Shaping up for structural glycomics: a predictive protocol for oligosaccharide conformational analysis applied to N-linked glycans

AbstractThe human glycome comprises a vast untapped repository of 3D-structural information that holds the key to glycan recognition and a new era of rationally designed mimetic chemical probes, drugs, and biomaterials. Toward routine prediction of oligosaccharide conformational populations and exchange rates at thermodynamic equilibrium, we apply hardware-accelerated aqueous molecular dynamics to model μs motions in N-glycans that underpin inflammation and immunity. In 10μs simulations, conformational equilibria of mannosyl cores, sialyl Lewis (sLe) antennae, and constituent sub-sequences agreed with prior refinements (X-ray and NMR). Glycosidic linkage and pyranose ring flexing were affected by branching, linkage position, and secondary structure, implicating sequence dependent motions in glycomic functional diversity. Linkage and ring conformational transitions that have eluded precise quantification by experiment and conventional (ns) simulations were predicted to occur on μs timescales. All rings populated non-chair shapes and the stacked galactose and fucose pyranoses of sLea and sLex were rigidified, suggesting an exploitable 3D-signature of cell adhesion protein binding. Analyses of sLex dynamics over 25μs revealed that only 10μs were sufficient to explore all aqueous conformers. This simulation protocol, which yields conformational ensembles that are independent of initial 3D-structure, is proposed as a route to understanding oligosaccharide recognition and structure–activity relationships, toward development of carbohydrate-based novel chemical entities

Effects of aging and recall of common and uncommon first names using the face-name association technique compared with the pure-lists technique over repeated trials

YesBackground: The face-name association technique (FNAT) is commonly used to investigate name recall in nonpathologic aging. This technique is appropriate for studying anomia, but the pure-list technique, in which participants see only names and do not need to form face-name associations, might be more appropriate for studying age-related name recall. Methods: Experiment 1 recruited 60 adults (30 younger and 30 older adults) to participate in the FNAT recognition task of 30 common and 30 uncommon names. In experiment 2, the same number and demographic of participants attempted to recall 30 common and 30 uncommon names. Both experiments utilized measurements of overall recall across 5 trials and a delayed recognition or recall trial. Measures of encoding (gained access) and consolidation (lost access) were also taken for the 5 initial trials in both experiments. Older participants received 50% extra study and recognition/recall time. Results: The FNAT experiment revealed an age-related episodic memory deficit for names. However, in cued recall, encoding, consolidation, retention/retrieval, and false alarm tests, older adults were significantly better than younger adults at recalling uncommon names, as opposed to common names. This lends support to the inhibition theory of name recall. Conversely, our second experiment revealed no age effect on any factors of name memory functioning, supporting node structure theory. Conclusions: The results of our experiments support previous findings that suggest an age-related deficit in name recall, but only in cases of anomia. Therefore, the FNAT methodology may be inappropriate for studying age-related name recall. It is possible that names are stored in the memory differently from nouns. We challenge the belief that older adults are significantly less able to recall names compared with other word types, which has implications for both memory self-efficacy questionnaires and research into eye-witness testimonies

The art of self‐testing by attempting cryptic crosswords in later life: the effect of cryptic crosswords on memory self‐efficacy, metacognition and memory functioning

YesPrevious research has suggested that older adults who are more cognitively active in later life show an attenuation in cognitive decline in healthy aging. Furthermore, cognitive intervention studies have indicated that ecologically valid cognitive interventions can promote cognitive functioning but only in taskspecific abilities. Since it has been shown that the art of self‐testing can promote metacognitive awareness in older adults, attempting cryptic crosswords may be used as a cognitive intervention for older adults. In Experiments 1 and 2, a questionnaire technique was used and demonstrated that older adults became more aware of their episodic memory deficits after attempting cryptic crossword clues. Based on this, Experiment 3 used an intervention technique over a six‐week period to investigate whether such awareness enabled older adults to improve cognitive functioning in a number of domains. This experiment used a revolutionary within‐subjects technique to control for potential mediating factors. The results supported previous research in that older adults showed an increase in the monitoring pathway of metacognition but were unable to use this enhanced awareness to change their behaviour when undertaking objective tests of cognitive ability. Post‐hoc analysis highlighted subgroups of older adults who showed improvements in certain cognitive abilities, such as episodic memory functioning and judgement of learning abilities. The standard clinical trial technique might be inappropriate when testing either cognitive interventions or pharmacological tests. The within‐subjects approach could be adapted to investigate follow‐up effects of different types of interventions including ecologically valid cognitive interventions.Harold Hyman Wingate Foundatio

