CREBBP (CBP or KAT3A) and its paralogue P300 (also KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise ten domains through which they interact with over 400 proteins, making them important transcriptional co-activators, and key nodes in the human protein-protein interactome. The bromodomain of CREBBP and P300 enables binding of acetylated lysine residues from histones, and a number of other important proteins, including p53, p73, E2F and GATA1. Here we report work to develop a high affinity, small molecule, ligand for the CREBBP and P300 bromodomains [(−)-OXFBD05] that shows >100-fold selectivity over the BET bromodomains. Key to the development of (−)-OXFBD05 were fundamental studies on molecular conformation in solution and when bound to the CREBBP bromodomain. In particular, the effect of an intramolecular hydrogen bond on solution state conformation, and use of an amide bioisostere, enabled the development of (−)-OXFBD05. Initial cellular studies using this ligand demonstrate that inhibition of the CREBBP/P300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc, and a modest but repeatable reduction in H3K18 acetylation. In hypoxia (<0.1% O2), inhibition of the CREBBP/P300 bromodomain results in enhanced stabilization of HIF-1α. This presents an opportunity for modulating proteins that are affected by HIF-1α levels, including ACE2, which mediates SARS-CoV-2 infection of human cells.

Previous studies have found that increased cognitive load during a task might result in the use of 'easier' motor strategies that nevertheless achieve task goals. Here, we investigated the influence of cognitive load on bimanual or unimanual strategy use in preschoolers, through a combination of secondary data analysis and new empirical data. Experiment 1 investigated block-stacking strategies under high, medium and low cognitive load tasks in 3-year-olds and showed that 3-year-olds demonstrated significantly more unimanual strategy use in the high cognitive load task. Experiment 2 investigated (i) whether this effect persisted across preschool years and (ii) whether it was modulated by differences in executive function abilities. There was no age effect in motor strategy use under high cognitive load from 3 to 5 years of age. However, individual differences in inhibitory control and working memory use were significantly associated with differences in unimanual strategy use. These results are interpreted as evidence for a cognitive/action trade-off in which higher cognitive demands result in the adjustment of motor strategies such as use of unimanual stacking instead of bimanual coordination in preschoolers.

The synthetic medicinal chemist plays a vital role in drug discovery. Today there are AI tools to guide next syntheses, but many are "Black Boxes" (BB). One learns little more than the prediction made. There are now also AI methods emphasizing visibility and "explainability" (thus explainable AI or XAI) that could help when "compositional data" are used, but they often still start from seemingly arbitrary learned weights and lack familiar probabilistic measures based on observation and counting from the outset. If probabilistic methods were used in a complementary way with BB methods and demonstrated comparable predictive power, they would provide guidelines about what groups to include and avoid in next syntheses and quantify the relationships in probabilistic terms. These points are demonstrated by blind test comparison of two main types of BB methods and a probabilistic "Glass Box" (GB) method new outside of medicine, but which appears well suited to the above. Because many probabilities can be involved, emphasis is on the predictive power of its simplest explanatory models. There are usually more inactive compounds by orders of magnitude, often a problem for machine learning methods. However, the approaches used here appear to work well for such "real world data".

The seventh blind test of crystal structure prediction (CSP) methods substantially increased the level of complexity of the target compounds relative to the previous tests organized by the Cambridge Crystallographic Data Centre. In this work, the performance of density-functional methods is assessed using numerical atomic orbitals and the exchange-hole dipole moment dispersion correction (XDM) for the energy-ranking phase of the seventh blind test. Overall, excellent performance was seen for the two rigid molecules (XXVII, XXVIII) and for the organic salt (XXXIII). However, for the agrochemical (XXXI) and pharmaceutical (XXXII) targets, the experimental polymorphs were ranked fairly high in energy amongst the provided candidate structures and inclusion of thermal free-energy corrections from the lattice vibrations was found to be essential for compound XXXI. Based on these results, it is proposed that the importance of vibrational free-energy corrections increases with the number of rotatable bonds.

Introduction Core aspects of executive functions (EFs) are known to be related to academic skills such as literacy and numeracy. However, school outcomes may also be related to higher-level functions such as planning. Nevertheless, few studies have considered assessing natural manifestations of higher-level EFs in children who are on the cusp of entering formal schooling. One reason for this is the difficulty of obtaining ecologically valid measures of EFs in preschool-aged children. Method We describe a novel task - building a striped Duplo tower subject to two constraints - designed to assess planning in real-world multi-action situation. Children were instructed to build a tower to a certain height by alternating between two different colors of blocks. Results Performance on one of the constraints in this task was found to vary with age. Importantly, distinct components of multiple constraints planning performance predicted laboratory-based measures of inhibitory control and working memory efficacy. Discussion Thus, this task provides a simple, cheap and effective way of assessing executive function in toddlers through the observation of natural behavior. It also opens up possibilities to investigate the neurodevelopment of EF in the real world.

The ease with which humans usually perform everyday activities masks their inherit complexity. Tasks such as setting a table prior to a meal or preparing a hot beverage require the coordination of several cognitive abilities. At the same time, many everyday activities are simple enough to afford investigation in controlled lab settings. One main goal of this issue is to raise awareness of everyday activities as a topic and a field of study in its own right, which allows investigating (a) selected cognitive abilities with high ecological validity and (b) the interplay and integration of key cognitive abilities. To this end, this topic consists of eight papers that span different aspects of everyday activities, ranging from neuroscience through philosophical considerations and implications to lessons from robotics.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

New heterometallic hydride complexes that involve the addition of {Mg–H} and {Zn–H} bonds to group 10 transition metals (Pd, Pt) are reported. The side-on coordination of a single {Mg–H} to Pd forms a well-defined σ-complex. In contrast, addition of three {Mg–H} or {Zn–H} bonds to Pd or Pt results in the formation of planar complexes with subtly different geometries. We compare their structures through experiment (X-ray diffraction, neutron diffraction, multinuclear NMR), computational methods (DFT, QTAIM, NCIPlot), and theoretical analysis (MO diagram, Walsh diagram). These species can be described as snapshots along a continuum of bonding between ideal trigonal planar and hexagonal planar geometries.

