| 1. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Buchanan, E. M., et al.
(författare)
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The Psychological Science Accelerator's COVID-19 rapid-response dataset
- 2023
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- In response to the COVID-19 pandemic, the Psychological Science Accelerator coordinated three large-scale psychological studies to examine the effects of loss-gain framing, cognitive reappraisals, and autonomy framing manipulations on behavioral intentions and affective measures. The data collected (April to October 2020) included specific measures for each experimental study, a general questionnaire examining health prevention behaviors and COVID-19 experience, geographical and cultural context characterization, and demographic information for each participant. Each participant started the study with the same general questions and then was randomized to complete either one longer experiment or two shorter experiments. Data were provided by 73,223 participants with varying completion rates. Participants completed the survey from 111 geopolitical regions in 44 unique languages/dialects. The anonymized dataset described here is provided in both raw and processed formats to facilitate re-use and further analyses. The dataset offers secondary analytic opportunities to explore coping, framing, and self-determination across a diverse, global sample obtained at the onset of the COVID-19 pandemic, which can be merged with other time-sampled or geographic data.
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| 17. |
- Alexander, Stephen P. H., et al.
(författare)
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The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
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Ingår i: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 18. |
- Bongers, B. J., et al.
(författare)
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Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- G Protein-coupled receptors (GPCRs) are the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used a dataset of mutations found in patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 genomes project. We explored cancer-related mutation patterns in all GPCR classes combined and individually. While the location of the mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment in cancer patients was observed among class-specific conserved motifs in GPCRs such as the Class A "DRY" motif. A Two-Entropy Analysis confirmed the correlation between residue conservation and cancer-related mutation frequency. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). Our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, but also discovered novel GPCRs which had not been linked to cancer before such as the P2Y Receptor 10 (P2RY10). Overall, this study presents a list of GPCRs that are amenable to experimental follow up to elucidate their role in cancer.
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| 21. |
- Fluitman, Kristina S., et al.
(författare)
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The Association of Olfactory Function with BMI, Appetite, and Prospective Weight Change in Dutch Community-Dwelling Older Adults
- 2019
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Ingår i: Journal of Nutrition Health & Aging. - : Springer Science and Business Media LLC. - 1279-7707 .- 1760-4788. ; 23:8, s. 746-752
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The olfactory decline that often accompanies aging is thought to contribute to undernutrition in older adults. It is believed to negatively affect eating pleasure, appetite, food intake and subsequently nutritional status. We have evaluated the associations of olfactory function with BMI, appetite and prospective weight change in a cohort of Dutch community-dwelling older adults. Design Cross-sectional cohort study. Participants Dutch community-dwelling older adults from the ongoing Longitudinal Aging Study Amsterdam (LASA). Measurements and setting In 2012-2013, the 40-item University of Pennsylvania Smell Identification Test (UPSIT) was administered to 824 LASA participants to evaluate their olfactory function. Body weight, height, appetite, comorbidity, cognitive status and socio-demographic factors were also assessed. Follow-up weight was measured after three years. Results 673 participants (aged 55-65 years) were included in the regression analyses. Median UPSIT-score was 33. When adjusted for potential confounders, lower UPSIT-score (indicative of poorer olfactory function) was not associated with poor appetite (OR = 1.062, p = 0.137) or prospective weight change (B = -0.027, p = 0.548). It was, however, associated with lower BMI in smokers (B = 0.178, p = 0.032), but not in non-smokers (B = -0.015, p = 0.732). Conclusion Lower olfactory function scores were associated with lower BMI in community-dwelling older adults who smoke, but not with appetite or prospective weight change. Therefore, smoking older adults with olfactory impairments may pose as a vulnerable group with respect to developing undernutrition.
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| 22. |
- Kurilshikov, Alexander, et al.
(författare)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 23. |
- Burggraaff, Lindsey, et al.
