Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging

Development of a Fragment-Based in Silico Profiler for Michael Addition Thiol Reactivity

The Adverse Outcome Pathway (AOP) paradigm details the existing knowledge that links the initial interaction between a chemical and a biological system, termed the molecular initiating event (MIE), through a series of intermediate events, to an adverse effect. An important example of a well-defined MIE is the formation of a covalent bond between a biological nucleophile and an electrophilic compound. This particular MIE has been associated with various toxicological end points such as acute aquatic toxicity, skin sensitization, and respiratory sensitization. This study has investigated the calculated parameters that are required to predict the rate of chemical bond formation (reactivity) of a dataset of Michael acceptors. Reactivity of these compounds toward glutathione was predicted using a combination of a calculated activation energy value (Eact, calculated using density functional theory (DFT) calculation at the B3YLP/6-31G+(d) level of theory, and solvent-accessible surface area values (SAS) at the α carbon. To further develop the method, a fragment-based algorithm was developed enabling the reactivity to be predicted for Michael acceptors without the need to perform the time-consuming DFT calculations. Results showed the developed fragment method was successful in predicting the reactivity of the Michael acceptors excluding two sets of chemicals: volatile esters with an extended substituent at the β-carbon and chemicals containing a conjugated benzene ring as part of the polarizing group. Additionally the study also demonstrated the ease with which the approach can be extended to other chemical classes by the calculation of additional fragments and their associated Eact and SAS values. The resulting method is likely to be of use in regulatory toxicology tools where an understanding of covalent bond formation as a potential MIE is important within the AOP paradigm

Validation of a fragment-based profiler for thiol reactivity for the prediction of toxicity: skin sensitisation and tetrahymena pyriformis

This study outlines the use of a recently developed fragment-based thiol reactivity profiler for Michael acceptors to predict toxicity towards Tetrahymena pyriformis and skin sensitisation potency as determined in the Local Lymph Node Assay (LLNA). The results showed that the calculated reactivity parameter from the profiler, -log RC50(calc), was capable of predicting toxicity for both endpoints with excellent statistics. However, the study highlighted the importance of a well-defined applicability domain for each endpoint. In terms of Tetrahymena pyriformis this domain was defined in terms of how fast or slowly a given Michael acceptor reacts with thiol leading to two separate quantitative structure-activity models. The first, for fast reacting chemicals required only –Log RC50(calc) as a descriptor, whilst the second required the addition of a descriptor for hydrophobicity. Modelling of the LLNA required only a single descriptor, -log RC50(calc), enabling potency to be predicted. The applicability domain excluded chemicals capable of undergoing polymerisation and those that were predicted to be volatile. The modelling results for both endpoints, using the –log RC50(calc) value from the profiler, were in keeping with previously published studies that have utilised experimentally determined measurements of reactivity. This results demonstrate the output from the fragment-based thiol reactivity profiler can be used to develop quantitative structure-activity relationship models where reactivity towards thiol is a driver of toxicity

Photodissociation and the Morphology of HI in Galaxies

Young massive stars produce Far-UV photons which dissociate the molecular gas on the surfaces of their parent molecular clouds. Of the many dissociation products which result from this ``back-reaction'', atomic hydrogen \HI is one of the easiest to observe through its radio 21-cm hyperfine line emission. In this paper I first review the physics of this process and describe a simplified model which has been developed to permit an approximate computation of the column density of photodissociated \HI which appears on the surfaces of molecular clouds. I then review several features of the \HI morphology of galaxies on a variety of length scales and describe how photodissociation might account for some of these observations. Finally, I discuss several consequences which follow if this view of the origin of HI in galaxies continues to be successful.Comment: 18 pages, 7 figures in 8 files, invited review paper for the conference "Penetrating Bars Through Masks of Cosmic Dust: The Hubble Tuning Fork Strikes a New Note", South Africa, June 2004. Proceedings to be published by Kluwer, eds. D.L. Block, K.C. Freeman, I. Puerari, R. Groess, & E.K. Bloc

Age-related differences in selection by visual saliency

We examined the ability of older adults to select local and global stimuli varying in perceptual saliency – a task requiring non-spatial visual selection. Participants were asked to identify in separate blocks a target at either the global or local level of a hierarchical stimulus, while the saliency of each level was varied (across different conditions either the local or the global form was the more salient and relatively easier to identify). Older adults were less efficient than young adults in ignoring distractors that were higher in saliency than targets, and this occurred across both the global and local levels of form. The increased effects of distractor saliency on older adults occurred even when the effects were scaled by overall differences in task performance. The data provide evidence for an age-related decline in non spatial attentional selection of low-salient hierarchical stimuli, not determined by the (global or local) level at which selection was required. We discuss the implications of these results for understanding both the interaction between saliency and hierarchical processing and the effects of aging on non-spatial visual attention

