In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.     

The Crosstalk of Adipose-Derived Stem Cells (ADSC), Oxidative Stress,and Inflammation in Protective and Adaptive Responses

The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties.     

Dual command travel times and miniload system throughput with turnover-based storage

We analyze travel times for automated storage/retrieval systems. In particular, we apply our travel time model to turnover-based storage systems and determine the mean and variance of dual command travel times. We present detailed numerical results for selected rack shape factors and ABC inventory profiles. We then investigate the effect of alternative rack configurations on travel time performance measures. We also show how to determine the throughput of miniload systems with turnover-based storage and exponentially distributed pick times.     

5-HPETE is a potent inhibitor of neuronal Na+, K(+)-ATPase activity

The effects of 1 microM concentrations of arachidonic acid hydroperoxide (HPETES) products of 5-, 12- and 15-lipoxygenase on Na+, K(+)-ATPase activity were investigated in synaptosomal membrane preparations from rat cerebral cortex. 5-HPETE inhibited Na+, K(+)-ATPase activity by up to 67 %. In contrast, 12-HPETE and 15-HPETE did not inhibit Na+, K(+)-ATPase activity. In addition, neither 5-HETE or LTA4 inhibited Na+, K(+)-ATPase activity. Dose-response studies indicated that 5-HPETE was a potent (IC25 = 10(-8) M) inhibitor of Na+, K(+)-ATPase activity. These findings indicate that 5-HPETE inhibits Na+, K(+)-ATPase activity by a mechanism that is dependent on the hydroperoxide position and independent of further metabolism by 5-lipoxygenase. It is proposed that 5-HPETE production by 5-lipoxygenase and subsequent inhibition of neuronal Na+, K(+)-ATPase activity may be a mechansim for modulating synaptic transmission.     

Formulation for Reliable Analysis of Structural Frames

Structural engineers use design codes formulated to consider uncertainty for both reinforced concrete and structural steel design. For a simple one-bay structural steel frame, we survey typical uncertainties and compute an interval solution for displacements and forces. The naive solutions have large over-estimations, so we explore the Mullen-Muhanna assembly strategy, scaling, and constraint propagation to achieve tight enclosures of the true ranges for displacements and forces in a fraction of the CPU time typically used for simulations. That we compute tight enclosures, even for large parameter uncertainties used in practice, suggests the promise of interval methods for much larger structures.     

The generation effect is no artifact: Generating makes words distinctive.

The generation effect occurs if people remember items they complete from fragments better than complete items they read. Four experiments investigate two questions. When does the effect occur, and why does it do so? Targets generated in related contexts are recognized better than read targets, and they are recalled better with the contexts as cues; the contexts are recognized equally well, and the relation between the context and target is not enhanced by generation. Furthermore, generated items exceed items read in pure lists even when read ones from the mixed list are no worse than the controls. The generation effect is real; it is not an artifact. However, there is nothing special about generation. Generating is a type of encoding, and like any other type of encoding, its effects are maximal on tests that require subjects to do again whatever they did at study. Generating makes targets distinctive by contrasting them with other relatives of the context, and, as a result, the targets enjoy benefits in later discriminations within their family. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Personal spaces — ePerSpace

This paper describes the ePerSpace research project which aims to significantly increase user acceptance of networked audiovisual systems and applications at home and virtually anywhere by enabling innovative interoperable value-added personalised networked services and applications. Moreover, it aims to develop an open architecture and a framework that will significantly increase the speed of developing novel value-added personalised services by reusing well-defined system components with open APIs. The structure of the paper follows the methodology of the project. It starts with a vision of future personalised services from the users’ perspective by developing five scenarios. These scenarios are then used to extract the requirements of the personalisation framework which is then described in terms of its personalisation, service management, digital home environment management and content adaptation capabilities.     

Rural electrification: The institutional dimension

The institutional aspects of rural electrification programmes are often given much less attention than their importance warrants. In a number of important ways, rural electrification is in conflia with the primary concerns of the utilities mandated to implement it. Resolving this dilemma requires a separation of functions, with the agency responsible for rural electrification being given substantial autonomy. The range of institutional options for achieving this is wide and the choice should be tailored to the local context ana programme objectives.