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Autonomous Sensory Meridian Response (ASMR) is a multisensory experience most often associated with feelings of relaxation and altered consciousness, elicited by stimuli which include whispering, repetitive movements, and close personal attention. Since 2015, ASMR research has grown rapidly, spanning disciplines from neuroscience to media studies but lacking a collaborative or interdisciplinary approach. To build a cohesive and connected structure for ASMR research moving forwards, a modified Delphi study was conducted with ASMR experts, practitioners, community members, and researchers from various disciplines. Ninety-eight participants provided 451 suggestions for ASMR research priorities which were condensed into 13 key areas: (1) Definition, conceptual clarification, and measurement of ASMR; (2) Origins and development of ASMR; (3) Neurophysiology of ASMR; (4) Understanding ASMR triggers; (5) Factors affecting the likelihood of experiencing/eliciting ASMR; (6) ASMR and individual/cultural differences; (7) ASMR and the senses; (8) ASMR and social intimacy; (9) Positive and negative consequences of ASMR in the general population; (10) Therapeutic applications of ASMR in clinical contexts; (11) Effects of long-term ASMR use; (12) ASMR platforms and technology; (13) ASMR community, culture, and practice. These were voted on by 70% of the initial participant pool using best/worst scaling methods. The resulting agenda provides a clear map for ASMR research to enable new and existing researchers to orient themselves towards important questions for the field and to inspire interdisciplinary collaborations.

Eps15 (epidermal growth factor receptor pathway substrate 15) homology domain-containing proteins (EHDs) comprise a family of eukaryotic dynamin-related ATPases that participate in various endocytic membrane trafficking pathways. Dysregulation of EHDs function has been implicated in various diseases, including cancer. The lack of small molecule inhibitors which acutely target individual EHD members has hampered progress in dissecting their detailed cellular membrane trafficking pathways and their function during disease. Here, we established a Malachite green-based assay compatible with high throughput screening to monitor the liposome-stimulated ATPase of EHD4. In this way, we identified a drug-like molecule that inhibited EHD4's liposome-stimulated ATPase activity. Structure activity relationship (SAR) studies indicated sites of preferred substitutions for more potent inhibitor synthesis. Moreover, the assay optimization in this work can be applied to other dynamin family members showing a weak and liposome-dependent nucleotide hydrolysis activity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mohd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The serotonin pathway has long been proposed as a promising target for pulmonary arterial hypertension (PAH)-a progressive and uncurable disease. We developed a highly specific inhibitor of the serotonin synthesizing enzyme tryptophan hydroxylase 1 (TPH1), TPT-001 (TPHi). In this study, the authors sought to treat severe PAH in the Sugen/hypoxia (SuHx) rat model with the oral TPHi TPT-001. Male Sprague Dawley rats were divided into 3 groups: 1) ConNx, control animals; 2) SuHx, injected subcutaneously with SU5416 and exposed to chronic hypoxia for 3 weeks, followed by 6 weeks in room air; and 3) SuHx+TPHi, SuHx animals treated orally with TPHi for 5 weeks. Closed-chest right- and left heart catheterization and echocardiography were performed. Lungs were subject to histologic and mRNA sequencing analyses. Compared with SuHx-exposed rats, which developed severe PAH and right ventricular (RV) dysfunction, TPHi-treated SuHx rats had greatly lowered RV systolic (mean ± SEM: 41 ± 2.3 mm Hg vs 86 ± 6.5 mm Hg; P  < 0.001) and end-diastolic (mean ± SEM: 4 ± 0.7 mm Hg vs 14 ± 1.7 mm Hg; P  < 0.001) pressures, decreased RV hypertrophy and dilation (all not significantly different from control rats), and reversed pulmonary vascular remodeling. We identified perivascular infiltration of CD3 + T cells and proinflammatory F4/80 + and CD68 + macrophages and proliferating cell nuclear antigen-positive alveolar epithelial cells all suppressed by TPHi treatment. Whole-lung mRNA sequencing in SuHx rats showed distinct gene expression patterns related to pulmonary arterial smooth muscle cell proliferation (Rpph1, Lgals3, Gata4), reactive oxygen species, inflammation (Tnfsrf17, iNOS), and vasodilation (Pde1b, Kng1), which reversed expression with TPHi treatment. Inhibition of TPH1 with a new class of drugs (here, TPT-001) has the potential to attenuate or even reverse severe PAH and associated RV dysfunction in vivo by blocking the serotonin pathway., Competing Interests: This study was funded by the Federal Ministry of Education and Research (01KC2001B and 03VP08053 to Dr Hansmann; 01KC2001A, 03VP08051, and 16GW0298 to Dr Bader). Dr Hansmann also receives funding from the German Research Foundation (DFG KFO311 grant HA4348/6-2) and the European Pediatric Pulmonary Vascular Disease Network. Dr Nazaré has received funding from the Federal Ministry of Economic Affairs (ZIM grant 16KN073251). Drs Specker, Nazaré, Matthes, and Bader hold patents on the novel class of TPHi. Drs Specker, Wesolowski, and Bader are founders of Trypto Therapeutics GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Beauty surrounds us in many ways every day. In three experience sampling (ESM) studies we investigated frequency, category of eliciting stimuli (natural vs human-made) and, the potential moderating role of several individual difference measures on such everyday experiences of beauty in an ecologically valid manner. Further, we explored the impact of such experiences on valence & arousal. Study 1 re-analysed data from a previous study, in line with the current aims. In Studies 2 and 3, we asked participants to report daily experiences of beauty using a mixed random and event-contingent sampling schedule. Mobile notifications (random sampling) prompted participants to take a photo and rate the beauty of their surroundings. Further, current valence and arousal were assessed. Notification frequency and total days of participation differed between these two studies. Participants were able to report additional experiences outside of the notification windows (event-contingent sampling). Our results indicate that we frequently encounter beauty in everyday life and that we find it in nature, in particular. Our results further suggest a mood-boosting effect of encounters with beauty. Lastly, our results indicate influences of individual differences however, these were inconclusive and require further attention., (© 2024. The Author(s).)

