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Temperature-related words such as cold-blooded and hot-headed can be used to describe criminal behavior. Words associated with coldness describe premeditated behavior and words associated with heat describe impulsive behavior. Building on recent research about the close interplay between physical and interpersonal coldness and warmth, we examined in a lab experiment how ambient temperature within a comfort zone influences judgments of criminals. Participants in rooms with low temperature regarded criminals to be more cold-blooded than participants in rooms with high temperature. Specifically, they were more likely to attribute premeditated crimes, ascribed crimes resulting in higher degrees of penalty, and attributed more murders to criminals. Likewise, participants in rooms with high temperature regarded criminals to be more hot-headed than participants in rooms with low temperature: They were more likely to attribute impulsive crimes. Results imply that cognitive representations of temperature are closely related to representations of criminal behavior and attributions of intent.

As one of the most abundant materials in the world, calcium carbonate, CaCO3, is the main constituent of the skeletons and shells of various marine organisms. It is used in the cement industry and plays a crucial role in the global carbon cycle and formation of sedimentary rocks. For more than a century, only three polymorphs of pure CaCO3—calcite, aragonite, and vaterite—were known to exist at ambient conditions, as well as two hydrated crystal phases, monohydrocalcite (CaCO3·1H2O) and ikaite (CaCO3·6H2O). While investigating the role of magnesium ions in crystallization pathways of amorphous calcium carbonate, we unexpectedly discovered an unknown crystalline phase, hemihydrate CaCO3·½H2O, with monoclinic structure. This discovery may have important implications in biomineralization, geology, and industrial processes based on hydration of CaCO3.

The orexin system regulates sleep and arousal in humans, with orexin receptor antagonists becoming promising therapeutics for insomnia; now, the X-ray crystal structure of the human OX 2 receptor in the presence of the insomnia drug suvorexant is solved. Antagonst-bound orexin receptor structures The orexin(hypocretin) system regulates sleep and arousal in humans, and orexin receptor antagonists are seen as promising therapeutics for insomnia. Here the authors solve the X-ray crystal structure of the human OX 2 orexin receptor in the presence of the suvorexant, a dual-orexin receptor antagonist anti-insomnia drug. The structure provides a molecular framework for understanding dual-orexin receptor antagonist binding. The authors use two different docking programs to predict how three other antagonists with different core structures may bind to this G-protein-coupled receptor. The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans 1 . Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia 2 . The human OX 2 receptor (OX 2 R) belongs to the β branch of the rhodopsin family of GPCRs 3 , and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant 4 . Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX 2 R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX 2 R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.

G-protein-coupled receptors do not only feature the orthosteric pockets, where most endogenous agonists bind, but also a multitude of other allosteric pockets that have come into the focus as potential binding sites for synthetic modulators. Here, to better characterise such pockets, we investigate 557 GPCR structures by exhaustively docking small molecular probes in silico and converting the ensemble of binding locations to pocket-defining volumes. Our analysis confirms all previously identified pockets and reveals nine previously untargeted sites. In order to test for the feasibility of functional modulation of receptors through binding of a ligand to such sites, we mutate residues in two sites, in two model receptors, the muscarinic acetylcholine receptor M 3 and β 2 -adrenergic receptor. Moreover, we analyse the correlation of inter-residue contacts with the activation states of receptors and show that contact patterns closely correlating with activation indeed coincide with these sites. G-protein-coupled receptors bind endogenous ligands at sites that are frequently highly conserved. Here, authors computationally describe alternative allosteric pockets, several of which have not been targeted by synthetic ligands before.

Organic aerosol (OA) particles affect climate forcing and human health, but their sources and evolution remain poorly characterized. We present a unifying model framework describing the atmospheric evolution of OA that is constrained by high-time-resolution measurements of its composition, volatility, and oxidation state. OA and OA precursor gases evolve by becoming increasingly oxidized, less volatile, and more hygroscopic, leading to the formation of oxygenated organic aerosol (OOA), with concentrations comparable to those of sulfate aerosol throughout the Northern Hemisphere. Our model framework captures the dynamic aging behavior observed in both the atmosphere and laboratory: It can serve as a basis for improving parameterizations in regional and global models.

