Artificial restoration of the linkage between laminin and dystroglycan ameliorates the disease progression of MDC1A muscular dystrophy at all stages

Laminin-α2 deficient congenital muscular dystrophy, classified as MDC1A, is a severe progressive muscle-wasting disease that leads to death in early childhood. MDC1A is caused by mutations in lama2, the gene encoding the laminin-α2 chain being part of laminin-2, the main laminin isoform present in the extracellular matrix of muscles and peripheral nerves. Via selfpolymerization, laminin-2 forms the primary laminin scaffold and binds with high affinity to α- dystroglycan on the cell surface, providing a connection to the cytoskeleton via the transmembranous protein β-dystroglycan. Deficiency in laminin-α2 leads to absence of laminin-2 and to upregulation of laminin-8, a laminin isoform that cannot self-polymerize and does not bind to α-dystroglycan. Therefore, in laminin α2-deficient muscle the chain of proteins linking the intracellular contractile apparatus via the plasma membrane to the extracellular matrix is interrupted. Consequently, muscle fibers loose their stability and degenerate what finally leads to a progressive muscle wasting. In previous studies, we have shown that a miniaturized form of the extracellular matrix protein agrin, which is not related to the disease-causing lama2 gene and was designed to contain highaffinity binding sites for the laminins and for α-dystroglycan, was sufficient to markedly improve muscle function and overall health in the dyW-/- mouse model of MDC1A. In a follow-up study we provided additional evidence that mini-agrin, both increases the tolerance to mechanical load but also improves the regeneration capacity of the dystrophic muscle. We now report on our progress towards further testing the use of this approach for the treatment of MDC1A. To test whether mini-agrin application after onset of the disease would still ameliorate the dystrophic symptoms, we have established the inducible tetracycline-regulated “tet-off” expression system in dyW-/- mice to temporally control mini-agrin expression in skeletal muscles. We show that mini-agrin slows down the progression of the dystrophy when applied at birth or in advanced stages of the disease. However, the extent of the amelioration depends on the dystrophic condition of the muscle at the time of mini-agrin application. Thus, the earlier miniagrin is applied, the higher is the profit of its beneficial properties. In addition to gene therapeutical approaches, the increase of endogenous agrin expression levels in skeletal muscles by pharmacologically active compounds would be a safe and promising strategy for the treatment of MDC1A. To evaluate the potential and pave the way to further expand on the development of such a treatment, we determined whether full-length agrin ameliorates the dystrophic phenotype to a comparable extent as it was observed by application of mini-agrin. We provide evidence that constitutive overexpression of chick full-length agrin in dyW-/- muscle ameliorates the dystrophic phenotype, although not as pronounced as mini-agrin does. In conclusion, our results are conceptual proof that linkage of laminin to the muscle fiber membrane is a means to treat MDC1A at any stage of the disease. Our findings definitely encourage to further expanding on this therapeutic concept, especially in combination with treatment using functionally different approaches. Moreover, these experiments set the basis for further developing clinically feasible and relevant application methods such as gene therapy4 and/or the screening of small molecules able to upregulate production of agrin in muscle

Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-alpha2-deficient congenital muscular dystrophy (MDC1A)

BACKGROUND: Laminin-alpha2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-beta and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. METHODS: L-158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. RESULTS: We found that TGF-beta signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. CONCLUSION: These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A

