Proteasome Lid Bridges Mitochondrial Stress with Cdc53/Cullin1 NEDDylation Status

Cycles of Cdc53/Cullin1 rubylation (a.k.a NEDDylation) protect ubiquitin-E3 SCF (Skp1-Cullin1-F-box protein) complexes from self-destruction and play an important role in mediating the ubiquitination of key protein substrates involved in cell cycle progression, development, and survival. Cul1 rubylation is balanced by the COP9 signalosome (CSN), a multi-subunit derubylase that shows 1:1 paralogy to the 26 S proteasome lid. The turnover of SCF substrates and their relevance to various diseases is well studied, yet, the extent by which environmental perturbations influence Cul1 rubylation/derubylation cycles per se is still unclear. In this study, we show that the level of cellular oxidation serves as a molecular switch, determining Cullin1 rubylation/derubylation ratio. We describe a mutant of the proteasome lid subunit, Rpn11 that exhibits accumulated levels of Cullin1-Rub1 conjugates, a characteristic phenotype of csn mutants. By dissecting between distinct phenotypes of rpn11 mutants, proteasome and mitochondria dysfunction, we were able to recognize the high reactive oxygen species (ROS) production during the transition of cells into mitochondrial respiration, as a checkpoint of Cullin1 rubylation in a reversible manner. Thus, the study adds the rubylation cascade to the list of cellular pathways regulated by redox homeostasis

Direct extreme UV-lithographic conversion of metal xanthates into nanostructured metal sulfide layers for hybrid photovoltaics

We present a versatile strategy toward the preparation of nanostructured metal sulfide layers, which exploits the photosensitivity of metal xanthates as a powerful tool for lithographic structuring. Using extreme ultraviolet interference lithography (EUV-IL), we successfully realized well-defined column and comb nanostructures. This approach provides new pathways to fabricate highly ordered structured metal sulfide layers with periodicities far below 100 nm for potential application in hybrid solar cells. © 2013 The Royal Society of Chemistry

Thermal AdS(3), BTZ and competing winding modes condensation

We study the thermal physics of AdS(3) and the BTZ black hole when embedded in String theory. The exact calculation of the Hagedorn temperature in TAdS(3) is reinterpreted as the appearance of a winding tachyon both in AdS(3) and BTZ. We construct a dual framework for analyzing the phases of the system. In this dual framework, tachyon condensation and geometric capping appear on the same footing, bridging the usual gap of connecting tachyon condensation to modifications of geometry. This allows us to construct in a natural way a candidate for the unstable phase, analogous to a small black hole in higher dimensions. Additional peculiar effects associated with the Hagedorn temperature and the Hawking-Page transition, some to do with the asymptotic structure of AdS(3) and some with strong curvature effects, are analyzed and explained.Comment: 40 pages, 5 figures, JHEP3 format. v2: added references, minor corrections and clarification

Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes.

Background: MicroRNAs (miRNAs) in circulation have emerged as promising biomarkers. In this study, we aimed to identify a circulating miRNA signature for osteoarthritis (OA) patients and in combination with bioinformatics analysis to evaluate the utility of selected differentially expressed miRNAs in the serum as potential OA biomarkers. Methods: Serum samples were collected from 12 primary OA patients, and 12 healthy individuals were screened using the Agilent Human miRNA Microarray platform interrogating 2549 miRNAs. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the deregulated miRNAs. Expression levels of selected miRNAs were validated by quantitative real-time PCR (qRT-PCR) in all serum and in articular cartilage samples from OA patients (n = 12) and healthy individuals (n = 7). Bioinformatics analysis was used to investigate the involved pathways and target genes for the above miRNAs. Results: We identified 279 differentially expressed miRNAs in the serum of OA patients compared to controls. Two hundred and five miRNAs (73.5%) were upregulated and 74 (26.5%) downregulated. ROC analysis revealed that 77 miRNAs had area under the curve (AUC) > 0.8 and p < 0.05. Bioinformatics analysis in the 77 miRNAs revealed that their target genes were involved in multiple signaling pathways associated with OA, among which FoxO, mTOR, Wnt, pI3K/akt, TGF-β signaling pathways, ECM-receptor interaction, and fatty acid biosynthesis. qRT-PCR validation in seven selected out of the 77 miRNAs revealed 3 significantly downregulated miRNAs (hsa-miR-33b-3p, hsa-miR-671-3p, and hsa-miR-140-3p) in the serum of OA patients, which were in silico predicted to be enriched in pathways involved in metabolic processes. Target-gene analysis of hsa-miR-140-3p, hsa-miR-33b-3p, and hsa-miR-671-3p revealed that InsR and IGFR1 were common targets of all three miRNAs, highlighting their involvement in regulation of metabolic processes that contribute to OA pathology. Hsa-miR-140-3p and hsa-miR-671-3p expression levels were consistently downregulated in articular cartilage of OA patients compared to healthy individuals. Conclusions: A serum miRNA signature was established for the first time using high density resolution miR-arrays in OA patients. We identified a three-miRNA signature, hsa-miR-140-3p, hsa-miR-671-3p, and hsa-miR-33b-3p, in the serum of OA patients, predicted to regulate metabolic processes, which could serve as a potential biomarker for the evaluation of OA risk and progression.Peer reviewedFinal Published versio

Lattice deformation at the sub-micron scale: X-ray nanobeam measurements of elastic strain in electron shuttling devices

The lattice strain induced by metallic electrodes can impair the functionality of advanced quantum devices operating with electron or hole spins. Here we investigate the deformation induced by CMOS-manufactured titanium nitride electrodes on the lattice of a buried, 10 nm-thick Si/SiGe Quantum Well by means of nanobeam Scanning X-ray Diffraction Microscopy. We were able to measure TiN electrode-induced local modulations of the strain tensor components in the range of $2 - 8 \times 10^{-4}$ with ~60 nm lateral resolution. We have evaluated that these strain fluctuations are reflected into local modulations of the potential of the conduction band minimum larger than 2 meV, which is close to the orbital energy of an electrostatic quantum dot. We observe that the sign of the strain modulations at a given depth of the quantum well layer depends on the lateral dimensions of the electrodes. Since our work explores the impact of device geometry on the strain-induced energy landscape, it enables further optimization of the design of scaled CMOS-processed quantum devices.Comment: 16 pages, 6 figure

Primary skin fibroblasts as a model of Parkinson's disease

Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

On Field Theory Thermalization from Gravitational Collapse

Motivated by its field theory interpretation, we study gravitational collapse of a minimally coupled massless scalar field in Einstein gravity with a negative cosmological constant. After demonstrating the accuracy of the numerical algorithm for the questions we are interested in, we investigate various aspects of the apparent horizon formation. In particular, we study the time and radius of the apparent horizon formed as functions of the initial Gaussian profile for the scalar field. We comment on several aspects of the dual field theory picture.Comment: 31 pages, 17 figures; V2 Some figures corrected, minor revision. arXiv admin note: substantial text overlap with arXiv:1106.233

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline