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.     

Peroxide crosslinking of rigid poly(vinyl chloride)

Peroxide crosslinking of unplasticized poly(vinyl chloride) with trimethylolpropane trimethacrylate was investigated. Formulations used in this work contained a nontoxic lead‐free stabilizer and showed good color and heat stability. The samples were examined by differential scanning calorimetry, and their tensile properties were measured at room temperature and at 130°C. Gel content or tetrahydrofuran‐insoluble material was measured as an indication of crosslinking. It was shown that premature crosslinking could be avoided during processing and that 190°C was the optimum processing temperature for maximum gel content. The residual unsaturation was monitored by using FTIR spectroscopy. J. VINYL ADDIT. TECHNOL., 2008. © 2008 Society of Plastics Engineers     

Fecal bile acid excretion and composition in response to changes in dietary wheat bran,fat and calcium in the rat

The effect and possible interactive influence of different dietary amounts of wheat bran, fat and calcium on the fecal excretion, concentration and composition of bile acids was studied in Fischer-344 rats. The fecal bile acids were analyzed using gas-liquid chromatography. Dietary wheat bran increased both total bile acid excretion and fecal weight without changes in fecal bile acid concentration. The proportion of fecal hyodeoxycholic acid decreased with increasing dietary fiber, whereas that of lithocholic and deoxycholic acids increased significantly with fiber intake. The percent content of fecal chenodeoxycholic acid did not change. Increasing dietary fat led to an increase in bile acid excretion without changes in either fecal weight or bile acid concentration. In contrast, the level of dietary calcium did not affect the total excretion of bile acids. However, since calcium increased the fecal weight, it consequently diluted bile acids and decreased their fecal concentration. Dietary fat and calcium had no influence on fecal bile acid composition. There were no interactive effects of wheat bran, fat and calcium on fecal bile acids. The finding in this study that dietary fiber, fat and calcium induce significant changes in fecal bile acids may be of relevance to the potential of bile acids to promote carcinogenesis.     

Universities in Evolutionary Systems of Innovation

This paper criticizes the current narrow view on the role of universities in knowledge‐based economies. We propose to extend the current policy framework of universities in national innovation systems (NIS) to a more dynamic one, based on evolutionary economic principles. The main reason is that this dynamic view fits better with the practice of innovation processes. We contribute on ontological and methodological levels to the literature and policy discussions on the effectiveness of university‐industry knowledge transfer and the third mission of universities. We conclude with a discussion of the policy implications for the main stakeholders.     

A variable-precision square root implementation for field programmable gate arrays

Applications requiring variable-precision arithmetic often rely on software implementations because custom hardware is either unavailable or too costly to build. By using the flexibility of the Xilinx XC4010 field programmable gate arrays, we present a hardware implementation of square root that is easily tailored to any desired precision. Our design consists of three types of modules: a control logic module, a data path module to extend the precision in 4-bit increments, and an interface module to span multiple chips. Our data path design avoids the common problem of large fan-out delay in the critical path. Cycle time is independent of precision, and operation latency can be independent of interchip communication delays.Notation S_j square root digit of weight 2^–j - S _j {–1, 0, 1} - S[j] computed square root value as of stepj - S _j ^s sign bit in the representation ofS _j in sign and magnitude form - S _j ^m magnitude bit in the representation ofS _j in sign and magnitude form - w[j] residual at stepj in two's complement carry-save representation - a sum vector in the carry-save representation of 2w[j] - b carry vector in the carry-save representation of 2w[j] - a _i bit of weight 2^–i in the sum vector,a - b_i bit of weight 2^–i in the carry vector,b - T[j]=–S[j – 1]s_j – s _j ² 2^–(j+1) T _i bit of weight 2^–i inT     

Trustworthy keyword search for compliance storage

Intense regulatory focus on secure retention of electronic records has led to a need to ensure that records are trustworthy, i.e., able to provide irrefutable proof and accurate details of past events. In this paper, we analyze the requirements for a trustworthy index to support keyword-based search queries. We argue that trustworthy index entries must be durable—the index must be updated when new documents arrive, and not periodically deleted and rebuilt. To this end, we propose a scheme for efficiently updating an inverted index, based on judicious merging of the posting lists of terms. Through extensive simulations and experiments with two real world data sets and workloads, we demonstrate that the scheme achieves online update speed while maintaining good query performance. We also present and evaluate jump indexes, a novel trustworthy and efficient index for join operations on posting lists for multi-keyword queries. Jump indexes support insert, lookup and range queries in time logarithmic in the number of indexed documents.