Nuclear dimension and Z-stability of pure C*-algebras

In this article I study a number of topological and algebraic dimension type properties of simple C*-algebras and their interplay. In particular, a simple C*-algebra is defined to be (tracially) (m,\bar{m})-pure, if it has (strong tracial) m-comparison and is (tracially) \bar{m}-almost divisible. These notions are related to each other, and to nuclear dimension. The main result says that if a separable, simple, nonelementary, unital C*-algebra A with locally finite nuclear dimension is (m,\bar{m})-pure, then it absorbs the Jiang-Su algebra Z tensorially. It follows that A is Z-stable if and only if it has the Cuntz semigroup of a Z-stable C*-algebra. The result may be regarded as a version of Kirchberg's celebrated theorem that separable, simple, nuclear, purely infinite C*-algebras absorb the Cuntz algebra O_\infty tensorially. As a corollary we obtain that finite nuclear dimension implies Z-stability for separable, simple, nonelementary, unital C*-algebras; this settles an important case of a conjecture by Toms and the author. The main result also has a number of consequences for Elliott's program to classify nuclear C*-algebras by their K-theory data. In particular, it completes the classification of simple, unital, approximately homogeneous algebras with slow dimension growth by their Elliott invariants, a question left open in the Elliott-Gong-Li classification of simple AH algebras. Another consequence is that for simple, unital, approximately subhomogeneous algebras, slow dimension growth and Z-stability are equivalent. In the case where projections separate traces, this completes the classification of simple, unital, approximately subhomogeneous algebras with slow dimension growth by their ordered K-groups.Comment: 65 pages. Terminology and title have been changed; the term "perfect" has been replaced by "pure" throughout. To appear in Inventione

Goods Follow Bytes: The Impact of ICT on EU Trade

This paper empirically assesses whether the deployment and use of Information and Communication Technology (ICT) infrastructure at the national level affects trade flows within the European Union (EU) and between the EU and its main trading partners. The analysis tests the hypothesis that availability and use of ICT enhances trade by reducing transaction costs and through network effects that materialize when both trading partners are advanced users of ICT. The empirical analysis is based on the application of gravity equations in various robust specifications. The results suggest that ICT does have a significant impact on EU trade. In particular, we find trade to be enhanced if both trading partners reveal advanced ICT endowments, which supports the expected network effects. Additionally, we observe trade diversion effects from less to highly ICT developed countries.Exports, ICT, gravity model, international trade, network effects

Muscular dystrophy meets protein biochemistry, the mother of invention

Muscular dystrophies result from a defect in the linkage between the muscle fiber cytoskeleton and the basement membrane (BM). Congenital muscular dystrophy type MDC1A is caused by mutations in laminin α2 that either reduce its expression or impair its ability to polymerize within the muscle fiber BM. Defects in this BM lead to muscle fiber damage from the force of contraction. In this issue of the JCI, McKee and colleagues use a laminin polymerization–competent, designer chimeric BM protein in vivo to restore function of a polymerization-defective laminin, leading to normalized muscle structure and strength in a mouse model of MDC1A. Delivery of such a protein to patients could ameliorate many aspects of their disease

Eddy Impacts on the Florida Current

The Gulf Stream in the Atlantic carries warm water northwards and forms both the return closure of the subtropical gyre as well as the upper limb of the meridional overturning circulation. Recent time series recorded east of the Bahamas at 26°N indicate that from May 2009 to April 2011, in contrast with past observations, the northward flowing Antilles Current covaried with the Gulf Stream in the Florida Straits—the Florida Current—even though the Florida and Antilles Currents are separated by banks and islands spanning 150?km. The peak-to-trough amplitude of transport variations during this period was 15?×?106?m3?s?1 for the Florida Current and 12?×?106?m3?s?1 for the Antilles Current, at time scales of 50?days to a year. From satellite observations, we show that the fluctuations in both the Florida and Antilles Currents between May 2009 and April 2011 are driven by eddy activity east of the Bahamas. Since the Florida Current time series is a critical time series for the state of the oceans, and often compared to climate models, this newly identified source of variability needs careful consideration when attributing the variability of the Florida Current to changes in the larger-scale circulations (e.g., gyre and overturning) or wind forcing.<br/