Time preferences and risk aversion: tests on domain differences

The design and evaluation of environmental policy requires the incorporation of time and risk elements as many environmental outcomes extend over long time periods and involve a large degree of uncertainty. Understanding how individuals discount and evaluate risks with respect to environmental outcomes is a prime component in designing effective environmental policy to address issues of environmental sustainability, such as climate change. Our objective in this study is to investigate whether subjects' time preferences and risk aversion across the monetary domain and the environmental domain differ. Crucially, our experimental design is incentivized: in the monetary domain, time preferences and risk aversion are elicited with real monetary payoffs, whereas in the environmental domain, we elicit time preferences and risk aversion using real (bee-friendly) plants. We find that subjects' time preferences are not significantly different across the monetary and environmental domains. In contrast, subjects' risk aversion is significantly different across the two domains. More specifically, subjects (men and women) exhibit a higher degree of risk aversion in the environmental domain relative to the monetary domain. Finally, we corroborate earlier results, which document that women are more risk averse than men in the monetary domain. We show this finding to, also, hold in the environmental domain

Using Read-Across to Build Physiologically-Based Kinetic Models: Part 2. Case Studies for atenolol and flumioxazin

Read-across, wherein information from a data-rich chemical is used to make a prediction for a similar chemical that lacks the relevant data, is increasingly being accepted as an alternative to animal testing. Identifying chemicals that can be considered as similar (analogues) is crucial to the process. Two resources have been developed previously to address the issue of analogue selection and facilitate physiologically-based kinetic (PBK) model development, using read-across. Chemical-specific PBK models, available in the literature, were collated to form a PBK model dataset (PMD) of over 7,500 models. A KNIME workflow was created to accompany this PMD that can aid the selection of appropriate chemical analogues from chemicals within this dataset (i.e. chemicals that are similar to a target of interest and are known to have an existing PBK model). Information from the PBK model for the source chemical can then be used in a read-across approach to inform the development of a new PBK model for the target. The application of these resources is tested here using two case studies (i) for the drug atenolol and (ii) for the plant protection product, flumioxazin. New PBK models were constructed for these two target chemicals using data obtained from source chemicals, identified by the workflow as being similar (analogues). In each case, the published PBK model for the source chemical was initially reproduced, as accurately as possible, before being adapted and used as a template for the target chemical. The performance of the new PBK models was assessed by comparing simulation outputs to existing data on key kinetic properties for the targets. The results demonstrate that a read-across approach can be successfully applied to develop new PBK models for data-poor chemicals, thus enabling their deployment during early-stage risk assessment. This assists prediction of internal exposure whilst reducing reliance on animal testing

Smoking Comorbidity in Alcoholism: Neurobiological and Neurocognitive Consequences

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65249/1/j.1530-0277.2006.00034.x.pd

Age and distraction are determinants of performance on a novel visual search task in aged Beagle dogs

Aging has been shown to disrupt performance on tasks that require intact visual search and discrimination abilities in human studies. The goal of the present study was to determine if canines show age-related decline in their ability to perform a novel simultaneous visual search task. Three groups of canines were included: a young group (N = 10; 3 to 4.5 years), an old group (N = 10; 8 to 9.5 years), and a senior group (N = 8; 11 to 15.3 years). Subjects were first tested for their ability to learn a simple two-choice discrimination task, followed by the visual search task. Attentional demands in the task were manipulated by varying the number of distracter items; dogs received an equal number of trials with either zero, one, two, or three distracters. Performance on the two-choice discrimination task varied with age, with senior canines making significantly more errors than the young. Performance accuracy on the visual search task also varied with age; senior animals were significantly impaired compared to both the young and old, and old canines were intermediate in performance between young and senior. Accuracy decreased significantly with added distracters in all age groups. These results suggest that aging impairs the ability of canines to discriminate between task-relevant and -irrelevant stimuli. This is likely to be derived from impairments in cognitive domains such as visual memory and learning and selective attention

Detecting failure of climate predictions

The practical consequences of climate change challenge society to formulate responses that are more suited to achieving long-term objectives, even if those responses have to be made in the face of uncertainty. Such a decision-analytic focus uses the products of climate science as probabilistic predictions about the effects of management policies. Here we present methods to detect when climate predictions are failing to capture the system dynamics. For a single model, we measure goodness of fit based on the empirical distribution function, and define failure when the distribution of observed values significantly diverges from the modelled distribution. For a set of models, the same statistic can be used to provide relative weights for the individual models, and we define failure when there is no linear weighting of the ensemble models that produces a satisfactory match to the observations. Early detection of failure of a set of predictions is important for improving model predictions and the decisions based on them. We show that these methods would have detected a range shift in northern pintail 20 years before it was actually discovered, and are increasingly giving more weight to those climate models that forecast a September ice-free Arctic by 2055