Leveraging unique structural characteristics of WNK kinases to achieve therapeutic inhibition

This is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this record.The with-no-lysine (K) WNK kinases are master regulators of the Na+-(K+)-Cl- cotransporters, including the renal-specific NCC and NKCC2 cotransporters. The discovery of WNK463, an orally bioavailable pan-WNK kinase inhibitor that exploits unique structural properties of the WNK catalytic domain to achieve high affinity and kinase selectivity, illustrates a strategy of leveraging distinct kinase features to develop specific inhibitors and validates the genetic predictions of the in vivo pharmacology of WNK inhibition

The new 150 MVAr, 18 kV static var compensator for SPS: background, design and commissioning

A new Static Var Compensator (SVC) was designed, installed and commissioned by ABB for CERN’s Super Proton Synchrotron (SPS) accelerator. Due to the sensitive nature of the pulsating power converter load for the SPS magnets, very strict requirements were imposed on the stabilisation of the 18 kV bus voltage and its harmonic distortion. The adopted solution comprises a 150 Mvar TCR and eight harmonic filters with a total power of 130 Mvar. The paper gives a detailed description of the project background, system design and SVC installation. Finally, the results of the SVC performance tests are presented

Complexity Measures from Interaction Structures

We evaluate new complexity measures on the symbolic dynamics of coupled tent maps and cellular automata. These measures quantify complexity in terms of $k$-th order statistical dependencies that cannot be reduced to interactions between $k-1$ units. We demonstrate that these measures are able to identify complex dynamical regimes.Comment: 11 pages, figures improved, minor changes to the tex

Quantifying structure in networks

We investigate exponential families of random graph distributions as a framework for systematic quantification of structure in networks. In this paper we restrict ourselves to undirected unlabeled graphs. For these graphs, the counts of subgraphs with no more than k links are a sufficient statistics for the exponential families of graphs with interactions between at most k links. In this framework we investigate the dependencies between several observables commonly used to quantify structure in networks, such as the degree distribution, cluster and assortativity coefficients.Comment: 17 pages, 3 figure

FAS-dependent cell death in α-synuclein transgenic oligodendrocyte models of multiple system atrophy

Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention

EuCARD Newsletter Issue 2

European Coordination for Accelerator Research and Development (EuCARD) Newsletter Issue 2: July - September 2009 * A word from the Governing Board Chairman * Amassing the neutrino community * Start by probing the crab cavities * Breaking news for Proton "Surfatrons" * For EuCARD members: Interim reportin

Implementing Fine/Medium Grained TLP Support in a Many-Core Architecture

Abstract. We believe that future many-core architectures should support a simple and scalable way to execute many threads that are generated by parallel programs. A good candidate to implement an efficient and scalable execution of threads is the DTA (Decoupled Threaded Architecture), which is designed to exploit fine/medium grained Thread Level Parallelism (TLP) by using a hardware scheduling unit and relying on existing simple cores. In this paper, we present an initial implementation of DTA concept in a many-core architecture where it interacts with other architectural components designed from scratch in order to address the problem of scalability. We present initial results that show the scalability of the solution that were obtained using a many-core simulator written in SARCSim (a variant of UNISIM) with DTA support

Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging

Observations of the geology and geomorphology of the 1999 Marsokhod test site

The Marsokhod rover returned data from six stations that were used to decipher the geomorphology and geology of a region not previously visited by members of the geomorphology field team. Satellite images and simulated descent images provided information about the regional setting. The landing zone was on an alluvial apron flanking a mountain block to the west and playa surface to the east. Rover color images, infrared spectra analysis of the mountains, and the apron surface provided insight into the rock composition of the nearby mountains. From the return data the geomorphology team interpreted the region to consist of compressionally deformed, ancient marine sediments and igneous rocks exposed by more recent extensional tectonics. Unconsolidated alluvial materials blanket the lower flanks of the mountains. An ancient shoreline cut into alluvial material marks a high stand of water during a past, wetter climate period. Playa sediments floor a present-day, seasonally, dry lake. Observations made by the rover using panoramic and close-up (hand specimens—scale) image data and color scene data confirmed the presence of boulders, cobbles, and fines of various provinces. Rover traverses to sites identified as geologically distinct, such as a fan, channel, shoreline, and playa, provided useful clues to the geologic interpretations. Analysis of local rocks was given context only through comparison with distant geologic features. These results demonstrated the importance of a multifaceted approach to site interpretation through comparison of interpretations derived by differing geologic techniques

Performance of the QWIP Focal Plane Arrays for NASA's Landsat Data Continuity Mission

The focal plane assembly for the Thermal Infrared Sensor (TIRS) instrument on NASA's Landsat Data Continuity Mission (LDCM) consists of three 512 x 640 GaAs Quantum Well Infrared Photodetector (QWIP) arrays. The three arrays are precisely mounted and aligned on a silicon carrier substrate to provide a continuous viewing swath of 1850 pixels in two spectral bands defined by filters placed in close proximity to the detector surfaces. The QWIP arrays are hybridized to Indigo ISC9803 readout integrated circuits (ROICs). QWIP arrays were evaluated from four laboratories; QmagiQ, (Nashua, NH), Army Research Laboratory, (Adelphi, MD}, NASA/ Goddard Space Flight Center, (Greenbelt, MD) and Thales, (Palaiseau, France). All were found to be suitable. The final discriminating parameter was the spectral uniformity of individual pixels relative to each other. The performance of the QWIP arrays and the fully assembled, NASA flight-qualified, focal plane assembly will be reviewed. An overview of the focal plane assembly including the construction and test requirements of the focal plane will also be described