav\uedk\u2010Flatey Fault (HFF), a transform fault that had previously been the source of several magnitude 6\u20137 earthquakes. This compelling case of the existence of a stress shadow has never been studied in detail, and the implications of such a stress shadow remain an open question. According to rate\u2010state models, intense stress shadows cause tens of years of low seismicity rate followed by a faster recovery phase of rate increase. Here, we compare the long\u2010term predictions from a Coulomb stress model of the rifting episode with seismological observations from the SIL catalog (1995\u20132011) in northern Iceland. In the analyzed time frame, we find that the rift\u2010induced stress shadow coincides with the eastern half of the fault where the observed seismicity rates are found to be significantly lower than expected, given the historical earthquake activity there. We also find that the seismicity rates on the central part of the HFF increased significantly in the last 17 years, with the seismicity progressively recovering from west to east. Our observations confirm that rate\u2010state theory successfully describes the long\u2010term seismic rate variation during the reloading phase of a fault invested by a negative Coulomb stress. Coincident with this recovery, we find that the b\u2010value of the frequency\u2010magnitude distribution changed significantly over time. We conclude that the rift\u2010induced stress shadow not only decreased the seismic rate on the eastern part of the HFF but also temporarily modified how the system releases seismic energy, with more large magnitude events in proportion to small ones. This behavior is currently being overturned, as rift\u2010induced locking is now being compensated by tectonic forcing

A Traffic Merging and Generation Framework for Realistic Synthesis of Network Traffic

The Internet is steadily growing and is of increasing importance for our economy and society. Due to this increased importance it is also in the focus of attacks, e.g. distributed denial of service (DDoS) attacks. As attackers dynamically change their attack behaviour, novel detection approaches that are able to automatically adjust to these dynamic attacks are needed. To train and test such network anomaly detection systems, it is necessary to provide realistic data. As of today, this area of research suffers from the lack of publicly available datasets that can be used to train and test anomaly detection systems and are exchangeable to allow reproducible research. Therefore, we propose a novel framework that enables researchers and developers to generate customizable synthetic datasets. It not only allows to generate fully-synthetic network traffic, but also to generate semi-synthetic network traffic by merging of multiple network captures from reallive environments. Further, it allows the mapping of IP addresses as well as the modi﬿cation of other header ﬿elds, if desired. This enables researchers and developers to exchange network traces from sensitive environments without revealing any sensitive end-user related information, while perceiving the relevant characteristics of the network(s) and attack(s). In the following, we provide a description of, the problem, our concept and the features of our solution, the architecture and functional model and ﬿nally provide a short summary together with an outlook for future work

Characterisation of wine yeasts isolated at different temperatures using the enrichment technique

Research NoteSaccharomyces cerevisiae strains isolated from fermenting grape must incubated at extreme fermentation temperatures (40 and 5 degrees C) were oenologically characterised. These cultures compared with S. cerevisiae wine strains, show a wider optimum temperature for growth and can ferment vigorously in a wider temperature range (27 to 35 degrees C)

Beam Coupling Impedance Contribution of Flange Aperture Gaps: A Numerical Study for Elettra 2.0

The accurate analysis of any possible source of beam instability is mandatory for the design of a new particle accelerator, especially for high-current and ultra-low emittance synchrotrons. In the specific case of instabilities driven by the coupling between the charged particle beam and the electromagnetic field excited by the beam itself, the corresponding effect is estimated through the beam coupling impedance. The modeling of this effect is essential to perform a rigorous evaluation of the coupling impedance budget able to account for all devices present in the entire machine. To deal with this problem, this paper focuses on the estimation of the contribution of the joints lying between the different vacuum chamber sections, by performing a comparative numerical analysis that takes into account different aperture gaps between the flanges. The results point out the criticality of many small-impedance contributions that, added together, must be lower than a predefined impedance threshold

Synthesis, variable temperature NMR investigations and solid state characterisation of novel octafluorofluorene compounds

