Novel Pathogenic Mutations and Copy Number Variations in the VPS13A Gene in Patients With Chorea-Acanthocytosis

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc. (C) 2011 Wiley-Liss, Inc.

Serial conditional discrimination and temporal bisection in rats selectively lesioned in the dentate gyrus

In positive serial conditional discrimination, animals respond during a target stimulus when it is preceded by a feature stimulus, but they do not respond when the same target stimulus is presented alone. Moreover, the feature and target stimuli are separated from each other by an empty interval. The present work aimed to investigate if two durations (4 or 16s) of the same feature stimulus (light) could modulate the operant responses of rats to different levers (A and B) during a 5-s target stimulus (tone). In the present study, lever A was associated with the 4-s light, and lever B was associated with the 16-s light. A 5-s empty interval was included between the light and the tone. In the same training procedure, the rats were also presented with the 5-s tone without the preceding light stimuli. In these trials, the responses were not reinforced. We evaluated the hippocampal involvement of these behavioral processes by selectively lesioning the dentate gyrus with colchicine. Once trained, the rats were submitted to a test using probe trials without reinforcement. They were presented with intermediate durations of the feature stimulus (light) to obtain a temporal bisection curve recorded during the exposure to the target stimuli. The rats from both groups learned to respond with high rates during tones preceded by light and with low rates during tones presented alone, which indicated acquisition of the serial conditional discrimination. The rats were able to discriminate between the 4- and 16-s lights by correctly choosing lever A or B. In the test, the temporal bisection curves from both experimental groups showed a bisection point at the arithmetic mean between 4 and 16s. Such processes were not impaired by the dentate gyrus lesion. Thus, our results showed that different durations of a feature stimulus could result in conditional properties. However, this processing did not appear to depend on the dentate gyrus alone. (C) 2011 Published by Elsevier B.V.

Intake, water consumption, ruminal fermentation, and stress response of beef heifers fed after different lengths of delays in the daily feed delivery time

Four rumen-fistulated Holstein heifers (134 +/- 1 kg initial BW) were used in a 4 x 4 Latin square design to determine the effects of delaying daily feed delivery time on intake, ruminal fermentation, behavior, and stress response. Each 3-wk experimental period was preceded by 1 wk in which all animals were fed at 0800 h. Feed bunks were cleaned at 0745 h and feed offered at 0800 h (T0, no delay), 0900 (T1), 1000 (T2), and 1100 (T3) from d1 to 21 with measurements taken during wk 1 and 3. Heifers were able to see each other at all times. Concentrate and barley straw were offered in separate compartments of the feed bunks, once daily and for ad libitum intake. Ruminal pH and saliva cortisol concentrations were measured at 0, 4, 8, and 12 h postfeeding on d 3 and 17 of each experimental period. Fecal glucocorticoid metabolites were measured on d 17. Increasing length of delay in daily feed delivery time resulted in a quadratic response in concentrate DMI (low in T1 and T2; P = 0.002), whereas straw DMI was greatest in T1 and T3 (cubic P = 0.03). Treatments affected the distribution of DMI within the day with a linear decrease observed between 0800 and 1200 h but a linear increase during nighttimes (2000 to 0800 h), whereas T1 and T2 had reduced DMI between 1200 and 1600 h (quadratic P = 0.04). Water consumption (L/d) was not affected but decreased linearly when expressed as liters per kilogram of DMI (P = 0.01). Meal length was greatest and eating rate slowest in T1 and T2 (quadratic P <= 0.001). Size of the first meal after feed delivery was reduced in T1 on d 1 (cubic P = 0.05) and decreased linearly on d 2 (P = 0.01) after change. Concentrate eating and drinking time (shortest in T1) and straw eating time (longest in T1) followed a cubic trend (P = 0.02). Time spent lying down was shortest and ruminating in standing position longest in T1 and T2. Delay of feeding time resulted in greater daily maximum salivary cortisol concentration (quadratic P = 0.04), which was greatest at 0 h in T1 and at 12 h after feeding in T2 (P < 0.05). Daily mean fecal glucocorticoid metabolites were greatest in T1 and T3 (cubic P = 0.04). Ruminal pH showed a treatment effect at wk 1 because of increased values in T1 and T3 (cubic P = 0.01). Delaying feed delivery time was not detrimental for rumen function because a stress response was triggered, which led to reduced concentrate intake, eating rate, and size of first meal, and increased straw intake. Increased salivary cortisol suggests that animal welfare is compromised.

