iPSCs: A Preclinical Drug Research Tool for Neurological Disorders

The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer’s (AD) and Parkinson’s disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).     

Cognitive control therapy with children: Rationale and technique.

Cognitive Control Therapy (CCT) is designed to treat children whose cognitive dysfunctions are a source of school failure and serious adjustment problems and who lack cognitive structures necessary to learn within verbally oriented psychotherapy. CCT techniques address three goals: a) restructuring hierarchically ordered cognitive functions so that information from external and internal environments is produced efficiently; b) restructuring the pathological cognitive orientation so that external information is balanced and integrated with fantasies and feelings (metaphors); and c) connecting thought and action so that a balanced integration of perceptions and metaphors results in adaptive actions which are assimilated to influence the original cognition. To restructure cognitive functions, the child is asked to work on a series of tasks graded developmentally in terms of complexity, emotionality, and delay, and requiring nonverbal and, later, verbal cognitive activity. To promote integrating internal and external information, and assimilating the results of actions into cognitive schema, one of five technical models is followed, depending upon the pathological cognitive orientation maintained. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Soil and rock reinforcements in tunnelling

Soil and rock improvement and reinforcement techniques are used to permit safe tunnel excavations in difficult geological conditions. The main methods are ground reinforcement, grouting, jet grouting, drainage, freezing, and mechanical precutting. The improvement methods are divided into two basic groups—improving interventions and preserving interventions. A critical analysis is of these methods given and a technical comparison between the main improvement techniques adopted in tunnelling is shown. Several ground reinforcement schemes are discussed. Examples from Italy of the various types of ground improvement and reinforcement techniques are given.     

Self organizing motor maps for color-mapped image re-indexing.

Palette re-ordering is an effective approach for improving the compression of color-indexed images. If the spatial distribution of the indexes in the image is smooth, greater compression ratios may be obtained. As is already known, obtaining an optimal re-indexing scheme is not a trivial task. In this paper, we provide a novel algorithm for palette re-ordering problem making use of a motor map neural network. Experimental results show the real effectiveness of the proposed method both in terms of compression ratio and zero-order entropy of local differences. Also, its computational complexity is competitive with previous works in the field.     

Calcium-dependent cyto- and genotoxicity of nickel metal and nickel oxide nanoparticles in human lung cells

Background

Genotoxicity is an important toxicological endpoint due to the link to diseases such as cancer. Therefore, an increased understanding regarding genotoxicity and underlying mechanisms is needed for assessing the risk with exposure to nanoparticles (NPs). The aim of this study was to perform an in-depth investigation regarding the genotoxicity of well-characterized Ni and NiO NPs in human bronchial epithelial BEAS-2B cells and to discern possible mechanisms. Comparisons were made with NiCl₂ in order to elucidate effects of ionic Ni.

Methods

BEAS-2B cells were exposed to Ni and NiO NPs, as well as NiCl₂, and uptake and cellular dose were investigated by transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS). The NPs were characterized in terms of surface composition (X-ray photoelectron spectroscopy), agglomeration (photon cross correlation spectroscopy) and nickel release in cell medium (ICP-MS). Cell death (necrosis/apoptosis) was investigated by Annexin V-FITC/PI staining and genotoxicity by cytokinesis-block micronucleus (cytome) assay (OECD 487), chromosomal aberration (OECD 473) and comet assay. The involvement of intracellular reactive oxygen species (ROS) and calcium was explored using the fluorescent probes, DCFH-DA and Fluo-4.

Results

NPs were efficiently taken up by the BEAS-2B cells. In contrast, no or minor uptake was observed for ionic Ni from NiCl₂. Despite differences in uptake, all exposures (NiO, Ni NPs and NiCl₂) caused chromosomal damage. Furthermore, NiO NPs were most potent in causing DNA strand breaks and generating intracellular ROS. An increase in intracellular calcium was observed and modulation of intracellular calcium by using inhibitors and chelators clearly prevented the chromosomal damage. Chelation of iron also protected against induced damage, particularly for NiO and NiCl₂.