The preparation of a number of new 9-substituted octafluorofluorene derivatives, solution NMR studies, and the first examples of solid state structures of octafluorofluorenes [1,2,3,4,5,6,7,8-octafluorofluorene, C13H2F8, 1; 1,2,3,4,5,6,7,8-octafluoro-9-(pentafluoro)phenylfluorene, C19HF13, 8; 1,1′,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,8,8′-hexadecafluoro-9,9′-bifluorenyl, C26H2F16, 11] are reported. Variable temperature 19F NMR investigations have been performed on the 9-aryl substituted compounds 1,2,3,4,5,6,7,8-octafluoro-9-(pentafluoro)phenyl-9-hydroxyfluorene, C19HF13O, 4, 1,2,3,4,5,6,7,8-octafluoro-9-(nonafluoro-4′-biphenylyl)-9-hydroxyfluorene, C25HF17O, 5, and 8, and the energetic barriers to rotation of the aryl have been determined. A lower rotational barrier is observed for compound 4 with respect to compound 8, while 5 does not show fluxional behaviour below 338 K. The results of the variable temperature experiments performed on 8 have been rationalized by 2D NMR studies, and compared to the solid state data resulting from the X-ray structural analysis

Análise dos petrotramas de eixos-C de quartzo: Zona de Cisalhamento Major Gercino (SC)

The analysis of quartz c-axis improved the kinematic characterization of the Major Gercino Shear Zone (MGSZ) in the Canelinha - Garcia area in central-eastern Santa Catarina State. This shear zone is one of the major lineaments that affect ali southern Brazilian and Uruguaian precambrian terrains. In Santa Catarina the MGSZ separates supracrustal rocks of the Brusque Group (northern part) from the Granitoid-Migmatitic Complex to the south. This zone is characterized by a regional NE trend, a dextral sense of movement, and predominantly ductile-brittle structures. The MGSZ is composed of two mylonitic belts to the northwest and southeast, respectively, separated by granitoid rocks probably associated with the development of the shear zone. Both shear zones have cataclastic to ultramylonitc rocks, but mylonites and protomylonites predominate. Most of the mylonitic rocks were produced under greenschist facies metamorphic conditions and a high strain rate. Although sinistral displacement is often observed, most of the mesoscopic structures and kinematic indicators show a predominance of dextral movement with an important oblique component. The results of c-axis analyses in quartz-rich rocks are in good agreement with this interpretation and also indicate a coaxial deformation produced by pure shear strain as can be seen in the symmetric pattern of the prefered orientations of the c-axis in many of the diagrams obtained in the MGSZ, as well as indicated by the presence of local sinistrai shear movements. The mylonitic rocks of the MGSZ have crystallographic orientations developed at relatively low temperatures, as confirmed by the low-grade metamorphic conditions. In spite of the low temperatures, the orientation developed under a high strain rate as shown by the deformed and stretched minerais and the commom parallelism of S and C surfaces.Este trabalho visa apresentar as principais conclusões obtidas da utilização de petrotramas de eixos-c de quartzo, aplicadas ao estudo da Zona de Cisalhamento Major Gercino (ZCMG), no trecho Canelinha - Garcia, região centro-leste do Estado de Santa Catarina. Este lineamento faz parte do importante sistema de cisalhamento de direção NE-SW que afeta a região sul-brasileira e uruguaia. Ao longo de toda sua extensão, a ZCMG separa duas áreas geologicamente diferentes que correspondem, em Santa Catarina, aos domínios interno (granitóides) e intermediário (supracrustais) do Cinturão Dom Feliciano (CDF). Esta zona de cisalhamento possui estruturação geral NE, características dúcteis-rúpteis e movimentação predominantemente dextral. A geração das rochas miloníticas deu-se, principalmente, no grau metamórfico xisto-verde. Na região estudada, a ZCMG caracteriza-se por duas faixas miloníticas onde predominam rochas com texturas protomiloníticas e miloníticas. Entre essas faixas ocorre um conjunto de granitóides associado ao desenvolvimento da ZCMG. A faixa milonítica norte limita os metassedimentos do Grupo Brusque a noroeste dos granitóides centrais e a faixa milonítica sul faz o contato entre esses granitóides e as rochas do Complexo-Granito-Migmatítico (Domínio Interno do CDF). A componente coaxial é sugerida nos petrotramas de eixos-c de quartzo por concentrações simétricas em relação à foliação milonítica, bem como pela existência de porfiroclastos simétricos em seções delgadas. A componente da deformação por cisalhamento puro pode ter acarretado, em inflexões locais, movimentações sinistrais. As rochas milomticas da ZCMG apresentam orientação cristalográfica desenvolvida sob temperaturas relativamente baixas, indicada pelo metamorfismo no fácies xisto-verde e pelos petrotramas. Apesar da baixa temperatura, o processo de cisalhamento ocorreu em condições de alta taxa de deformação, evidenciada pela presença de minerais deformados e estirados e pela geração de rochas milomticas e ultramiloníticas, onde comumente ocorre total paralelização das superfícies S e C

