Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies

History, Commemoration, and Belief: Abraham Lincoln in American Memory, 1945-2001

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91765/1/Schuman-History_Commemoration_Belief.pd

Sensitive gene expression profiling of human T cell subsets reveals parallel post-thymic differentiation for CD4+ and CD8+ lineages.

The differentiation of CD4(+) or CD8(+) T cells following priming of naive cells is central in the establishment of the immune response against pathogens or tumors. However, our understanding of this complex process and the significance of the multiple subsets of differentiation remains controversial. Gene expression profiling has opened new directions of investigation in immunobiology. Nonetheless, the need for substantial amount of biological material often limits its application range. In this study, we have developed procedures to perform microarray analysis on amplified cDNA from low numbers of cells, including primary T lymphocytes, and applied this technology to the study of CD4 and CD8 lineage differentiation. Gene expression profiling was performed on samples of 1000 cells from 10 different subpopulations, defining the major stages of post-thymic CD4(+) or CD8(+) T cell differentiation. Surprisingly, our data revealed that while CD4(+) and CD8(+) T cell gene expression programs diverge at early stages of differentiation, they become increasingly similar as cells reach a late differentiation stage. This suggests that functional heterogeneity between Ag experienced CD4(+) and CD8(+) T cells is more likely to be located early during post-thymic differentiation, and that late stages of differentiation may represent a common end in the development of T-lymphocytes

Influence of tests results on serial production of EXFEL superconducting cavities

The European XFEL (EXFEL) 1.3 GHz cavities were produced without any final cold RF performance guarantee for characteristics like accelerating gradient, quality factor or field emission. In the case of low-performance, DESY provided all re-treatment procedures in order to improve these characteristics getting closer to specification levels. But EXFEL cavities have very tight tolerances for the parameters like cavity length, cells eccentricity, fundamental mode frequency and field distribution on the operational mode. Usage of modern infrastructure, analytical methods and powerful tools of the database analysis allows us not only keeping these characteristics in specified ranges, but also investigate the cavity shape uncertainties and improve the damping of the higher order modes

Production of Superconducting 1.3-GHz Cavities for the European X-Ray Free Electron Laser

The production of over 800 1.3-GHz superconducting (SC) cavities for the European X-ray Free Electron Laser (EXFEL), the largest in the history of cavity fabrication, has now been successfully completed. In the past, manufacturing of SC resonators was only partly industrialized; the main challenge for the EXFEL production was transferring the high-performance surface treatment to industry. The production was shared by the two companies RI Research Instruments GmbH (RI) and Ettore Zanon S.p.A. (EZ) on the principle of “build to print”. DESY provided the high-purity niobium and NbTi for the resonators. Conformity with the European Pressure Equipment Directive (PED) was developed together with the contracted notified body TUEV NORD. New or upgraded infrastructure has been established at both companies. Series production and delivery of fully-equipped cavities ready for cold rf testing was started in December 2012, and finished in December 2015. More than half the cavities delivered to DESY as specified (referred to “as received”) fulfilled the EXFEL specification. Further improvement of low-performing cavities was achieved by supplementary surface treatment at DESY or at the companies. The final achieved average gradient exceeded the EXFEL specification by approximately 25%. In the following paper, experience with the 1.3-GHz cavity production for EXFEL is reported and the main lessons learned are discussed