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

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/

Spatial distribution of ions in a linear octopole radio-frequency ion trap in the space-charge limit

We have explored the spatial distribution of an ion cloud trapped in a linear octopole radio-frequency (rf) ion trap. The two-dimensional distribution of the column density of stored silver dimer cations was measured via photofragment-ion yields as a function of the position of the incident laser beam over the transverse cross section of the trap. The profile of the ion distribution was found to be dependent on the number of loaded ions. Under high ion-loading conditions with a significant space-charge effect, ions form a ring profile with a maximum at the outer region of the trap, whereas they are localized near the center axis region at low loading of the ions. These results are explained quantitatively by a model calculation based on equilibrium between the space-charge-induced potential and the effective potential of the multipole rf field. The maximum adiabaticity parameter \eta_max is estimated to be about 0.13 for the high ion-density condition in the present octopole ion trap, which is lower than typical values reported for low ion densities; this is probably due to additional instability caused by the space charge.Comment: 8 pages, 5 figure

Upper ocean manifestations of a reducing meridional overturning circulation

Most climate models predict a slowing down of the Atlantic Meridional Overturning Circulation during the 21st century. Using a 100year climate change integration of a high resolution coupled climate model, we show that a 5.3Sv reduction in the deep southward transport in the subtropical North Atlantic is balanced solely by a weakening of the northward surface western boundary current, and not by an increase in the southward transport integrated across the interior ocean away from the western boundary. This is consistent with Sverdrup balance holding to a good approximation outside of the western boundary region on decadal time scales, and may help to spatially constrain past and future change in the overturning circulation. The subtropical gyre weakens by 3.4Sv over the same period due to a weakened wind stress curl. These changes combine to give a net 8.7Sv reduction in upper western boundary transport. © 2012. American Geophysical Union. All Rights Reserved

Gewasmanagement in semi-gesloten kassen: Simulaties van gewasgroei en -ontwikkeling

Experimenten van het project ‘Gewasmanagement bij geconditioneerd telen’ zijn met het Intkam simulatiemodel doorgerekend om te analyseren welke klimaatfactor in welke mate verantwoordelijk is voor verschillen in productie

Description and Educational Impact of Pennsylvania\u27s Manure Hauler and Broker Certification Program

We describe Pennsylvania\u27s Commercial Manure Hauler and Broker Certification Program and discuss results of an industry survey. Survey knowledge questions were centered on state-mandated program competencies designed to minimize environmental losses of manure nutrients. Survey results demonstrated that participation in state-directed, Extension-led educational programming resulted in greater knowledge for those required to complete more rigorous certification education and for those exposed to more continuing education. Educational impact is expected to be far-reaching as survey respondents worked on an average of 38.5 farms annually. Extension\u27s role is critical in this certification program that endeavors to improve water quality

Production Technology and Competitiveness In the Hungarian Manufacturing Industry

Following the big transformations of the 1990s, enterprise structure and technological level seem to have become stabilised in Hungary. Under these circumstances it is especially interesting to identify the elements responsible for competitiveness in general, and the role technology plays in development in particular, according to managers experienced in production and marketing. This empirical study – based on in-depth interviews and field research – summarises characteristics of the technological level in the sectors examined, role of technology and labour in production, effects of foreign direct investment, relations between competition and firm-level factors determining competitiveness, and concludes by summing up those most frequently mentioned proposals that should be incorporated into economic policy according to managers. Main findings indicate that more qualified, more intensive and cheaper labour can be substituted for high technology. The competitiveness of an enterprise is not determined by technology alone, but rather by a combination of technology, the parameters of available labour and the costs of investment increasing productivity. The insufficiency of inter-company relations, together with a shortage of available assets necessary for investment constitute the major threat undermining the competitiveness of enterprises in present-day Hungary

A prototype system for observing the Atlantic Meridional Overturning Circulation - scientific basis, measurement and risk mitigation strategies, and first results

The Atlantic Meridional Overturning Circulation (MOC) carries up to one quarter of the global northward heat transport in the Subtropical North Atlantic. A system monitoring the strength of the MOC volume transport has been operating since April 2004. The core of this system is an array of moored sensors measuring density, bottom pressure and ocean currents. A strategy to mitigate risks of possible partial failures of the array is presented, relying on backup and complementary measurements. The MOC is decomposed into five components, making use of the continuous moored observations, and of cable measurements across the Straits of Florida, and wind stress data. The components compensate for each other, indicating that the system is working reliably. The year-long average strength of the MOC is 18.7±5.6 Sv, with wind-driven and density-inferred transports contributing equally to the variability. Numerical simulations suggest that the surprisingly fast density changes at the western boundary are partially linked to westward propagating planetary wave

Chimeric protein repair of laminin polymerization ameliorates muscular dystrophy phenotype

Mutations in laminin α2-subunit (Lmα2, encoded by LAMA2) are linked to approximately 30% of congenital muscular dystrophy cases. Mice with a homozygous mutation in Lama2 (dy2J mice) express a nonpolymerizing form of laminin-211 (Lm211) and are a model for ambulatory-type Lmα2-deficient muscular dystrophy. Here, we developed transgenic dy2J mice with muscle-specific expression of αLNNd, a laminin/nidogen chimeric protein that provides a missing polymerization domain. Muscle-specific expression of αLNNd in dy2J mice resulted in strong amelioration of the dystrophic phenotype, manifested by the prevention of fibrosis and restoration of forelimb grip strength. αLNNd also restored myofiber shape, size, and numbers to control levels in dy2J mice. Laminin immunostaining and quantitation of tissue extractions revealed increased Lm211 expression in αLNNd-transgenic dy2J mice. In cultured myotubes, we determined that αLNNd expression increased myotube surface accumulation of polymerization-deficient recombinant laminins, with retention of collagen IV, reiterating the basement membrane (BM) changes observed in vivo. Laminin LN domain mutations linked to several of the Lmα2-deficient muscular dystrophies are predicted to compromise polymerization. The data herein support the hypothesis that engineered expression of αLNNd can overcome polymerization deficits to increase laminin, stabilize BM structure, and substantially ameliorate muscular dystrophy

Elaborating a coiledâ coilâ assembled octahedral protein cage with additional protein domains

De novo design of protein nanoâ cages has potential applications in medicine, synthetic biology, and materials science. We recently developed a modular, symmetryâ based strategy for protein assembly in which short, coiledâ coil sequences mediate the assembly of a protein building block into a cage. The geometry of the cage is specified by the combination of rotational symmetries associated with the coiledâ coil and protein building block. We have used this approach to design wellâ defined octahedral and tetrahedral cages. Here, we show that the cages can be further elaborated and functionalized by the addition of another protein domain to the free end of the coiledâ coil: in this case by fusing maltoseâ binding protein to an octahedral protein cage to produce a structure with a designed molecular weight of ~1.8 MDa. Importantly, the addition of the maltose binding protein domain dramatically improved the efficiency of assembly, resulting in ~ 60â fold greater yield of purified protein compared to the original cage design. This study shows the potential of using small, coiledâ coil motifs as offâ theâ shelf components to design MDaâ sized protein cages to which additional structural or functional elements can be added in a modular manner.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146469/1/pro3497.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146469/2/pro3497_am.pd