Alternative diagnostic diagrams and the `forgotten` population of weak line galaxies in the SDSS

A numerous population of weak line galaxies (WLGs) is often left out of statistical studies on emission-line galaxies (ELGs) due to the absence of an adequate classification scheme, since classical diagnostic diagrams, such as [O iii]/H beta versus [N ii]/H alpha (the BPT diagram), require the measurement of at least four emission lines. This paper aims to remedy this situation by transposing the usual divisory lines between star-forming (SF) galaxies and active galactic nuclei (AGN) hosts and between Seyferts and LINERs to diagrams that are more economical in terms of line quality requirements. By doing this, we rescue from the classification limbo a substantial number of sources and modify the global census of ELGs. More specifically, (1) we use the Sloan Digital Sky Survey Data Release 7 to constitute a suitable sample of 280 000 ELGs, one-third of which are WLGs. (2) Galaxies with strong emission lines are classified using the widely applied criteria of Kewley et al., Kauffmann et al. and Stasinska et al. to distinguish SF galaxies and AGN hosts and Kewley et al. to distinguish Seyferts from LINERs. (3) We transpose these classification schemes to alternative diagrams keeping [N ii]/H alpha as a horizontal axis, but replacing H beta by a stronger line (H alpha or [O ii]), or substituting the ionization-level sensitive [O iii]/H beta ratio with the equivalent width of H alpha (W(H alpha)). Optimized equations for the transposed divisory lines are provided. (4) We show that nothing significant is lost in the translation, but that the new diagrams allow one to classify up to 50 per cent more ELGs. (5) Introducing WLGs in the census of galaxies in the local Universe increases the proportion of metal-rich SF galaxies and especially LINERs. In the course of this analysis, we were led to make the following points. (i) The Kewley et al. BPT line for galaxy classification is generally ill-used. (ii) Replacing [O iii]/H beta by W(H alpha) in the classification introduces a change in the philosophy of the distinction between LINERs and Seyferts, but not in its results. Because the W(H alpha) versus [N ii]/H alpha diagram can be applied to the largest sample of ELGs without loss of discriminating power between Seyferts and LINERs, we recommend its use in further studies. (iii) The dichotomy between Seyferts and LINERs is washed out by WLGs in the BPT plane, but it subsists in other diagnostic diagrams. This suggests that the right wing in the BPT diagram is indeed populated by at least two classes, tentatively identified with bona fide AGN and `retired` galaxies that have stopped forming stars and are ionized by their old stellar populations.

The impact of fragmentation and density regulation on forest succession in the Atlantic rain forest

The Atlantic Rain Forest, an important biodiversity hot spot, has faced severe habitat loss since the last century which has resulted in a highly fragmented landscape with a large number of small forest patches (<100 ha). For conservation planning it is essential to understand how current and future forest regeneration depends on ecological processes, fragment size and the connection to the regional seed pool. We have investigated the following questions by applying the forest growth simulation model FORMIND to the situation of the Atlantic Forest in the state of Sao Paulo, SE Brazil: (1) which set of parameters describing the local regeneration and level of density regulation can reproduce the biomass distribution and stem density of an old growth forest in a reserve? (2) Which additional processes apart from those describing the dynamics of an old growth forest, drive forest succession of small isolated fragments? (3) Which role does external seed input play during succession? Therefore, more than 300 tree species have been classified into nine plant functional types (PFTs), which are characterized by maximum potential height and shade tolerance. We differentiate between two seed dispersal modes: (i) local dispersal, i.e. all seedlings originated from fertile trees within the simulated area and (ii) external seed rain. Local seed dispersal has been parameterized following the pattern oriented approach, using biomass estimates of old growth forest. We have found that moderate density regulation is essential to achieve coexistence for a broad range of regeneration parameters. Considering the expected uncertainty and variability in the regeneration processes it is important that the forest dynamics are robust to variations in the regeneration parameters. Furthermore, edge effects such as increased mortality at the border and external seed rain have been necessary to reproduce the patterns for small isolated fragments. Overall, simulated biomass is much lower in the fragments compared to the continuous forest, whereas shade tolerant species are affected most strongly by fragmentation. Our simulations can supplement empirical studies by extrapolating local knowledge on edge effects of fragments to larger temporal and spatial scales. In particular our results show the importance of external seed rain and therefore highlight the importance of structural connectivity between regenerating fragments and mature forest stands. (C) 2009 Elsevier B.V. All rights reserved.

Insights on eukaryotic translation initiation factor 5A (eIF5A) in the brain and aging

Long-term memory, a persistent form of synaptic plasticity, requires translation of a subset of mRNA present in neuronal dendrites during a short and critical period through a mechanism not yet fully elucidated. Western blotting analysis revealed a high content of eukaryotic translation initiation factor 5A (eIF5A) in the brain of neonatal rats, a period of intense neurogenesis rate, differentiation and synaptic establishment, when compared to adult rats. Immunohistochemistry analysis revealed that eIF5A is present in the whole brain of adult rats showing a variable content among the cells from different areas (e.g. cortex, hippocampus and cerebellum). A high content of eIF5A in the soma and dendrites of Purkinje cells, key neurons in the control of motor long-term memory in the cerebellum, was observed. Detection of high eIF5A content was revealed in dendritic varicosities of Purkinje cells. Evidence is presented herein that a reduction of eIF5A content is associated to brain aging. (C) 2008 Elsevier B.V. All rights reserved.