(författare)
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Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors
- 2020
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Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 60:9, s. 4283-4295
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Tidskriftsartikel (refereegranskat)abstract
- Kinases are frequently studied in the context of anticancer drugs. Their involvement in cell responses, such as proliferation, differentiation, and apoptosis, makes them interesting subjects in multitarget drug design. In this study, a workflow is presented that models the bioactivity spectra for two panels of kinases: (1) inhibition of RET, BRAF, SRC, and S6K, while avoiding inhibition of MKNK1, TTK, ERK8, PDK1, and PAK3, and (2) inhibition of AURKA, PAK1, FGFR1, and LKB1, while avoiding inhibition of PAK3, TAK1, and PIK3CA. Both statistical and structure-based models were included, which were thoroughly benchmarked and optimized. A virtual screening was performed to test the workflow for one of the main targets, RET kinase. This resulted in 5 novel and chemically dissimilar RET inhibitors with remaining RET activity of <60% (at a concentration of 10 mu M) and similarities with known RET inhibitors from 0.18 to 0.29 (Tanimoto, ECFP6). The four more potent inhibitors were assessed in a concentration range and proved to be modestly active with a pIC(50) value of 5.1 for the most active compound. The experimental validation of inhibitors for RET strongly indicates that the multitarget workflow is able to detect novel inhibitors for kinases, and hence, this workflow can potentially be applied in polypharmacology modeling. We conclude that this approach can identify new chemical matter for existing targets. Moreover, this workflow can easily be applied to other targets as well.
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| 24. |
- Christopoulos, Arthur, et al.
(författare)
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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.
- 2021
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Ingår i: British journal of pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 178 Suppl 1
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Forskningsöversikt (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 26. |
- Ebersole, Charles R., et al.
(författare)
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Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability
- 2020
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Ingår i: Advances in Methods and Practices in Psychological Science. - : Sage. - 2515-2467 .- 2515-2459. ; 3:3, s. 309-331
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Tidskriftsartikel (refereegranskat)abstract
- Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3-9; median total sample = 1,279.5, range = 276-3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Delta r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00-.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19-.50).
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| 27. |
- Gutlerrez-de-Teran, Hugo, et al.
(författare)
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The Role of a Sodium Ion Binding Site in the Allosteric Modulation of the A(2A) Adenosine G Protein-Coupled Receptor
- 2013
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Ingår i: Structure. - : Elsevier BV. - 0969-2126 .- 1878-4186. ; 21:12, s. 2175-2185
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Tidskriftsartikel (refereegranskat)abstract
- The function of G protein-coupled receptors (GPCRs) can be modulated by a number of endogenous allosteric molecules. In this study, we used molecular dynamics, radioligand binding, and thermostability experiments to elucidate the role of the recently discovered sodium ion binding site in the allosteric modulation of the human A(2A) adenosine receptor, conserved among class A GPCRs. While the binding of antagonists and sodium ions to the receptor was noncompetitive in nature, the binding of agonists and sodium ions appears to require mutually exclusive conformational states of the receptor. Anniloride analogs can also bind to the sodium binding pocket, showing distinct patterns of agonist and antagonist modulation. These findings suggest that physiological concentrations of sodium ions affect functionally relevant conformational states of GPCRs and can help to design novel synthetic allosteric modulators or bitopic ligands exploiting the sodium ion binding pocket.
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| 28. |
- Herrema, H., et al.
(författare)
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Emerging role of intestinal microbiota and microbial metabolites in metabolic control
- 2017
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 60:4, s. 613-617
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Tidskriftsartikel (refereegranskat)abstract
- The role of the intestinal microbiota and microbial metabolites in the maintenance of host health and development of metabolic disease has gained significant attention over the past decade. Mechanistic insight revealing causality, however, is scarce. Work by Ussar and co-workers demonstrates that a complex interaction between microbiota, host genetics and environmental factors is involved in metabolic disease development in mice. In addition, Perry and coworkers show that the microbial metabolite acetate augments insulin resistance in rats. These studies underscore an important role of the microbiota in the development of obesity and symptoms of type 2 diabetes in rodents. If causality can be demonstrated in humans, development of novel diagnostic and therapeutic tools that target the gut microbiota will have high potential.
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| 29. |
- Jespers, Willem, et al.
(författare)
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Deciphering conformational selectivity in the A(2A) adenosine G protein-coupled receptor by free energy simulations
- 2021
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A(2A) adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A(2A)AR agonists with different efficacies. The modulatory effects of point mutations on the basal activity of the receptor or on ligand efficacies could also be detected. This methodology can guide GPCR ligand design with tailored pharmacological properties, or allow the identification of mutations that modulate receptor activation with potential clinical implications.
