Pathomechanisms of ALS8: altered autophagy and defective RNA binding protein (RBP) homeostasis due to the VAPB P56S mutation.

Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy

Coronal-Line Forest AGN: the best view of the inner edge of the AGN torus?

We introduce Coronal-Line Forest Active Galactic Nuclei (CLiF AGN), AGN which have a rich spectrum of forbidden high-ionization lines (FHILs, e.g. [FeVII], [FeX] and [NeV]), as well as relatively strong narrow ($\sim$300 km s$^{-1}$) H$\alpha$ emission when compared to the other Balmer transition lines. We find that the kinematics of the CLiF emitting region are similar to those of the forbidden low-ionization emission-line (FLIL) region. We compare emission line strengths of both FHILs and FLILs to CLOUDY photoionization results and find that the CLiF emitting region has higher densities (10$^{4.5}$ $<$ n$_H$ $<$ 10$^{7.5}$ cm$^{-3}$) when compared to the FLIL emitting region (10$^{3.0}$ $<$ n$_H$ $<$ 10$^{4.5}$ cm$^{-3}$). We use the photoionization results to calculate the CLiF regions radial distances (0.04 $<$ R$_{CLiF}$ $<$ 32.5 pc) and find that they are comparable to the dust grain sublimation distances (0.10 $<$ R$_{SUB}$ $<$ 4.3 pc). As a result we suggest that the inner torus wall is the most likely location of the CLiF region, and the unusual strength of the FHILs is due to a specific viewing angle giving a maximal view of the far wall of the torus without the continuum being revealed.Comment: 22 pages, 14 Figures and 12 Tables. Resubmitted to MNRAS after minor correction

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Entwicklung und Synthese von NHC-Metallkomplexen

NHC-Metallkomplexen werden für unterschiedliche Katalysereaktionen benötigt. Die im ersten Teils vorgestellten NHC-Metallkomplexe sind sterisch sehr anspruchsvoll. Daraus ergibt sich eine hohe Aktivität für Gold-katalysierte Hydrierungen von Alkinen zu den entsprechenden Ketonen. Der zweite zeigt auf, wie mit Hilfe von NHC-Iridiumkomplexen Kohlenmonoxid "riechbar" gemacht werden kann

Entwicklung und Synthese von NHC-Metallkomplexen

NHC-Metallkomplexen werden für unterschiedliche Katalysereaktionen benötigt. Die im ersten Teils vorgestellten NHC-Metallkomplexe sind sterisch sehr anspruchsvoll. Daraus ergibt sich eine hohe Aktivität für Gold-katalysierte Hydrierungen von Alkinen zu den entsprechenden Ketonen. Der zweite zeigt auf, wie mit Hilfe von NHC-Iridiumkomplexen Kohlenmonoxid "riechbar" gemacht werden kann

Synthesis of an ortho -Methyl-N ,N′ -bis(triptycenyl) N-Heterocyclic Carbene Ligand and Its Metal Complexes

A new N,N′-bis(triptycenyl)-NHC ligand with methyl groups in the ortho position has been synthesized starting from 2,3-dimethyltriptycene-1,4-quinone. The respective metal complexes [ML(NHC)] [ML = CuBr, AuCl, PdCl(allyl), RhCl(cod), IrCl(cod), RhCl(CO)2, IrCl(CO)2, and RuCl2(=CHC6H4OiPr)] were obtained by standard procedures. All the complexes were initially mixtures of syn and anti isomers. The ruthenium complex was separated into the syn and anti isomers. The crystal structure of the anti complex [RhCl(cod)(8)] has been determined