Slicing the metric space to provide quick indexing of complex data in the main memory

Searching in a dataset for elements that are similar to a given query element is a core problem in applications that manage complex data, and has been aided by metric access methods (MAMs). A growing number of applications require indices that must be built faster and repeatedly, also providing faster response for similarity queries. The increase in the main memory capacity and its lowering costs also motivate using memory-based MAMs. In this paper. we propose the Onion-tree, a new and robust dynamic memory-based MAM that slices the metric space into disjoint subspaces to provide quick indexing of complex data. It introduces three major characteristics: (i) a partitioning method that controls the number of disjoint subspaces generated at each node; (ii) a replacement technique that can change the leaf node pivots in insertion operations; and (iii) range and k-NN extended query algorithms to support the new partitioning method, including a new visit order of the subspaces in k-NN queries. Performance tests with both real-world and synthetic datasets showed that the Onion-tree is very compact. Comparisons of the Onion-tree with the MM-tree and a memory-based version of the Slim-tree showed that the Onion-tree was always faster to build the index. The experiments also showed that the Onion-tree significantly improved range and k-NN query processing performance and was the most efficient MAM, followed by the MM-tree, which in turn outperformed the Slim-tree in almost all the tests. (C) 2010 Elsevier B.V. All rights reserved.

Formal validation of automated policy refinement in the management of network security systems

Policy hierarchies and automated policy refinement are powerful approaches to simplify administration of security services in complex network environments. A crucial issue for the practical use of these approaches is to ensure the validity of the policy hierarchy, i.e. since the policy sets for the lower levels are automatically derived from the abstract policies (defined by the modeller), we must be sure that the derived policies uphold the high-level ones. This paper builds upon previous work on Model-based Management, particularly on the Diagram of Abstract Subsystems approach, and goes further to propose a formal validation approach for the policy hierarchies yielded by the automated policy refinement process. We establish general validation conditions for a multi-layered policy model, i.e. necessary and sufficient conditions that a policy hierarchy must satisfy so that the lower-level policy sets are valid refinements of the higher-level policies according to the criteria of consistency and completeness. Relying upon the validation conditions and upon axioms about the model representativeness, two theorems are proved to ensure compliance between the resulting system behaviour and the abstract policies that are modelled.

QCD sum rule calculation for the charmonium-like structures in the J/psi phi and J/psi omega invariant mass spectra

Using the QCD sum rules we test if the charmonium-like structure Y(4274), observed in the J/psi phi invariant mass spectrum, can be described with a D(s)(D) over bar (s0)(2317)+ h.c. molecular current with J(PC) = 0(-+). We consider the contributions of condensates up to dimension ten and we work at leading order in alpha(s). We keep terms which are linear in the strange quark mass m(s). The mass obtained for such state is mD(s)D(s0) = (4.78 +/- 0.54) GeV. We also consider a molecular 0(-+) D (D) over bar (0)(2400)+ h.c. current and we obtain m(DD0) = (4.55 +/- 0.49) GeV. Our study shows that the newly observed Y(4274) in the J/psi phi invariant mass spectrum can be, considering the uncertainties, described using a molecular charmonium current. (C) 2011 Elsevier B.V. All rights reserved.

Advanced functionality for radio analysis in the Offline software framework of the Pierre Auger Observatory

The advent of the Auger Engineering Radio Array (AERA) necessitates the development of a powerful framework for the analysis of radio measurements of cosmic ray air showers. As AERA performs ""radio-hybrid"" measurements of air shower radio emission in coincidence with the surface particle detectors and fluorescence telescopes of the Pierre Auger Observatory, the radio analysis functionality had to be incorporated in the existing hybrid analysis solutions for fluorescence and surface detector data. This goal has been achieved in a natural way by extending the existing Auger Offline software framework with radio functionality. In this article, we lay out the design, highlights and features of the radio extension implemented in the Auger Offline framework. Its functionality has achieved a high degree of sophistication and offers advanced features such as vectorial reconstruction of the electric field, advanced signal processing algorithms, a transparent and efficient handling of FFTs, a very detailed simulation of detector effects, and the read-in of multiple data formats including data from various radio simulation codes. The source code of this radio functionality can be made available to interested parties on request. (C) 2011 Elsevier B.V. All rights reserved.

