CACHE (Critical Assessment of Computational Hit-finding Experiments): A public–private partnership benchmarking initiative to enable the development of computational methods for hit-finding

One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small-molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small-molecule binders for new and biologically relevant protein targets representing different prediction scenarios. Predicted compounds will be tested rigorously in an experimental hub, and all predicted binders as well as all experimental screening data, including the chemical structures of experimentally tested compounds, will be made publicly available and not subject to any intellectual property restrictions. The ability of a range of computational approaches to find novel binders will be evaluated, compared and openly published. CACHE will launch three new benchmarking exercises every year. The outcomes will be better prediction methods, new small-molecule binders for target proteins of importance for fundamental biology or drug discovery and a major technological step towards achieving the goal of Target 2035, a global initiative to identify pharmacological probes for all human proteins. [Figure not available: see fulltext.

Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals

Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [11C]raclopride and [11C]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity

The Staphylococcus aureus RNome and Its Commitment to Virulence

Staphylococcus aureus is a major human pathogen causing a wide spectrum of nosocomial and community-associated infections with high morbidity and mortality. S. aureus generates a large number of virulence factors whose timing and expression levels are precisely tuned by regulatory proteins and RNAs. The aptitude of bacteria to use RNAs to rapidly modify gene expression, including virulence factors in response to stress or environmental changes, and to survive in a host is an evolving concept. Here, we focus on the recently inventoried S. aureus regulatory RNAs, with emphasis on those with identified functions, two of which are directly involved in pathogenicity

Dynamic Energy Landscapes of Riboswitches Help Interpret Conformational Rearrangements and Function

Riboswitches are RNAs that modulate gene expression by ligand-induced conformational changes. However, the way in which sequence dictates alternative folding pathways of gene regulation remains unclear. In this study, we compute energy landscapes, which describe the accessible secondary structures for a range of sequence lengths, to analyze the transcriptional process as a given sequence elongates to full length. In line with experimental evidence, we find that most riboswitch landscapes can be characterized by three broad classes as a function of sequence length in terms of the distribution and barrier type of the conformational clusters: low-barrier landscape with an ensemble of different conformations in equilibrium before encountering a substrate; barrier-free landscape in which a direct, dominant “downhill” pathway to the minimum free energy structure is apparent; and a barrier-dominated landscape with two isolated conformational states, each associated with a different biological function. Sharing concepts with the “new view” of protein folding energy landscapes, we term the three sequence ranges above as the sensing, downhill folding, and functional windows, respectively. We find that these energy landscape patterns are conserved in various riboswitch classes, though the order of the windows may vary. In fact, the order of the three windows suggests either kinetic or thermodynamic control of ligand binding. These findings help understand riboswitch structure/function relationships and open new avenues to riboswitch design

Smart home sensing and monitoring in households with dementia: user-centered design approach

Background: As life expectancy grows, so do the challenges of caring for an ageing population. Older adults, including people with dementia, want to live independently and feel in control of their lives for as long as possible. Assistive technologies powered by Artificial Intelligence and Internet of Things devices are being proposed to provide living environments that support the users’ safety, psychological, and medical needs through remote monitoring and interventions. Objective: This study investigates the functional, psychosocial, and environmental needs of people living with dementia, their caregivers, clinicians, and health and social care service providers towards the design and implementation of smart home systems. Methods: We used an iterative user-centered design approach comprising nine sub-studies. First, semi-structured interviews (N = 9 people with dementia, 9 caregivers, 10 academic and clinical staff), ethnographic observations in clinics (N = 10 people with dementia, 10 caregivers, 3 clinical monitoring team members), and workshops (N = 35 pairs of people with dementia and caregivers, 12 health and social care clinicians) were conducted to define the needs of people with dementia, home caregivers and professional stakeholders in both daily activities and technology-specific interactions. Then, the spectrum of needs identified was represented via patient-caregiver personas and discussed with stakeholders in a workshop (N = 14 occupational therapists, 4 National Health Service pathway directors, 6 researchers in occupational therapy, neuropsychiatry and engineering) and two focus groups with managers of healthcare services (N = 8), eliciting opportunities for innovative care technologies and public health strategies. Finally, these opportunities were discussed in semi-structured interviews with participants of a smart home trial involving environmental sensors, physiological measurement devices, smart watches, and tablet-based chatbots and cognitive assessment puzzles (N = 10 caregivers, 2 people with dementia). A thematic analysis revealed factors that motivate household members to use these technologies. Results: Outcomes of these activities include the definition of clinically relevant patient-caregiver personas, a qualitative and quantitative analysis of patient, caregiver and clinician needs, and the identification of challenges and opportunities for the design and implementation of remote monitoring systems in public health pathways. Conclusions: Participatory design methods increased the impact of public-patient-involvement by supporting the triangulation of perspectives, the development of more patient-centered interventions, and their translation to clinical practice and public health strategy. We discuss the implications and limitations of these dementia-specific findings, the value and the applicability of our methodology, and directions for future research