The EU-OPENSCREEN (EU-OS) European Research Infrastructure Consortium (ERIC) is a multinational, not-for-profit initiative that integrates high-capacity screening platforms and chemistry groups across Europe to facilitate research in chemical biology and early drug discovery. Over the years, the EU-OS has assembled a high-throughput screening compound collection, the European Chemical Biology Library (ECBL), that contains approximately 100 000 commercially available small molecules and a growing number of thousands of academic compounds crowdsourced through our network of European and non-European chemists. As an extension of the ECBL, here we describe the computational design, quality control and use case screenings of the European Fragment Screening Library (EFSL) composed of 1056 mini and small chemical fragments selected from a substructure analysis of the ECBL. Access to the EFSL is open to researchers from both academia and industry. Using EFSL, eight fragment screening campaigns using different structural and biophysical methods have successfully identified fragment hits in the last two years. As one of the highlighted projects for antibiotics, we describe the screening by Bio-Layer Interferometry (BLI) of the EFSL, the identification of a 35 μM fragment hit targeting the beta-ketoacyl-ACP synthase 2 (FabF), its binding confirmation to the protein by X-ray crystallography (PDB 8PJ0), its subsequent rapid exploration of its surrounding chemical space through hit-picking of ECBL compounds that contain the fragment hit as a core substructure, and the final binding confirmation of two follow-up hits by X-ray crystallography (PDB 8R0I and 8R1V)., Competing Interests: X. J. and J. M. are currently employees of the company Chemotargets, of which J. M. is co-founder and co-owner., (This journal is © The Royal Society of Chemistry.)