Strong Mixing and Recirculation in the Northwestern Argentine Basin

The Atlantic component of the Meridional Overturning Circulation (AMOC) is a key contributor to the global meridional transport of volume, salt, and heat, and thus plays a central role in global climate. As part of ongoing efforts to monitor the intensity and variability of the AMOC in the South Atlantic, hydrographic sections have been regularly occupied since 2009 near the western boundary along a zonal line at 34.5°S. Here this high-quality, high-resolution data set is analyzed to establish the average hydrographic conditions of the northwestern Argentine Basin and the water mass spatial and temporal variability. The water mass analysis also reveals the pathways of the flow in this region, which are further corroborated by full-depth direct velocity measurements. The repeated hydrographic sections capture an extremely rich vertical structure, characterized by seven distinct water mass layers of northern and southern origin, each with unique property signatures. Almost all of these layers exhibit a sharp zonally banded structure, which is indicative of recirculation cells offshore from the western boundary. The circulation at intermediate levels includes a previously undetected recirculation cell confined very close to the western boundary and superimposed on the classical intermediate water pathway beneath the South Atlantic subtropical gyre. The deep level flow is characterized by the Deep Western Boundary Current (DWBC) and a northward recirculation ~500 km east from the slope.Fil: Valla, Daniel. Ministerio de Defensa. Armada Argentina. Servicio de Hidrografía Naval; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias de la Atmósfera y los Océanos; ArgentinaFil: Piola, Alberto Ricardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias de la Atmósfera y los Océanos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Ministerio de Defensa. Armada Argentina. Servicio de Hidrografía Naval; ArgentinaFil: Meinen, Christopher S.. Atlantic Oceanographic and Meteorological Laboratory; Estados UnidosFil: Campos, Edmo. Universidade de Sao Paulo; Brasi

FTIR-ATR spectroscopy – a new approach in root discrimination of crop and weed species

Crop and weed species often compete for the same resources. To analyse below-ground competitive processes, crop and weed roots have to be distinguished from one another. Up to now, a reliable and easy method for plant root discrimination does not exist. In a recent study, Fourier transform infrared (FTIR) spectroscopy with an attenuated total reflection (ATR) device was successfully applied in root discrimination of distantly related plant species (pea/oat). In this experiment, we wanted to test the potential of FTIR-ATR spectroscopy to discriminate roots of closely related crop/weed-combinations. In a greenhouse experiment, two crop and associated weed species were cultivated: Maize/barnyard grass (Zea mays/Echinochloa crus-galli) and sugar beet/common lambsquarters (Beta vulgaris/Chenopodium album). To allow inter- and intra-specific competition, plants were grown sole and in crop/weed-combinations. Six weeks after sowing, root biomass was harvested and rinsed with water to remove soil particles. The absorbance patterns of fresh and dry rootlets were recorded by FTIRATR spectroscopy. Spectra of fresh rootlets within one plant family showed similar peak distribution, while dry rootles differ in peak location and height. Cluster analyses grouped the absorbance patterns of the dry crop and weed roots according to their similarity and revealed a complete root discrimination of crop and weed species. Keywords: Beta vulgaris, Chenopodium album, Echinochloa crus-galli, spectral distribution, Zea maysFTIR-ATR Spektroskopie – ein neuer Ansatz zur Wurzelunterscheidung von Nutzpflanzen- und UnkrautartenNutzpflanzen und Unkräuter konkurrieren häufig um die gleichen Ressourcen. Eine Voraussetzung zur Untersuchung von unterirdischer Konkurrenz ist, dass Wurzeln von Nutzpflanzen- und Unkrautarten unterschieden werden können. Eine schnelle und einfache Methode hierzu existiert bisher nicht. In einer früheren Studie wurde Fourier Transform Infrarot (FTIR) Spektroskopie mit abgeschwächter Totalreflektion (ATR) erfolgreich zur Wurzelunterscheidung bei entfernt verwandten Pflanzenarten (Erbse/Hafer) angewendet. In diesem Experiment wollten wir das Potenzial der FTIR-ATR Spektroskopie zur Wurzelunterscheidung bei nahverwandten Nutzpflanze/Unkraut-Kombinationen testen. In einem Gefäßversuch wurden Mais/Gemeine Hühnerhirse (Zea mays/Echinochloa crus-galli) sowie Zuckerrübe/Weißer Gänsefuß (Beta vulgaris/ Chenopodium album) angezogen. Um inter- und intraspezifische Konkurrenz zu ermöglichen, sind die Pflanzen einzeln und in Nutzpflanze/Unkraut-Kombinationen gewachsen. Sechs Wochen nach dem Säen wurden Wurzelsegmente geerntet und mit Wasser von Erdpartikeln gereinigt. Die Absorptionsmuster der frischen und getrockneten Wurzelstücke wurden mittels FTIR-ATR Spektroskopie erfasst. Die Spektren der frischen Wurzeln einer Pflanzenfamilie zeigten ähnliche Peakverteilungen und Peakhöhen, während getrocknete Wurzelstücke unterschiedliche Absorptionsmuster aufwiesen. Eine Clusteranalyse gruppierte die Spektren hinsichtlich ihrer Ähnlichkeit. Diese Analyse zeigte eine komplette Auftrennung der getrockneten Wurzelstücke entsprechend ihrer Artzugehörigkeit. Stichwörter: Beta vulgaris, Chenopodium album, Echinochloa crus-galli, spektrale Verteilung, Zea may

