Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination

Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has been reported for several neurodegenerative disorders and ataxin-3 is known to deubiquitinylate parkin, a key protein required for canonical mitophagy. In this study, we analyzed mitochondrial function and mitophagy in a patient-derived SCA3 cell model. Human fibroblast lines isolated from SCA3 patients were immortalized and characterized. SCA3 patient fibroblasts revealed circular, ring-shaped mitochondria and featured reduced OXPHOS complexes, ATP production and cell viability. We show that wildtype ataxin-3 deubiquitinates VDAC1 (voltage-dependent anion channel 1), a member of the mitochondrial permeability transition pore and a parkin substrate. In SCA3 patients, VDAC1 deubiquitination and parkin recruitment to the depolarized mitochondria is inhibited. Increased p62-linked mitophagy, autophagosome formation and autophagy is observed under disease conditions, which is in line with mitochondrial fission. SCA3 fibroblast lines demonstrated a mitochondrial phenotype and dysregulation of parkin-VDAC1-mediated mitophagy, thereby promoting mitochondrial quality control via alternative pathways.     

New Cav1.2 Channelopathy with High-Functioning Autism,Affective Disorder,Severe Dental Enamel Defects,a Short QT Interval,and a Novel CACNA1C Loss-of-Function Mutation

Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.     

A beam profile monitor for heavy ion beams at high impact energies

A beam profile monitor for heavy ion beams has been developed for the use in experiments at the Heavy Ion Synchrotron SIS at Gesellschaft für Schwerionenforschung Darmstadt (GSI). Four thin scintillation fibres are mounted on one wheel and scan the ion beam sequentially in two linearly independent directions. They are read out via one single photomultiplier common to all four fibres into one time spectrum, which provides all information about beam position, beam extension, time structure and lateral homogeneity of the beam. The system operates in a wide dynamic range of beam intensities.     

Cloud Computing Based Optimal Driving for a Parallel Hybrid Electric Vehicle

A cloud computing based optimal driving method is proposed and its feasibility is validated through a real-world scenario simulation. Based on principles of vehicle dynamics, the driving optimization problem has been formulated into an optimal control problem constrained by traffic rules, directed at achieving lower equivalent fuel consumption and shorter travel time. In order to conveniently specify the constraints and facilitate the application of the dynamic programming (DP) algorithm, the driving optimization problem is transformed into spatial domain and discretized properly. Considering the heavy computational costs of the DP algorithm, a cloud computing based platform structure is proposed to solve the optimal driving problem in real-time. A case study is simulated based on a real-world traffic scenario in Matlab. Simulation results demonstrate that the cloud computing framework is promising toward realizing the real-time energy management for hybrid electric vehicles.     

Towards a definition of large scale products

The range of structure sizes for industrial products produced today is increasingly expanding. This trend is evident both at the bottom end of the scale as well as the top end. Examples include the ever-smaller miniaturization of devices in the semiconductor industry and the increase in rotor diameter of wind turbines. While definitions already exist for smaller scale device structures e.g. nanotechnology, the conceptual distinction between conventional large products and large scale products is currently insufficient. In this study, we present a potential basis for the definition of large scale products. To achieve this, we first of all derive hypotheses and examine these in the context of an empirical study using the examples of threaded nuts, screw presses and passenger aircraft. The study shows that the transition from conventional products to large scale products is characterized by a disproportionate increase in product costs due to the augmentation of a characteristic product feature. Based on the findings described, we then derive a proposed definition which characterizes large scale products on the basis that man encounters his technical, organizational and economic limits with the methods and tools available at the time of observation, in the context of product creation.