Uridine diphosphate N-acetylglucosamine 2-epimerase (GNE) is a key enzyme in the sialic acid biosynthesis pathway. Sialic acids are primarily terminal carbohydrates on glycans and play fundamental roles in health and disease. In search of effective GNE inhibitors not based on a carbohydrate scaffold, we performed a high-throughput screening campaign of 68,640 drug-like small molecules against recombinant GNE using a UDP detection assay. We validated nine of the primary actives with an orthogonal real-time NMR assay and verified their IC 50 values in the low micromolar to nanomolar range manually. Stability and solubility studies revealed three compounds for further evaluation. Thermal shift assays, analytical size exclusion, and interferometric scattering microscopy demonstrated that the GNE inhibitors acted on the oligomeric state of the protein. Finally, hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed which sections of GNE were shifted upon the addition of the inhibitors. In summary, we have identified three small molecules as GNE inhibitors with high potency in vitro, which serve as promising candidates to modulate sialic acid biosynthesis in more complex systems., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Metastasis is directly linked to poor prognosis of cancer patients and warrants search for effective anti-metastatic drugs. MACC1 is a causal key molecule for metastasis. High MACC1 expression is prognostic for metastasis and poor survival. Here, we developed novel small molecule inhibitors targeting MACC1 expression to impede metastasis formation. We performed a human MACC1 promoter-driven luciferase reporter-based high-throughput screen (HTS; 118.500 compound library) to identify MACC1 transcriptional inhibitors. HTS revealed 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds as efficient transcriptional inhibitors of MACC1 expression, able to decrease MACC1-induced cancer cell motility in vitro. Structure-activity relationships identified the essential inhibitory core structure. Best candidates were evaluated for metastasis inhibition in xenografted mouse models demonstrating metastasis restriction. ADMET showed high drug-likeness of these new candidates for cancer therapy. The NFκB pathway was identified as one mode of action targeted by these compounds. Taken together, 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds are effective MACC1 inhibitors and pose promising candidates for anti-metastatic therapies particularly for patients with MACC1-overexpressing cancers, that are at high risk to develop metastases. Although further preclinical and clinical development is necessary, these compounds represent important building blocks for an individualized anti-metastatic therapy for solid cancers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ulrike Stein reports financial support was provided by SPARK Berlin. Wolfgang Walther reports financial support was provided by SPARK Berlin. Dennis Kobelt reports financial support was provided by SPARK Berlin. Ulrike Stein reports financial support was provided by German Cancer Consortium. Shixian Yan reports financial support was provided by China Scholarship Council. Paul Schoepe reports financial support was provided by Berlin School of Integrative Oncology. Ulrike Stein has patent #1. Stein U, Kobelt D, Walther W, Shixian Y, Nazaré M, Specker E, Schöpe P, Lindemann P. Identification of novel compounds for targeted therapy of MACC1-driven metastasis. EP 21169702.4, 21.10.2022 issued to none., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound 32 (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.

Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure-activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors called PITCOINs. Cocrystal structures and docking experiments supported the rationalization of the structural determinants essential for inhibitor activity and high selectivity. Profiling of PITCOINs in a panel of more than 118 diverse kinases showed no off-target kinase inhibition. Notably, by addressing a selectivity pocket, PITCOIN4 showed nanomolar inhibition of PI3K-C2α and >100-fold selectivity in a general kinase panel. Our study paves the way for the development of novel therapies for diseases related to PI3K-C2α function.