In order to explore the effect of normal aging on executive function, we tested 25 younger adults and 25 neurologically healthy older adults on the Wisconsin Card Sorting Test (WCST) and the Brixton Spatial Anticipation Test (BRXT), two classic tests of executive function. We found that older participants were more likely than younger participants to err on both tasks, but the additional errors of older participants tended to be related to task set maintenance and rule inference rather than perseveration. We further found that the tendency to perseverate (across all participants) on the WCST was related to the tendency to produce stimulus or response perseverations on the BRXT, rather than any tendency to perseverate on BRXT rule application. Finally, on both tasks, older participants were also slower, particularly on trials following an error, than younger participants. To explore the neurocomputational basis for the observed behaviours we then extended an existing model of schema-modulated action selection on the WCST to the BRXT. We argue on the basis of the model that the performance of older participants on both tasks reflects a slower update of schema thresholds within the basal ganglia, coupled with a decrease in sensitivity to feedback.

CREBBP (CBP or KAT3A) and its paralogue P300 (also KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise ten domains through which they interact with over 400 proteins, making them important transcriptional co-activators, and key nodes in the human protein-protein interactome. The bromodomain of CREBBP and P300 enables binding of acetylated lysine residues from histones, and a number of other important proteins, including p53, p73, E2F and GATA1. Here we report work to develop a high affinity, small molecule, ligand for the CREBBP and P300 bromodomains [(−)-OXFBD05] that shows >100-fold selectivity over the BET bromodomains. Key to the development of (−)-OXFBD05 were fundamental studies on molecular conformation in solution and when bound to the CREBBP bromodomain. In particular, the effect of an intramolecular hydrogen bond on solution state conformation, and use of an amide bioisostere, enabled the development of (−)-OXFBD05. Initial cellular studies using this ligand demonstrate that inhibition of the CREBBP/P300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc, and a modest but repeatable reduction in H3K18 acetylation. In hypoxia (<0.1% O2), inhibition of the CREBBP/P300 bromodomain results in enhanced stabilization of HIF-1α. This presents an opportunity for modulating proteins that are affected by HIF-1α levels, including ACE2, which mediates SARS-CoV-2 infection of human cells.

Structure determination from single crystal diffraction data occasionally runs into problems during the refinement, analysis and publication stages: either the headline quality measures (R-values, residual density) are worse than anticipated or online validation tools [1] throw up warnings which require investigation, correction, or justification.Crystal structure data -typically in .insand .hklformat -can be easily imported into the crystal structure analysis package CRYSTALS [2] where a number of useful plots and analyses of the data are available.We find that these tools enable a rapid overview and identification of problems, whether we are looking at our own data, refereeing data for journals, or assisting colleagues with problematic datasets.Examples and discussion of the causes of these problems will be presented.Interested crystallographers or reviewers are encouraged to install the CRYSTALS package which is available from http://www.xtl.ox.ac.uk/

The Independent Atom Model (IAM) of electron density is used in routine X-ray data analysis. However, this model does not give a quantitative description of the electron-density distribution. A better model that allows for modelling of aspherical charge density deformations is introduced by the Hansen-Coppens variant of the multipole model of electron density. However, the application of this model requires crystals of excellent quality and high-resolution XRD data which are quite often difficult criteria to fulfil. Therefore, Mo K alpha and Cu K alpha data of three model compounds (tricyclic imide, xylitol and methyluracil) were refined using IAM and new methods which enabled the refinement and reconstruction of charge density based on the Cu K alpha data. These methods were the Bond-Oriented Deformation Density (BODD) model, Hirshfeld Atom Refinement (HAR) and the Transferable Aspherical Atom Model (TAAM). The final results were compared to the model obtained from neutron diffraction experiments. Our results demonstrated not only that Cu K alpha data may be refined using BODD, HAR and TAAM methods, but also revealed systematic errors arising from the use of Cu K alpha data. These errors were a result of the limited information in the low-resolution data set that manifested as higher values for the anisotropic displacement parameters (ADPs) and smaller maxima and minima of the residual electron density for the Cu K alpha data compared to the Mo K alpha data. Notably, these systematic errors were much less significant than those found for the IAM. Therefore, the application of B ODD, HAR and TAAM on Cu K alpha data has a more significant influence on the final results of refinement than for the Mo K alpha data.

Executing goal-directed action sequences is fundamental to our behavior. Planning and controlling these action sequences improves greatly over the preschool years. In this study, we examined preschoolers' ability to plan action sequences. A total of 69 3- to 5-year-olds were assessed on an action sequence planning task with a hierarchical goal structure and on several executive function tasks. Planning abilities improved with age. Improvements in inhibition were related to avoidance of actions irrelevant to the goal hierarchy. Updating skill appears to be associated with executing actions relevant to different subgoals. Using optical motion capture, we showed that children who followed the subgoals displayed less movement with their nonreaching hand within a subgoal. This effect was enhanced in children with better inhibitory skills, suggesting that such skills allow greater focus on executing the current subgoal. Thus, we provide evidence that structuring of subgoals in action sequence planning emerges during the preschool years and that improvements in performance in action sequence planning are related to executive functions.