Literatura: por que ler para as crianças na educação infantil?

Trabalho de Conclusão do Curso de Especialização em Educação Infantil - primeira Edição – Polo Chapecó, para a obtenção do Grau de Especialista em Educação Infantil.O presente artigo foi elaborado a partir de uma prática de intervenção pedagógica realizada como critério para a conclusão do Curso de Especialização em Educação Infantil, da Universidade Federal de Santa Catarina. O projeto de intervenção tinha como tema a Literatura Infantil. Para o planejamento e a realização da prática buscou-se orientação teórica na abordagem histórico-cultural, teoria que também orientou a análise dos resultados da intervenção. Dentre os objetivos, constava analisar as contribuições da leitura dos clássicos da Literatura Infantil e de livros contemporâneos, para a aprendizagem e o desenvolvimento das crianças na Educação Infantil. Também tinha-se por objetivos: contribuir para o desenvolvimento da imaginação criadora nas crianças; contribuir para que as crianças tornemse leitores e apreciadores de livros; possibilitar às crianças a vivência de diferentes emoções e a apropriação de valores, por meio da leitura e vivência de histórias infantis; bem como analisar as contribuições dos livros infantis para o processo de humanização das crianças na Educação Infantil. Os resultados das análises da pesquisa intervenção indicam que a prática realizada contribuiu para o desenvolvimento da imaginação criadora nas crianças e também para que as crianças tornem-se leitores e apreciadores de livros. Possibilitou-se também às crianças a vivência de diferentes emoções assim como a apropriação de valores, como por exemplo, solidariedade, bondade, lealdade e honestidade. Entende-se que os livros de histórias infantis podem contribuir para o processo de humanização das crianças na Educação Infantil, contudo enfatiza-se a responsabilidade que tem um educador ao fazer a escolha dos livros

A Gravity Investigation of the Fayette Structural Zone and Surrounding Area, Northeast Iowa

A gravity survey was conducted over approximately 2600 square kilometers of northeast Iowa. The survey was undertaken to provide detailed gravity coverage at approximately one mile intervals and to investigate the sources of gravity anomalies in the study area. An additional objective was to verify with gravity data the presence of the Fayette Structural Zone, previously identified on the basis of magnetic linears. Four hundred and twenty-seven gravity stations were occupied and data from these stations combined with extant data from the Geological Survey Bureau of the Iowa Department of Natural Resources to produce the gravity interpretation. A Bouger gravity anomaly map was prepared and profile analysis undertaken to examine the source-configuration of intrusive bodies located within the basement of the study area. The gravity data, when combined with available magnetic and drill hole information, indicate a predominantly felsic basement with several gabbro and ultramafic intrusive bodies. Modeling of the gravity data failed to confirm either faulting or a dike at the presumed location of the Fayette Structural zone