Targeting the Frizzled family (FZD 1-10 ) of WNT receptors pharmacologically has, despite substantial therapeutic potential, proven difficult. Given an almost complete lack of validated, effective small molecules targeting FZDs, no putative ligand binding site has so far been identified. In order to target FZD 7 , a potential target for the treatment of intestinal tumors, we combine an approach of adapted docking setups and large molecular library docking screens, identifying compound C407. Applying pharmacological assays, genetically-encoded biosensors, site-directed mutagenesis, cryo-electron microscopy and molecular dynamics simulations, the compound binding site in the core of the seven transmembrane bundle is validated and C407 is confirmed as a negative allosteric modulator of WNT-induced and FZD-mediated WNT/ β -catenin signaling. In summary, we provide here the proof-of-principle that targeting FZDs with small molecule compounds is possible and effective. Future hit optimization and functional validation in disease-relevant in vitro and in vivo models will pave the way towards clinical exploration. Although FZDs are promising drug targets, so far no small molecules targeting them were described. Here, the authors report the a FZD7 core-targeting small molecule negative allosteric modulators of WNT-induced signaling, confirmed by pharmacology, structure determination and MD simulations.

Orexins are neuropeptides that activate the rhodopsin-like G proteincoupled receptors OX1R and OX2R. The orexin system plays an important role in the regulation of the sleep-wake cycle and the regulation of feeding and emotions. The nonselective orexin receptor antagonist suvorexant has been the first drug on the market targeting the orexin system and is prescribed for the treatment of insomnia. Subtype-selective OX1R antagonists are valuable tools to further investigate the functions and physiological role of the OX1R in vivo and promising lead compounds for the treatment of drug addiction, anxiety, pain or obesity. Starting from the OX1R and OX2R crystal structures bound to suvorexant, we exploited a single amino acid difference in the orthosteric binding site by using molecular docking and structure-based drug design to optimize ligand interactions with the OX1R while introducing repulsive interactions with the OX2R. A newly established enantiospecific synthesis provided ligands showing up to 75-fold selectivity for the OX1R over the OX2R subtype. The structure of a new OX1R antagonist with subnanomolar affinity (JH112) was determined by crystallography in complex with the OX1R and corresponded closely to the dockingpredicted geometry. JH112 exhibits high selectivity over a panel of different GPCRs, is able to cross the blood–brain barrier and acts as slowly diffusing and insurmountable antagonist for Gq protein activation and in particular β-arrestin-2 recruitment at OX1R. This study demonstrates the potential of structure-based drug design to develop more subtype-selective GPCR ligands with potentially reduced side effects and provides an attractive probe molecule and lead compound.

Recent developments in stem cell biology have enabled the study of cell fate decisions in early human development that are impossible to study in vivo. However, understanding how development varies across individuals and, in particular, the influence of common genetic variants during this process has not been characterised. Here, we exploit human iPS cell lines from 125 donors, a pooled experimental design, and single-cell RNA-sequencing to study population variation of endoderm differentiation. We identify molecular markers that are predictive of differentiation efficiency of individual lines, and utilise heterogeneity in the genetic background across individuals to map hundreds of expression quantitative trait loci that influence expression dynamically during differentiation and across cellular contexts. Studying the genetic effects on early stages of human development is challenging due to a scarcity of biological material. Here, the authors utilise induced pluripotent stem cells from 125 donors to track gene expression changes and expression quantitative trait loci at single cell resolution during in vitro endoderm differentiation.

Background Novel, less-invasive technologies to screen for Barrett’s esophagus (BE) may enable a paradigm shift in early detection strategies for esophageal adenocarcinoma (EAC). Understanding professionals’ perspectives on screening is important to determine how to proceed. We aimed to explore and compare professionals’ perceptions of screening for BE and EAC screening in three countries. Methods In this study, 29 Dutch, 20 British and 18 American health care professionals (clinicians, researchers and policy makers) participated in concept mapping: a mixed-methods consensus building methodology. Statements on perceived barriers, facilitators, advantages, disadvantages, implications or worries associated with screening for BE and EAC were collected in asynchronous digital brainstorm sessions. Subsequently, participants sorted the statements into groups according to thematic similarity and assessed the relevance of each statement in evaluating the acceptability of BE and EAC screening. Multidimensional scaling and cluster analysis were used to map the associations between generated statements. Results Professionals across three countries identified eight consistent themes that relate to their perceptions of screening for BE and EAC: (1) Benefits, (2) Harms, (3) Clinical effectiveness concerns, (4) Screening population, (5) Screening modality, (6) Resources, (7) Ownership, and (8) Public communication. Dutch and American professionals prioritized the potential health benefits of screening but also questioned clinical impact. In contrast, British participants prioritized identification of the screening population and suitable test. Conclusions Most professionals see potential in less-invasive screening tests for BE and EAC but underline the need to define the target screening population and determine benefits and harms before widely employing them. Successful implementation will require thoughtful consideration of the involvement of general practitioners, readiness of endoscopy and pathology services, balanced public communication, and country-specific regulations.