Comprehensive mutagenesis on yeast cytosine deaminase yields improvements in 5-fluorocytosine toxicity in HT1080 cells

Improved prodrug-activating enzymes have the potential to increase the therapeutic efficacy of gene-directed enzyme prodrug therapy (GDEPT). Yeast cytosine deaminase (yCD) is commonly used to convert the prodrug 5-fluorocytosine (5-FC) to the chemotherapeutic 5-fluorouracil for GDEPT. Mutagenesis studies on yCD aimed at improving its application in GDEPT have been limited to subsets of residues or have sought to improve a single property of the enzyme. We performed comprehensive site-saturation mutagenesis (CSM) on yCD designed to create all 2,983 possible unique protein mutants with a single amino acid substitution. We identified active variants through Escherichia coli genetic complementation and screened these mutants, and combinations thereof, for increased ability to sensitize E. coli and HT1080 fibrosarcoma cells to 5-FC. Several mutants identified in this study showed increased sensitization ability for both E. coli and HT1080 cells indicating that CSM is an effective directed evolution tool for identifying unexpectedly beneficial mutations.     

On the influence of baseline startle reactivity on the indexation of prepulse inhibition.

Prepulse inhibition (PPI) of the startle reflex refers to the reduction of the reflexive startle response to an intense pulse stimulus when its presentation is shortly preceded by a weak prepulse stimulus. PPI is considered as a cross-species translational model of sensorimotor gating, and deficient PPI has been reported in a number of neuropsychiatric disorders. Although a part of the literature is based on the assumption that PPI is independent of the baseline startle reaction, there is accumulating evidence (Csomor et al., 2006; Sandner & Canal, 2007; Yee, Chang, Pietropaolo, & Feldon, 2005) that argues against such an independency. The authors systematically investigated whether PPI indexed as percentage or difference score is dependent on the magnitude of baseline startle reactivity in healthy human volunteers and in C57BL/6 mice. The results revealed that both indexations of PPI were affected by the magnitude of the baseline startle. The authors highlight the pitfalls of different methods to index PPI, especially when startle reactivity differs considerably between groups under comparison, and offer practical recommendations to satisfactorily deal with such baseline differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory and aging: Selected research directions and application issues.

Everyday memory failures and long-term memory changes are among the most empirically established, socially expected, personally disconcerting, and widely misinterpreted aspects of human aging. A large, sophisticated, and still growing theoretical research base on memory aging has accumulated over the last several decades. Following a brief summary of a broad swath of selected basic memory aging phenomena, we identify a small subset of relatively recent but well-researched topics that may hold promise for optimizing memory adaptation in late life. Linking research with potential application, we sketch key objectives for three potential directions of intervention in memory and aging. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Searching by rules: Pigeons' (Columba livia) landmark-based search according to constant bearing or constant distance.

Pigeons (Columba livia) searched for a goal location defined by a constant relative spatial relationship to 2 landmarks. For one group, landmark-to-goal bearings remained constant while distance varied. For another group, landmark-to-goal distances remained constant while direction varied. Birds were trained with 4 interlandmark distances and then tested with 5 novel interlandmark distances. Overall error magnitude was similar across groups and was larger than previously reported for Clark's nutcrackers (Nucifraga columbiana). During training, error magnitude increased with interlandmark distance for constant-bearing but not constant-distance birds. Both groups searched less accurately along the axis parallel to landmarks than along the perpendicular axis. Error magnitude increased with novel extrapolated interlandmark distances but not with novel interpolated distances. Results suggest modest geometric rule learning by pigeons. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activity and Imagined Activity Can Enhance Young Children's Reading Comprehension.

The Indexical Hypothesis suggests a new method for enhancing children's reading comprehension. Young readers may not consistently "index," or map, words to the objects the words represent. Consequently, these readers fail to derive much meaning from the text. The instructional method involves manipulating toy objects referred to in the text (e.g., a barn, a tractor, a horse, in a text about a farm) to simulate the actions described in the text. Correctly manipulating the objects forces indexing and facilitates the derivation of meaning. Both actual manipulation and imagined manipulation resulted in markedly better (compared with rereading) memory for and comprehension of the text material, thereby lending strong support to the Indexical Hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Folding and aggregation of designed proteins

Protein aggregation is studied by following the simultaneous folding of two designed identical 20-letter amino acid chains within the framework of a lattice model and using Monte Carlo simulations. It is found that protein aggregation is determined by elementary structures (partially folded intermediates) controlled by local contacts among some of the most strongly interacting amino acids and formed at an early stage in the folding process.     

Performance evaluation of a floating lidar buoy in nearshore conditions

This work provides a signal‐processing and statistical‐error analysis methodology to assess key performance indicators for a floating Doppler wind lidar. The study introduces the raw‐to‐clean data processing chain, error assessment indicators and key performance indicators, as well as two filtering methods at post‐processing level to alleviate the impact of angular motion and spatial variability of the wind flow on the performance indicators. Towards this aim, the study mainly revisits horizontal wind speed (HWS) and turbulence intensity measurements with a floating ZephIR 300 lidar buoy during a 38 day nearshore test campaign in Pont del Petroli (Barcelona). Typical day cases along with overall statistics for the whole campaign are discussed to illustrate the methodology and processing tools developed. Copyright © 2017 John Wiley & Sons, Ltd.     

数字认证水印的防伪技术研究

随着计算机网络技术的发展,多媒体信息依靠自身的优势加快了知识和信息的交流与传播。但与此同时,也产生了一些对多媒体信息恶意篡改、攻击、伪造不法行为。数字水印技术,可以在不能被人的知觉系统觉察情况下,将一些标志性的信息嵌入媒体中,从而在不影响多媒体信息欣赏的情况下,起到防伪的效果。     

Modeling the alpha-helix to beta-hairpin transition mechanism and the formation of oligomeric aggregates of the fibrillogenic peptide Abeta(12-28): insights from all-atom molecular dynamics simulations

In this paper, all-atom molecular dynamics simulations in explicit solvent are used to investigate the structural and dynamical determinants of the alpha-helical to beta-hairpin conformational transition of the 12-28 fragment from the full length Abeta Alzheimer's peptide. The transition from alpha-helical to beta-structure requires the peptide to populate intermediate beta-bend geometries in which several mainly hydrophobic interactions are partially formed. This is followed by the sudden collapse to ordered beta-hairpin structures and the simultaneous disruption of the hydrophobic side-chain interactions with a consequent increase in solvent exposure. The solvent exposure of hydrophobic side-chains belonging to a sequence of five consecutive residues in the beta-hairpin defines a possible starting point for the onset of the aggregation mechanisms. Several different conformations of model oligomeric (dimeric and tetrameric) aggregates are then investigated. These simulations show that while hydrophobic contacts are important to bring together different monomers with a beta-hairpin like conformation, more specific interactions such as hydrogen-bonding and coulombic interactions, should be considered necessary to provide further stabilization and ordering to the nascent fibrillar aggregates.