Cast Stone Oxidation Front Evaluation: Preliminary Results For Samples Exposed To Moist Air

The rate of oxidation is important to the long-term performance of reducing salt waste forms because the solubility of some contaminants, e.g., technetium, is a function of oxidation state. TcO{sub 4}{sup −} in the salt solution is reduced to Tc(IV) and has been shown to react with ingredients in the waste form to precipitate low solubility sulfide and/or oxide phases. Upon exposure to oxygen, the compounds containing Tc(IV) oxidize to the pertechnetate ion, Tc(VII)O{sub 4}{sup −}, which is very soluble. Consequently the rate of technetium oxidation front advancement into a monolith and the technetium leaching profile as a function of depth from an exposed surface are important to waste form performance and ground water concentration predictions. An approach for measuring contaminant oxidation rate (effective contaminant specific oxidation rate) based on leaching of select contaminants of concern is described in this report. In addition, the relationship between reduction capacity and contaminant oxidation is addressed. Chromate (Cr(VI) was used as a non-radioactive surrogate for pertechnetate, Tc(VII), in Cast Stone samples prepared with 5 M Simulant. Cast Stone spiked with pertechnetate was also prepared and tested. Depth discrete subsamples spiked with Cr were cut from Cast Stone exposed to Savannah River Site (SRS) outdoor ambient temperature fluctuations and moist air. Depth discrete subsamples spiked with Tc-99 were cut from Cast Stone exposed to laboratory ambient temperature fluctuations and moist air. Similar conditions are expected to be encountered in the Cast Stone curing container. The leachability of Cr and Tc-99 and the reduction capacities, measured by the Angus-Glasser method, were determined for each subsample as a function of depth from the exposed surface. The results obtained to date were focused on continued method development and are preliminary and apply to the sample composition and curing / exposure conditions described in this report. The Cr oxidation front (depth to which soluble Cr was detected) for the Cast Stone sample exposed for 68 days to ambient outdoor temperatures and humid air (total age of sample was 131 days) was determined to be about 35 mm below the top sample surface exposed. The Tc oxidation front, depth at which Tc was insoluble, was not determined. Interpretation of the results indicates that the oxidation front is at least 38 mm below the exposed surface. The sample used for this measurement was exposed to ambient laboratory conditions and humid air for 50 days. The total age of the sample was 98 days. Technetium appears to be more easily oxidized than Cr in the Cast Stone matrix. The oxidized forms of Tc and Cr are soluble and therefore leachable. Longer exposure times are required for both the Cr and Tc spiked samples to better interpret the rate of oxidation. Tc spiked subsamples need to be taken further from the exposed surface to better define and interpret the leachable Tc profile. Finally Tc(VII) reduction to Tc(IV) appears to occur relatively fast. Results demonstrated that about 95 percent of the Tc(VII) was reduced to Tc(IV) during the setting and very early stage setting for a Cast Stone sample cured 10 days. Additional testing at longer curing times is required to determine whether additional time is required to reduce 100 % of the Tc(VII) in Cast Stone or whether the Tc loading exceeded the ability of the waste form to reduce 100 % of the Tc(VII). Additional testing is required for samples cured for longer times. Depth discrete subsampling in a nitrogen glove box is also required to determine whether the 5 percent Tc extracted from the subsamples was the result of the sampling process which took place in air. Reduction capacity measurements (per the Angus-Glasser method) performed on depth discrete samples could not be correlated with the amount of chromium or technetium leached from the depth discrete subsamples or with the oxidation front inferred from soluble chromium and technetium (i.e., effective Cr and Tc oxidation fronts). Residual reduction capacity in the oxidized region of the test samples indicates that the remaining reduction capacity is not effective in re-reducing Cr(VI) or Tc(VII) in the presence of oxygen. Depth discrete sampling and leaching is a useful for evaluating Cast Stone and other chemically reducing waste forms containing ground granulated blast furnace slag (GGBFS) or other reduction / sequestration reagents to control redox sensitive contaminant chemistry and leachability in the near surface disposal environment. Based on results presented in this report, reduction capacity measured by the Angus-Glasser Ce(IV) method is not an appropriate or meaningful parameter for determining or predicting Tc and Cr oxidation / retentions, speciation, or solubilities in cementitious materials such as Cast Stone. A model for predicting Tc(IV) oxidation to soluble Tc(VII) should consider the waste form porosity (pathway for oxygen ingress), oxygen source, and the contaminant specific oxidation rates and oxidation fronts. Depth discrete sampling of materials exposed to realistic conditions in combination with short term leaching of crushed samples has potential for advancing the understanding of factors influencing performance. This information can be used to support conceptual model development