Microglia are the immune effector cells of the central nervous system (CNS) and react to pathologic events with a complex process including the release of nitric oxide (NO). NO is a free radical, which is toxic for all cells at high concentrations. To target an exaggerated NO release, we tested a library of 16 544 chemical compounds for their effect on lipopolysaccharide (LPS)-induced NO release in cell line and primary neonatal microglia. We identified a compound (C1) which significantly reduced NO release in a dose-dependent manner, with a low IC50 (252 nM) and no toxic side effects in vitro or in vivo. Target finding strategies such as in silico modelling and mass spectroscopy hint towards a direct interaction between C1 and the nitric oxide synthase making C1 a great candidate for specific intra-cellular interaction with the NO producing machinery., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jordan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Increased execution of replication studies contributes to the effort to restore credibility of empirical research. However, a second generation of problems arises: the number of potential replication targets is at a serious mismatch with available resources. Given limited resources, replication target selection should be well-justified, systematic and transparently communicated. At present the discussion on what to consider when selecting a replication target is limited to theoretical discussion, self-reported justifications and a few formalized suggestions. In this Registered Report, we proposed a study involving the scientific community to create a list of considerations for consultation when selecting a replication target in psychology. We employed a modified Delphi approach. First, we constructed a preliminary list of considerations. Second, we surveyed psychologists who previously selected a replication target with regards to their considerations. Third, we incorporated the results into the preliminary list of considerations and sent the updated list to a group of individuals knowledgeable about concerns regarding replication target selection. Over the course of several rounds, we established consensus regarding what to consider when selecting a replication target. The resulting checklist can be used for transparently communicating the rationale for selecting studies for replication., (© 2023 The Authors.)

The accurate prediction of protein-ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen-π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots.

Tryptophan hydroxylases catalyze the first and rate-limiting step in the synthesis of serotonin. Serotonin is a key neurotransmitter in the central nervous system and, in the periphery, functions as a local hormone with multiple physiological functions. Studies in genetically altered mouse models have shown that dysregulation of peripheral serotonin levels leads to metabolic, inflammatory, and fibrotic diseases. Overproduction of serotonin by tumor cells causes severe symptoms typical for the carcinoid syndrome, and tryptophan hydroxylase inhibitors are already in clinical use for patients suffering from this disease. Here, we describe a novel class of potent tryptophan hydroxylase inhibitors, characterized by spanning all active binding sites important for catalysis, specifically those of the cosubstrate pterin, the substrate tryptophan as well as directly chelating the catalytic iron ion. The inhibitors were designed to efficiently reduce serotonin in the periphery while not passing the blood-brain barrier, thus preserving serotonin levels in the brain.

When experienced in-person, engagement with art has been associated-in a growing body of evidence-with positive outcomes in wellbeing and mental health. This represents an exciting new field for psychology, curation, and health interventions, suggesting a widely-accessible, cost-effective, and non-pharmaceutical means of regulating factors such as mood or anxiety. However, can similar impacts be found with online presentations? If so, this would open up positive outcomes to an even-wider population-a trend accelerating due to the current COVID-19 pandemic. Despite its promise, this question, and the underlying mechanisms of art interventions and impacts, has largely not been explored. Participants ( N = 84) were asked to engage with one of two online exhibitions from Google Arts and Culture (a Monet painting or a similarly-formatted display of Japanese culinary traditions). With just 1-2 min exposure, both improved negative mood, state-anxiety, loneliness, and wellbeing. Stepdown analysis suggested the changes can be explained primarily via negative mood, while improvements in mood correlated with aesthetic appraisals and cognitive-emotional experience of the exhibition. However, no difference was found between exhibitions. We discuss the findings in terms of applications and targets for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Trupp, Bignardi, Chana, Specker and Pelowski.)

The pain- and stress-reducing effects of music are well-known, but the effects of visual art, and the combination of these two, are much less investigated. We aim to (1) investigate the pain- and (2) stress-reducing effects of multimodal (music + visual art) aesthetic experience as we expect this to have stronger effects than a single modal aesthetic experience (music/ visual art), and in an exploratory manner, (3) investigate the underlying mechanisms of aesthetic experience, and the (4) individual differences. In a repeated-measures design (music, visual art, multimodal aesthetic experience, control) participants bring self-selected "movingly beautiful" visual artworks and pieces of music to the lab, where pain and stress are induced by the cold pressor test. Activity of the pain and stress responsive systems are measured by subjective reports, autonomic (electrocardiography, electrodermal activity, salivary alpha-amylase) and endocrine markers (salivary cortisol)., Competing Interests: The authors have declared that no competing interests exist.