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| 30. |
- Massink, Arnault, et al.
(författare)
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Sodium Ion Binding Pocket Mutations and Adenosine A(2A) Receptor Function
- 2015
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Ingår i: Molecular Pharmacology. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0026-895X .- 1521-0111. ; 87:2, s. 305-313
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Tidskriftsartikel (refereegranskat)abstract
- Recently we identified a sodium ion binding pocket in a high-resolution structure of the human adenosine A(2A) receptor. In the present study we explored this binding site through site-directed mutagenesis and molecular dynamics simulations. Amino acids in the pocket were mutated to alanine, and their influence on agonist and antagonist affinity, allosterism by sodium ions and amilorides, and receptor functionality was explored. Mutation of the polar residues in the Na+ pocket were shown to either abrogate (D52A(2.50) and N284A(7.49)) or reduce (S91A(3.39), W246A(6.48), and N280A(7.45)) the negative allosteric effect of sodium ions on agonist binding. Mutations D52A(2.50) and N284A(7.49) completely abolished receptor signaling, whereas mutations S91A(3.39) and N280A(7.45) elevated basal activity and mutations S91A(3.39), W246A(6.48), and N280A(7.45) decreased agonist-stimulated receptor signaling. In molecular dynamics simulations D52A(2.50) directly affected the mobility of sodium ions, which readily migrated to another pocket formed by Glu13(1.39) and His278(7.43). The D52A(2.50) mutation also decreased the potency of amiloride with respect to ligand displacement but did not change orthosteric ligand affinity. In contrast, W246A(6.48) increased some of the allosteric effects of sodium ions and amiloride, whereas orthosteric ligand binding was decreased. These new findings suggest that the sodium ion in the allosteric binding pocket not only impacts ligand affinity but also plays a vital role in receptor signaling. Because the sodium ion binding pocket is highly conserved in other class A G protein-coupled receptors, our findings may have a general relevance for these receptors and may guide the design of novel synthetic allosteric modulators or bitopic ligands.
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| 31. |
- Moshontz, Hannah, et al.
(författare)
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The Psychological Science Accelerator: Advancing Psychology Through a Distributed Collaborative Network
- 2018
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Ingår i: Advances in Methods and Practices in Psychological Science. - : SAGE Publications. - 2515-2459 .- 2515-2467. ; 1:4, s. 501-515
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Tidskriftsartikel (refereegranskat)abstract
- Concerns about the veracity of psychological research have been growing. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions or replicate prior research in large, diverse samples. The PSA’s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time limited), efficient (in that structures and principles are reused for different projects), decentralized, diverse (in both subjects and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside the network). The PSA and other approaches to crowdsourced psychological science will advance understanding of mental processes and behaviors by enabling rigorous research and systematic examination of its generalizability.
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| 32. |
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| 33. |
- Wang, Xuesong, et al.
(författare)
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Identification of V6.51L as a selectivity hotspot in stereoselective A(2B) adenosine receptor antagonist recognition
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The four adenosine receptors (ARs) A(1)AR, A(2A)AR, A(2B)AR(,) and A(3)AR are G protein-coupled receptors (GPCRs) for which an exceptional amount of experimental and structural data is available. Still, limited success has been achieved in getting new chemical modulators on the market. As such, there is a clear interest in the design of novel selective chemical entities for this family of receptors. In this work, we investigate the selective recognition of ISAM-140, a recently reported A(2B)AR reference antagonist. A combination of semipreparative chiral HPLC, circular dichroism and X-ray crystallography was used to separate and unequivocally assign the configuration of each enantiomer. Subsequently affinity evaluation for both A(2A) and A(2B) receptors demonstrate the stereospecific and selective recognition of (S)-ISAM140 to the A(2B)AR. The molecular modeling suggested that the structural determinants of this selectivity profile would be residue V250(6.51) in A(2B)AR, which is a leucine in all other ARs including the closely related A(2A)AR. This was herein confirmed by radioligand binding assays and rigorous free energy perturbation (FEP) calculations performed on the L249V(6.51) mutant A(2A)AR receptor. Taken together, this study provides further insights in the binding mode of these A(2B)AR antagonists, paving the way for future ligand optimization.
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