Novel feature selection methods for construction of accurate epigenetic clocks.

Epigenetic clocks allow us to accurately predict the age and future health of individuals based on the methylation status of specific CpG sites in the genome and are a powerful tool to measure the effectiveness of longevity interventions. There is a growing need for methods to efficiently construct epigenetic clocks. The most common approach is to create clocks using elastic net regression modelling of all measured CpG sites, without first identifying specific features or CpGs of interest. The addition of feature selection approaches provides the opportunity to optimise the identification of predictive CpG sites. Here, we apply novel feature selection methods and combinatorial approaches including newly adapted neural networks, genetic algorithms, and 'chained' combinations. Human whole blood methylation data of ~470,000 CpGs was used to develop clocks that predict age with R2 correlation scores of greater than 0.73, the most predictive of which uses 35 CpG sites for a R2 correlation score of 0.87. The five most frequent sites across all clocks were modelled to build a clock with a R2 correlation score of 0.83. These two clocks are validated on two external datasets where they maintain excellent predictive accuracy. When compared with three published epigenetic clocks (Hannum, Horvath, Weidner) also applied to these validation datasets, our clocks outperformed all three models. We identified gene regulatory regions associated with selected CpGs as possible targets for future aging studies. Thus, our feature selection algorithms build accurate, generalizable clocks with a low number of CpG sites, providing important tools for the field.

Multimodal coding and strategic approach in young and older adults' visual working memory performance.

Visual working memory (WM) was investigated in young (18-35 yrs) and older (63-88 yrs) adults by assessing use of visual and verbal processing, and strategic approach. Experiment 1 comprised a visual interference paradigm, to investigate visual rehearsal during an abstract visual WM task. Results suggested both groups used a visual strategy, but older adults struggled more when visual interference was administered first, perhaps due to difficulty developing non-visual strategies. In Experiment 2, a more meaningful task version was additionally administered, offering greater opportunity for multimodal coding. Despite the marked effect of age, both groups benefited from semantic availability to the same extent. Young adults reported a verbal strategy more than older adults, who reported less verbal labeling and more visual refreshing, and a less efficient approach overall. The results highlight age-related limitations in visual WM capacity and strategy use, but show potential for compensation, and a role for task practice.

Consensus-based good practice guidelines for clinical psychologists to support care staff in enabling sexual expression in people with intellectual disabilities-A Delphi study.

BACKGROUND: Care staff supporting people with intellectual disabilities (PWID) report accepting views on PWID's sexual expression, but people with intellectual disabilities report their sexual expression is restricted by care staff. METHODS: We recruited a panel of 17 UK clinical psychologists experienced in helping care staff support PWID's sexual expression. We used the Delphi Method to develop consensus-based practice guidelines for UK clinical psychologists supporting care staff in this way. RESULTS: Having proposed three guidelines each in Round One, panel members reached consensus (≥90% agreement) that 12 were important, falling under four themes: "Addressing staff attitudes," "Addressing uncertainty about rights and responsibilities of people with intellectual disabilities," "Locating the problem, being part of the solution," and "Supporting care staff to understand and reflect upon their role." CONCLUSIONS: Clinical psychologists help care staff support PWID's sexual expression by normalizing care staff concerns, encouraging reflection, clarifying PWID's rights, and prompting those at managerial and service level to support care staff.

Molecular mechanisms underlying striatal synaptic plasticity: relevance to chronic alcohol consumption and seeking.

The striatum, the input structure of the basal ganglia, is a major site of learning and memory for goal-directed actions and habit formation. Spiny projection neurons of the striatum integrate cortical, thalamic, and nigral inputs to learn associations, with cortico-striatal synaptic plasticity as a learning mechanism. Signaling molecules implicated in synaptic plasticity are altered in alcohol withdrawal, which may contribute to overly strong learning and increased alcohol seeking and consumption. To understand how interactions among signaling molecules produce synaptic plasticity, we implemented a mechanistic model of signaling pathways activated by dopamine D1 receptors, acetylcholine receptors, and glutamate. We use our novel, computationally efficient simulator, NeuroRD, to simulate stochastic interactions both within and between dendritic spines. Dopamine release during theta burst and 20-Hz stimulation was extrapolated from fast-scan cyclic voltammetry data collected in mouse striatal slices. Our results show that the combined activity of several key plasticity molecules correctly predicts the occurrence of either LTP, LTD, or no plasticity for numerous experimental protocols. To investigate spatial interactions, we stimulate two spines, either adjacent or separated on a 20-µm dendritic segment. Our results show that molecules underlying LTP exhibit spatial specificity, whereas 2-arachidonoylglycerol exhibits a spatially diffuse elevation. We also implement changes in NMDA receptors, adenylyl cyclase, and G protein signaling that have been measured following chronic alcohol treatment. Simulations under these conditions suggest that the molecular changes can predict changes in synaptic plasticity, thereby accounting for some aspects of alcohol use disorder.