Research has failed to find evidence for a genuineness effect: the idea that aesthetic experiences are better when looking at real artworks versus reproductions of those artworks. One common explanation for this lack of an effect is the facsimile accommodation hypothesis. This hypothesis states that people can "look past" the limitations of a reproduction, which obscures the effect. However, this hypothesis itself has never been tested. In the current paper, we therefore test the facsimile accommodation hypothesis. In Study 1 (N = 120) we found no evidence for the facsimile accommodation hypothesis: there was no difference between the non-accommodation (instructed to evaluate the artwork as it is presented on the screen), the accommodation condition (instructed to evaluate the artwork as they imagine it would look in real life), and the control condition (no instructions). Though the control and accommodation condition did not differ which would be in line with the facsimile accommodation hypothesis, neither differed from the non-accommodation condition which they should have if the facsimile accommodation hypothesis was correct. We substantiate these findings by a pre-registered replication study (Study 2, N = 205), using Bayes Factors as well as equivalence testing to provide evidence for a null-effect, again finding no evidence for the facsimile accommodation hypothesis and even finding substantial evidence in favor of the null-hypothesis. In sum, we conclude that there is no evidence for the facsimile accommodation hypothesis and that we need to consider alternative explanations in order to understand the lack of empirical evidence for the genuineness effect., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Jumonji domain-containing lysine demethylase (KDM) enzymes are encoded by genes of the KDM superfamily. Activities of the KDM4 subfamily promote aggressive phenotypes associated with prostate cancer (PCa). Previously, we discovered a benzimidazole pyrazole molecule that inhibited KDM4 isoforms with properties tractable for development. Here, we demonstrate that a benzyl-substituted variant of this inhibitor exhibits improved potency in biochemical assays, is cell-permeable, and kills PCa cells at low micromolar concentrations. By X-ray crystallography and kinetics-based assays, we demonstrate that the mechanism of inhibition is complex, proceeding via competition with the enzyme for binding of active-site Fe 2+ and by populating a distal site on the enzyme surface. Furthermore, we provide evidence that the inhibitor's cytostatic properties arise from direct intracellular inhibition of KDM4 enzymes. PCa cells treated with the inhibitor exhibit reduced expression of genes regulated by the androgen receptor, an outcome accompanied by epigenetic maintenance of a heterochromatic state.

Background: The pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome-targeting treatment strategies for irritant contact dermatitis., Methods: A high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck-like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)-1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome-mediated cytokines IL-1β and IL-18., Results: Disulfiram induced a dose-dependent inhibition of ASC speck formation and IL-1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS-induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle ( p  < 0.001) and/or mometasone ( p  < 0.001). Also, corneocyte IL-18 levels were significantly reduced after application of disulfiram compared to vehicle ( p  < 0.001)., Conclusion: We show that disulfiram is a dose-dependent inhibitor of inflammasome pathway activation in vitro and inhibitor of SDS-induced eczema in vivo. Topical application of disulfiram represents a potential treatment option for irritant contact dermatitis., Competing Interests: Carolina Vera, Angela Abad‐Perez, Silke Radetzki, Martin Neuenschwander, Edgar Specker, Marc Nazaré, Jens v. Kries, Niklas Amadeus Mahnke, Jörg Scheffel and Stefan Frischbutter have no conflict of interest. Eicke Latz is the co‐founder and consultant to IFM Therapeutics. Hanna Bonnekoh received honoria (advisory board, speaker) from Novartis. Marcus Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Alnylam, Amgen, Aralez, ArgenX, AstraZeneca, BioCryst, Blueprint, Celldex, Centogene, CSL Behring, Dyax, FAES, Genentech, GIInnovation, Innate Pharma, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pharming, Pharvaris, Roche, Sanofi/Regeneron, Shire/Takeda, ThirdHarmonicBio, UCB, and Uriach. Karoline Krause has received grants from Novartis and Roche and payment for lectures and/or consultancies from Novartis, Roche, and SOBI., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Fragment-based screening has evolved as a remarkable approach within the drug discovery process both in the industry and academia. Fragment screening has become a more structure-based approach to inhibitor development, but also towards development of pathway-specific clinical probes. However, it is often witnessed that the availability, immediate and long-term, of a high quality fragment-screening library is still beyond the reach of most academic laboratories. Within iNEXT (Infrastructure for NMR, EM and X-rays for Translational research), a EU-funded Horizon 2020 program, a collection of 782 fragments were assembled utilizing the concept of "poised fragments" with the aim to facilitate downstream synthesis of ligands with high affinity by fragment ligation. Herein, we describe the analytical procedure to assess the quality of this purchased and assembled fragment library by NMR spectroscopy. This quality assessment requires buffer solubility screening, comparison with LC/MS quality control and is supported by state-of-the-art software for high throughput data acquisition and on-the-fly data analysis. Results from the analysis of the library are presented as a prototype of fragment progression through the quality control process.

