Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia

Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ‘tethering’ proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity

Fatty Acid Composition of Streptomyces hygroscopicus Populations

The composition of total fatty acids of Streptomyces hygroscopicus , strain 111-81 and of its spontaneous mutants was analysed by capillary gas chromatography. Parent culture and most variants, white and oligosporic showed similar fatty acid profiles and antibiotic metabolites. Asporogenic and Nocardia-like variants were characterised by different antibiotic spectra and by shifts in fatty acid ratios compared with the parent strain. Results are discussed with reference to antibiotic biosynthesis

Fatty Acid Composition of Streptomyces hygroscopicus Populations

The composition of total fatty acids of Streptomyces hygroscopicus   , strain 111-81 and of its spontaneous mutants was analysed by capillary gas chromatography. Parent culture and most variants, white and oligosporic showed similar fatty acid profiles and antibiotic metabolites. Asporogenic and Nocardia-like variants were characterised by different antibiotic spectra and by shifts in fatty acid ratios compared with the parent strain. Results are discussed with reference to antibiotic biosynthesis

CVD CARBONYL THIN FILMS OF TUNGSTEN AND MOLYBDENUM AND THEIR SILICIDES - A GOOD ALTERNATIVE TO CVD FLUORIDE TUNGSTEN TECHNOLOGY

By thermal decomposition of W(CO)6 and Mo(CO)6 at temperatures below 400°C and atmospheric pressure thin films on Si wafers were grown. This technology ia shown to be an alternative to the fluotide one which uses WF6 as a source material. Low resistivities together with a lack of errosion of Si substrate are possible. As-deposited films contain considerable amount of carbon and oxygen. By proper thermal annealing in H2 atmosphere as well as by rapid thermal annealing in vacuum optimum conditions were found to obtain low resistive metal and metal silicides films. Auger electron spectroscopy and XRD-studies were used to show the connection between the chemical composition and structure of the two kinds of films on the one hand and their resistivities on the other

Properties of µPCVD poly-silicon films after rapid thermal annealing

Polly-Silicon Films obtained by µPCVD were studied with respect to their structural and electrical properties influenced by rapid thermal annealing (RTA) in vacuum. In addition an annealing in H2 atmosphere at atmospheric pressure was curried out. The structure and the morphology of the films were studied by Reflection High Energy Electron Diffraction (RHEED) technique and Scanning Electron Microscopy (SEM), respectively. An effect of increase of the crystallinity of the poly-Si films was observed as a result of RTA annealing. These observations coincide well with the measured sheet resistance of the layers. It was found that sheet resistance of the as-deposited films is about [MATH] and it decreases to a value of about [MATH] in dependence on the annealing

Investigation a single-spiral vortex in a swirl flow

The work is aimed at a detailed study of large-scale helical vortex structures emerging in a high turbulent intensively swirling flow. It was shown that the vortex formed in the chamber by installing diaphragm with shifted outlet is folded into a single-helical vortex. The flow visualization shows that although the vortex axis performs slow oscillations (precession), on average this structure is fixed in space. The velocity fields were measured with the aid of a nonintrusive method of flow diagnostics (PIV). Verification of the calculation results obtained using a LES simulation was performed based on measured experimental data to confirm the correctness of the chosen mathematical modelling approach. It has been asserted that the investigated regimes are in a self-similarity area relative to Reynolds number

Investigation a single-spiral vortex in a swirl flow

The work is aimed at a detailed study of large-scale helical vortex structures emerging in a high turbulent intensively swirling flow. It was shown that the vortex formed in the chamber by installing diaphragm with shifted outlet is folded into a single-helical vortex. The flow visualization shows that although the vortex axis performs slow oscillations (precession), on average this structure is fixed in space. The velocity fields were measured with the aid of a nonintrusive method of flow diagnostics (PIV). Verification of the calculation results obtained using a LES simulation was performed based on measured experimental data to confirm the correctness of the chosen mathematical modelling approach. It has been asserted that the investigated regimes are in a self-similarity area relative to Reynolds number