Multivariate analysis of 3D ToF-SIMS images: method validation and application to cultured neuronal networks

Advanced data analysis tools are crucial for the application of ToF-SIMS analysis to biological samples. Here, we demonstrate that by using a training set approach principal components analysis (PCA) can be performed on large 3D ToF-SIMS images of neuronal cell cultures. The method readily provides access to sample component information and significantly improves the images’ signal-to-noise ratio (SNR)

Unusual Skin Toxicity after a Chemotherapic Combination

As known calciphylaxis (CPX) is a rare condition involving subcutaneous vascular calcification and cutaneous necrosis, mostly observed in patients with renal failure. However CPX may also appear in patients affected by polymyositis, Sjogren syndrome, Lupus Erythematosus systemicus, Sarcoidosis and rheumatoid arthritis, especially in children. Clinically CPX can present itself as subcutaneous nodules, infiltrate plaques or purpuric-like and livedo-like plaques, while in the late stages necrotic ulcers (with a bizarre shape and severe pain) may be the main cutaneous manifestations

Flunitrazepam Excretion Patterns using the Abuscreen OnTrak and OnLine Immunoassays: Comparison with GC-MS

A study was conducted to compare the performance of the OnLine and OnTrak immunoassays for benzodiazepines with gas chromatographic-mass spectrometric (GC-MS) analysis in detecting flunitrazepam (FNP) and its metabolites in human urine. Urine was collected over a 72-h period from six individuals (four male and two female) who had taken a single oral dose of either 1 or 4 mg of FNP. The OnTrak assay was run at a 100-ng/mL cutoff of nordiazepam (NDP), and the OnLine assay was run with a standard curve from zero to 200 ng/mL of NDP with and without β-glucuronidase treatment. Each sample was analyzed by GC-MS using FNP, 7-amino-FNP, 3-hydroxy-FNP, desmethyl-FNP, 7-amino-3-hydroxy-FNP, and desmethyl-3-hydroxy-FNP as standards with β-glucuronidase treatment. The specimens from the 1-mg dose did not yield a positive result by immunoassay over the 72-h collection period. Specimens from the 4-mg dose did yield positive results in both immunoassays. The time of the first positive result ranged from 4 to 12 h, and the time to the last positive result ranged from 18 to 60 h. Treatment of the samples with β-glucuronidase increased the OnLine values between 20 and 60%, but it did not appreciably increase the detection time. GC-MS analysis showed no detectable levels of FNP, 3-hydroxy-FNP, desmethyl-FNP, 7-amino-3-hydroxy-FNP, and desmethyl-3-hydroxy-FNP. However, all samples collected past time zero showed detectable levels of 7-amino-FNP (> 2 ng/mL) with peak concentrations at 12-36 h. The peak levels of 7-amino-FNP by GC-MS paralleled the peak levels of the immunoassay response. The amount of 7-amino-FNP metabolite quantitated by GC-MS, however, accounted for only 15-20% of the total immunoassay crossreactive FNP metabolite