Binary classification has numerous applications. For one, lie detection methods typically aim to classify each tested person either as "liar" or as "truthteller" based on the given test results. To infer practical implications, as well as to compare different methods, it is essential to assess the diagnostic efficiency, such as demonstrating the number of correctly classified persons. However, this is not always straightforward. In Concealed Information Tests (CITs), the key predictor value (probe-irrelevant difference) for "truthtellers" is always similar (zero on average), and "liars" are always distinguished by a larger value (i.e., a larger number resulting from the CIT test, as compared to the zero baseline). Thereby, in general, the larger predictor values a given CIT method obtains for "liars" on average, the better this method is assumed to be. This has indeed been assumed in countless studies, and therefore, when comparing the classification efficiencies of two different designs, the mean difference of "liar" predictor values in the two designs were simply compared to each other (hence not collecting "truthteller" data to spare resources). We show, based on the meta-data of 12 different experimental designs collected in response time-based CIT studies, that differences in dispersion (i.e., variance in the data, e.g. the extent of random deviations from the zero average in case of "truthtellers") can substantially influence classification efficiency-to the point that, in extreme cases, one design may even be superior in classification despite having a larger mean "liar" predictor value. However, we also introduce a computer simulation procedure to estimate classification efficiency in the absence of "truthteller" data, and validate this procedure via a meta-analysis comparing outcomes based on empirical data versus simulated data., Competing Interests: The authors have declared that no competing interests exist.

There is increasing awareness that the perception of art is affected by the way it is presented. In 2018, the Austrian Gallery Belvedere redisplayed its permanent collection. Our multidisciplinary team seized this opportunity to investigate the viewing behavior of specific artworks both before and after the museum's rearrangement. In contrast to previous mobile eye tracking (MET) studies in museums, this study benefits from the comparison of two realistic display conditions (without any research interference), an unconstrained study design (working with regular museum visitors), and a large data sample (comprising 259 participants). We employed a mixed-method approach that combined mobile eye tracking, subjective mapping (a drawing task in conjunction with an open interview), and a questionnaire in order to relate gaze patterns to processes of meaning-making. Our results show that the new display made a difference in that it 1) generally increased the viewing times of the artworks; 2) clearly extended the reading times of labels; and 3) deepened visitors' engagement with the artworks in their exhibition reflections. In contrast, interest in specific artworks and art form preferences proved to be robust and independent of presentation modes., Competing Interests: The authors declare that the contents of the article are in agreement with the ethics described in http://biblio.unibe.ch/portale/elibrary/BOP/jemr/ethics.html and that there is no conflict of interest regarding the publication of this paper. The study was approved by the ethics committee of the University of Vienna, participants signed a detailed consent form, and no visitors under 18 took part.