Conclusions

This study has revealed chromosomal damage by Ni and NiO NPs as well as Ni ionic species and provides novel evidence for a calcium-dependent mechanism of cyto- and genotoxicity.

     

Transparent Speculative Parallelization of Discrete Event Simulation Applications Using Global Variables

Parallelizing (compute-intensive) discrete event simulation (DES) applications is a classical approach for speeding up their execution and for making very large/complex simulation models tractable. This has been historically achieved via parallel DES (PDES) techniques, which are based on partitioning the simulation model into distinct simulation objects (somehow resembling objects in classical object-oriented programming), whose states are disjoint, which are executed concurrently and rely on explicit event-exchange (or event-scheduling) primitives as the means to support mutual dependencies and notification of their state updates. With this approach, the application developer is necessarily forced to reason about state separation across the objects, thus being not allowed to rely on shared information, such as global variables, within the application code. This implicitly leads to the shift of the user-exposed programming model to one where sequential-style global variable accesses within the application code are not allowed. In this article we remove this limitation by providing support for managing global variables in the context of DES code developed in ANSI-C, which gets automatically parallelized. Particularly, we focus on speculative (also termed optimistic) PDES systems that run on top of multi-core machines, where simulation objects can concurrently process their events with no guarantee of causal consistency and actual violations of causality rules are recovered through rollback/recovery schemes. In compliance with the nature of speculative processing, in our proposal global variables are transparently mapped to multi-versions, so as to avoid any form of safety predicate verification upon their updates. Consistency is ensured via the introduction of a new rollback/recovery scheme based on detecting global variables’ reads on non-correct versions. At the same time, efficiency in the execution is guaranteed by managing multi-version variables’ lists via non-blocking algorithms. Furthermore, the whole approach is fully transparent, being it based on automatized instrumentation of the application software (particularly ELF objects). Hence the programmer is exposed to the classical (and easy to code) sequential-style programming scheme while accessing any global variable. An experimental assessment of our proposal, based on a suite of case study applications, run on top of an off-the-shelf Linux machine equipped with 32 CPU-cores and 64 GB of RAM, is also presented.     

Compact Fenwick trees for dynamic ranking and selection

The Fenwick tree is a classical implicit data structure that stores an array in such a way that modifying an element, accessing an element, computing a prefix sum and performing a predecessor search on prefix sums all take logarithmic time. We introduce a number of variants which improve the classical implementation of the tree: in particular, we can reduce its size when an upper bound on the array element is known, and we can perform much faster predecessor searches. Our aim is to use our variants to implement an efficient dynamic bit vector: our structure is able to perform updates, ranking and selection in logarithmic time, with a space overhead in the order of a few percents, outperforming existing data structures with the same purpose. Along the way, we highlight the pernicious interplay between the arithmetic behind the Fenwick tree and the structure of current CPU caches, suggesting simple solutions that improve performance significantly.     

The influence of company identity on the perception of vehicle sounds

In order to determine how the interior of a car should sound, automotive manufacturers often rely on obtaining data from individual evaluations of vehicle sounds. Company identity could play a role in these appraisals, particularly when individuals are comparing cars from opposite ends of the performance spectrum. This research addressed the question: does company identity influence the evaluation of automotive sounds belonging to cars of a similar performance level and from the same market segment? Participants listened to car sounds from two competing manufacturers, together with control sounds. Before listening to each sound, participants were presented with the correct company identity for that sound, the incorrect identity or were given no information about the identity of the sound. The results showed that company identity did not influence appraisals of high performance cars belonging to different manufacturers. These results have positive implications for methodologies employed to capture the perceptions of individuals. STATEMENT OF RELEVANCE: A challenge in automotive design is to set appropriate targets for vehicle sounds, relying on understanding subjective reactions of individuals to such sounds. This paper assesses the role of company identity in influencing these subjective reactions and will guide sound evaluation studies, in which the manufacturer is often apparent.