Glassy states in the stochastic Potts model

We have studied by numerical simulations the relaxation of the stochastic seven-state Potts model after a quench from a high temperature down to a temperature below the first-order transition. For quench temperatures just below the transition temperature the phase ordering occurs by simple coarsening under the action of surface tension. For sufficient low temperatures however the straightening of the interface between domains drives the system toward a metastable disordered state, identified as a glassy state. Escaping from this state occurs, if the quench temperature is nonzero, by a thermal activated dynamics that eventually drives the system toward the equilibrium state. (C) 2009 Elsevier B.V. All rights reserved.

Restoring the azimuthal symmetry of lateral distributions of charged particles in the range of the KASCADE-Grande experiment

The reconstruction of Extensive Air Showers (EAS) observed by particle detectors at the ground is based on the characteristics of observables like the lateral particle density and the arrival times. The lateral densities, inferred for different EAS components from detector data, are usually parameterised by applying various lateral distribution functions (LDFs). The LDFs are used in turn for evaluating quantities like the total number of particles or the density at particular radial distances. Typical expressions for LDFs anticipate azimuthal symmetry of the density around the shower axis. The deviations of the lateral particle density from this assumption arising from various reasons are smoothed out in the case of compact arrays like KASCADE, but not in the case of arrays like Grande, which only sample a smaller part of the azimuthal variation. KASCADE-Grande, an extension of the former KASCADE experiment, is a multi-component Extensive Air Shower (EAS) experiment located at the Karlsruhe Institute of Technology (Campus North), Germany. The lateral distributions of charged particles are deduced from the basic information provided by the Grande scintillators - the energy deposits - first in the observation plane, then in the intrinsic shower plane. In all steps azimuthal dependences should be taken into account. As the energy deposit in the scintillators is dependent on the angles of incidence of the particles, azimuthal dependences are already involved in the first step: the conversion from the energy deposits to the charged particle density. This is done by using the Lateral Energy Correction Function (LECF) that evaluates the mean energy deposited by a charged particle taking into account the contribution of other particles (e.g. photons) to the energy deposit. By using a very fast procedure for the evaluation of the energy deposited by various particles we prepared realistic LECFs depending on the angle of incidence of the shower and on the radial and azimuthal coordinates of the location of the detector. Mapping the lateral density from the observation plane onto the intrinsic shower plane does not remove the azimuthal dependences arising from geometric and attenuation effects, in particular for inclined showers. Realistic procedures for applying correction factors are developed. Specific examples of the bias due to neglecting the azimuthal asymmetries in the conversion from the energy deposit in the Grande detectors to the lateral density of charged particles in the intrinsic shower plane are given. (C) 2011 Elsevier B.V. All rights reserved.

How language can help discrimination in the Neural Modelling Fields framework

The relationship between thought and language and, in particular, the issue of whether and how language influences thought is still a matter of fierce debate. Here we consider a discrimination task scenario to study language acquisition in which an agent receives linguistic input from an external teacher, in addition to sensory stimuli from the objects that exemplify the overlapping categories that make up the environment. Sensory and linguistic input signals are fused using the Neural Modelling Fields (NMF) categorization algorithm. We find that the agent with language is capable of differentiating object features that it could not distinguish without language. In this sense, the linguistic stimuli prompt the agent to redefine and refine the discrimination capacity of its sensory channels. (C) 2007 Elsevier Ltd. All rights reserved.

Search for first harmonic modulation in the right ascension distribution of cosmic rays detected at the Pierre Auger Observatory

We present the results of searches for dipolar-type anisotropies in different energy ranges above 2.5 x 10(17) eV with the surface detector array of the Pierre Auger Observatory, reporting on both the phase and the amplitude measurements of the first harmonic modulation in the right-ascension distribution. Upper limits on the amplitudes are obtained, which provide the most stringent bounds at present, being below 2% at 99% C.L. for EeV energies. We also compare our results to those of previous experiments as well as with some theoretical expectations. (C) 2011 Elsevier B.V. All rights reserved.

A study of the effect of molecular and aerosol conditions in the atmosphere on air fluorescence measurements at the Pierre Auger Observatory

The air fluorescence detector of the Pierre Auger Observatory is designed to perforin calorimetric measurements of extensive air showers created by Cosmic rays of above 10(18) eV. To correct these measurements for the effects introduced by atmospheric fluctuations, the Observatory contains a group Of monitoring instruments to record atmospheric conditions across the detector site, ail area exceeding 3000 km(2). The atmospheric data are used extensively in the reconstruction of air showers, and are particularly important for the correct determination of shower energies and the depths of shower maxima. This paper contains a summary of the molecular and aerosol conditions measured at the Pierre Auger Observatory since the start of regular operations in 2004, and includes a discussion of the impact of these measurements oil air shower reconstructions. Between 10(18) and 10(20) eV, the systematic Uncertainties due to all atmospheric effects increase from 4% to 8% in measurements of shower energy, and 4 g cm(-2) to 8 g cm(-2) in measurements of the shower maximum. (C) 2010 Elsevier B.V. All rights reserved.