The idea that simple visual elements such as colors and lines have specific, universal associations-for example red being warm-appears rather intuitive. Such associations have formed a basis for the description of artworks since the 18th century and are still fundamental to discourses on art today. Art historians might describe a painting where red is dominant as "warm," "aggressive," or "lively," with the tacit assumption that beholders would universally associate the works' certain key forms with specific qualities, or "aesthetic effects". However, is this actually the case? Do we actually share similar responses to the same line or color? In this paper, we tested whether and to what extent this assumption of universality (sharing of perceived qualities) is justified. We employed-for the first time-abstract artworks as well as single elements (lines and colors) extracted from these artworks in an experiment in which participants rated the stimuli on 14 "aesthetic effect" scales derived from art literature and empirical aesthetics. To test the validity of the assumption of universality, we examined on which of the dimensions there was agreement, and investigated the influence of art expertise, comparing art historians with lay people. In one study and its replication, we found significantly lower agreement than expected. For the whole artworks, participants agreed on the effects of warm-cold, heavy-light, and happy-sad, but not on 11 other dimensions. Further, we found that the image type (artwork or its constituting elements) was a major factor influencing agreement; people agreed more on the whole artwork than on single elements. Art expertise did not play a significant role and agreement was especially low on dimensions usually of interest in empirical aesthetics (e.g., like-dislike). Our results challenge the practice of interpreting artworks based on their aesthetic effects, as these effects may not be as universal as previously thought., Competing Interests: The authors have declared that no competing interests exist.

Lysophosphatidic acid (LPA) species in the extracellular environment induce downstream signaling via six different G protein-coupled receptors (LPAR1-6). These signaling cascades are essential for normal brain development and function of the nervous system. However, in response to acute or chronic central nervous system (CNS) damage, LPA levels increase and aberrant signaling events can counteract brain function. Under neuro-inflammatory conditions signaling along the LPA/LPAR5 axis induces a potentially neurotoxic microglia phenotype indicating the need for new pharmacological intervention strategies. Therefore, we compared the effects of two novel small-molecule LPAR5 antagonists on LPA-induced polarization parameters of the BV-2 microglia cell line. AS2717638 is a selective piperidine-based LPAR5 antagonist (IC 50 0.038 μM) while compound 3 is a diphenylpyrazole derivative with an IC 50 concentration of 0.7 μM in BV-2 cells. Both antagonists compromised cell viability, however, at concentrations above their IC 50 concentrations. Both inhibitors blunted LPA-induced phosphorylation of STAT1 and STAT3, p65, and c-Jun and consequently reduced the secretion of pro-inflammatory cyto-/chemokines (IL-6, TNFα, IL-1β, CXCL10, CXCL2, and CCL5) at non-toxic concentrations. Both compounds modulated the expression of intracellular (COX-2 and Arg1) and plasma membrane-located (CD40, CD86, and CD206) polarization markers yet only AS2717638 attenuated the neurotoxic potential of LPA-activated BV-2 cell-conditioned medium towards CATH.a neurons. Our findings from the present in vitro study suggest that the two LPAR5 antagonists represent valuable pharmacological tools to interfere with LPA-induced pro-inflammatory signaling cascades in microglia., (Copyright © 2019 Plastira, Joshi, Bernhart, Schoene, Specker, Nazare and Sattler.)

