Evidence of mild founder LMOD3 mutations causing nemaline myopathy 10 in Germany and Austria

Objective To expand the clinical and genetic spectrum of nemaline myopathy 10 by a series of Austrian and German patients with a milder disease course and missense mutations in LMOD3. Methods We characterized the clinical features and the genetic status of 4 unrelated adolescent or adult patients with nemaline myopathy. Results The 4 patients showed a relatively mild disease course. They all have survived into adulthood, 3 of 4 have remained ambulatory, and all showed marked facial weakness. Muscle biopsy specimens gave evidence of nemaline bodies. All patients were unrelated but originated from Austria (Tyrol and Upper Austria) and Southern Germany (Bavaria). All patients carried the missense variant c.1648C>T, p.(Leu550Phe) in the LMOD3 gene, either on both alleles or in trans with another missense variant (c.1004A>G, p.Gln335Arg). Both variants were not reported previously. Conclusions In 2014, a severe form of congenital nemaline myopathy caused by disrupting mutations in LMOD3 was identified and denoted as NEM10. Unlike the previously reported patients, who had a severe clinical picture with a substantial risk of early death, our patients showed a relatively mild disease course. As the missense variant c.1648C>T is located further downstream compared to all previously published LMOD3 mutations, it might be associated with higher protein expression compared to the reported loss-of-function mutations. The apparent clusters of 2 mild mutations in Germany and Austria in 4 unrelated families may be explained by a founder effect

Optical calibration and performance of the adaptive secondary mirror at the Magellan telescope

In this paper we describe the procedure for the optical calibration of large size deformable mirrors, acting as wavefront correctors for adaptive optics systems. Adaptive optics compensate the disturbance due to the atmospheric turbulence to restore the telescope resolution. We will showcase in particular the activities performed for the Adaptive Secondary Mirror (ASM) of the Magellan Adaptive Optics system (MagAO), which is an instrument for the 6.5 m Magellan Clay Telescope, located at Las Campanas Observatory, in Chile. The MagAO ASM calibration is part of the MagAO-2K project, a major MagAO upgrade that started in 2016 with the goal of boosting adaptive optics (AO) correction at visible wavelengths to image exoplanets. For the first time, the optical quality of MagAO mirror is reported. We describe the procedures developed to achieve high SNR interferometric measurements of the ASM modes under the presence of dome convection noise and telescope vibrations. These measurements were required to produce an improved control matrix with up to 500 modes to close the AO loop on sky with enhanced performances. An updated slaving algorithm was developed to improve the control of actuators vignetted by the central obscuration. The calibrations yielded also a new ASM flattening command, updating the one in use since the MagAO commissioning in 2013. With the new flattening command, a 22 nm RMS surface error was achieved. Finally, we present on-sky results showing the MagAO performance achieved with the new calibrations

Assemblathon 2: evaluating de novo methods of genome assembly in three vertebrate species

Background: The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results: In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. Conclusions: Many current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another

Evaluation of the haemostatic potential of factor VIII-heparin cofactor II hybrid proteins in a mouse model

We constructed factor VIII-heparin cofactor II (FVIII-HCII) hybrid molecules, which are more readily activated by thrombin in vitro than the respective wild-type molecules. The hybrid proteins were tested in a murine model of haemophilia A to investigate their haemostatic efficacy in vivo. Bleeding characteristics, measured using standard tail-tip cutting techniques, were total blood loss, bleeding time and survival rate. FVIII-HCII hybrids were found to be effective in preventing bleeding in FVIII knockout mice. While in vitro experiments showed that the chimaeric molecules had higher haemostatic functions than the wild-type proteins, the variables analysed in vivo were similar for both protein