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.     

The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications

Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand–receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications.     

Consideration of the BDNF gene in relation to two phenotypes: Hoarding and obesity.

The gene coding for the brain derived neurotrophic factor (BDNF) has emerged as an interesting candidate for multiple brain and brain disorder-related phenomena. The primary aim of the present investigation was to consider the relationship between the BDNF Val66Met variant and two phenotypes: compulsive hoarding as a symptom dimension of obsessive–compulsive disorder (OCD), and body mass index (BMI). We examined the BDNF gene in a large (N = 301) clinical sample of probands with OCD. Participants were classified as hoarding or nonhoarding using a strict, multimeasure grouping approach. Results revealed that the Val/Val genotype was linked with hoarding classification and more severe hoarding behaviors, as well as greater BMI levels. Hoarding status was also associated with greater BMI scores, with individuals in the hoarding group being far more likely to be classified as obese compared with the nonhoarding group. Our findings may provide a distinct avenue through which hoarding and BMI could be linked. These findings are suggestive of a complex gene, body weight, and psychopathology relationship wherein a primitive, survival “thrifty gene” strategy may be conserved and represented in a subgroup of humans manifesting severe hoarding symptoms. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Efficient shape optimization for certain and uncertain aerodynamic design

In this paper, we present novel developments in aerodynamic shape optimization based on shape calculus as well as the proper treatment of aleatoric uncertainties in the field of aerodynamic design.     

New high-speed bipolar XOR gate with absolutely symmetrical circuit configuration

A new monolithic integrated exclusive OR gate (XOR) in E/sup 2/CL circuit design is presented. The symmetry with respect to both inputs makes it superior to the standard XOR gates in ECL or E/sup 2/CL for several applications. The circuit was realised using a conservative 2 mu m standard silicon bipolar technology.<>     

On cosets of the generalized first-order reed-muller code with low PMEPR

Golay sequences are well suited for use as codewords in orthogonal frequency-division multiplexing (OFDM), since their peak-to-mean envelope power ratio (PMEPR) in q-ary phase-shift keying (PSK) modulation is at most 2. It is known that a family of polyphase Golay sequences of length 2^m organizes in m!/2 cosets of a q-ary generalization of the first-order Reed-Muller code, RM_q(1,m). In this paper, a more general construction technique for cosets of RM _q(1,m) with low PMEPR is established. These cosets contain so-called near-complementary sequences. The application of this theory is then illustrated by providing some construction examples. First, it is shown that the m!/2 cosets of RM_q(1,m) comprised of Golay sequences just arise as a special case. Second, further families of cosets of RM_q(1,m) with maximum PMEPR between 2 and 4 are presented, showing that some previously unexplained phenomena can now be understood within a unified framework. A lower bound on the PMEPR of cosets of RM_q(1,m) is proved as well, and it is demonstrated that the upper bound on the PMEPR is tight in many cases. Finally, it is shown that all upper bounds on the PMEPR of cosets of RM_q(1,m) also hold for the peak-to-average power ratio (PAPR) under the Walsh-Hadamard transform (WHT)