Parkinson's disease (PD) is a progressing neurodegenerative disease predominantly involving the loss of dopamine producing neurons with hallmark symptoms of motor disorders and cognitive, motivational, emotional, and perceptual impairments. Intriguingly, PD can also be connected-often anecdotally-with a sudden burst of artistic creativity, motivation, or changed quality/style of produced art. This has led to growing empirical interest, promising a window into brain function and the unique neurological signature of artists. This topic also fits a growing interest from researchers in other areas, including Alzheimer's or other dementia, which have suggested that specific changes in art production/appraisal may provide a unique basis for therapy, diagnosis, or understanding of these diseases. However, whether PD also shows similar impacts on how we perceive and evaluate art has never been systematically addressed. We compared a cohort of PD patients against age-matched healthy controls, asking participants to rate paintings using scales of liking and beauty and terms pertaining to artworks' formal and conceptual qualities previously designed to provide a rubric for symptom identification. We found no evidence for PD-related differences in liking or beauty. However, PD patients showed higher ratings on assessed "emotionality," potentially relating to the tie between PD, dopamine pathways, and emotion/reward., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report two studies considering the potential for gallery lighting conditions to modulate appraisals and emotional experience with works of visual art. As recently documented in a number of papers, art appreciation represents a complex blend of formal artwork factors, personalities and backgrounds of viewers, and multiple aspects of context regarding where and how art is experienced. Among the latter, lighting would be expected to play a fundamental role. However, surprisingly, this has received little empirical assessment, with almost no ecologically valid gallery analyses and no between-participant designs which would minimize awareness of lighting changes themselves. Here, we employed a controlled paradigm using a spontaneous art viewing context, a gallery-like setting, and a proprietary lighting system which allowed the minute adjustment of lighting intensity/temperature (CCT). Participants viewed a selection of original representational and abstract art under three different CCT conditions (Study 1), modulated between participants, and then reported on their artwork appraisal and emotional experience. The selected lighting temperatures were chosen based on an initial investigation of existing art museums within the Vienna area, addressing how these institutions themselves light their art-a question which, also somewhat surprisingly, has not often been considered. We also allowed the same participants to set the light temperature themselves in order to test hypotheses regarding what might be an 'ideal' lighting condition for art. In Study 2, we explored the question of whether artworks made by an artist to match specific lighting conditions show a resulting connection to the ratings of viewers when shown in the same or different light. Results showed almost no effects from lighting changes in both studies. Viewers' self-set light temperature (mean = 3777 K) did roughly coincide with the suggested most enjoyable conditions for everyday living and some past research on art viewing, but again showed wide interpersonal variance. Results, and a general review of lighting factors are considered in order to provide art researchers and curators with a tool for conducting future study., (Copyright © 2019 Pelowski, Graser, Specker, Forster, von Hinüber and Leder.)

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.

Background: The thyrotropin receptor (TSHR) is the target for autoimmune thyroid stimulating antibodies (TSAb) triggering hyperthyroidism. Whereas elevated thyroid hormone synthesis by the thyroid in Graves' disease can be treated by antithyroid agents, for the pathogenic activation of TSHR in retro-orbital fibroblasts of the eye, leading to Graves' orbitopathy (GO), no causal TSHR directed therapy is available., Methods: Due to the therapeutic gap for severe GO, TSHR inhibitors were identified by high-throughput screening in Chinese hamster ovary cells expressing the TSHR. Stereo-selective synthesis of the screening hits led to the molecule S37, which contains seven chiral centers. Enantiomeric separation of the molecule S37 resulted in the enantiopure molecule S37a-a micro-molar antagonist of thyrotropin-induced cyclic adenosine monophosphate accumulation in HEK 293 cells expressing the TSHR., Results: The unique rigid bent shape of molecule S37a may mediate the observed high TSHR selectivity. Most importantly, the closely related follitropin and lutropin receptors were not affected by this compound. S37a not only inhibits the TSHR activation by thyrotropin itself but also activation by monoclonal TSAb M22 (human), KSAb1 (murine), and the allosteric small-molecule agonist C2. Disease-related ex vivo studies in HEK 293 cells expressing the TSHR showed that S37a also inhibits cyclic adenosine monophosphate formation by oligoclonal TSAb, which are highly enriched in GO patients' sera. Initial in vivo pharmacokinetic studies revealed no toxicity of S37a and a remarkable 53% oral bioavailability in mice., Conclusion: In summary, a novel highly selective inhibitor for the TSHR is presented, which has promising potential for further development for the treatment of GO.

Fragment-based drug discovery is a powerful complement to conventional high-throughput screening, especially for difficult targets. Screening low-molecular-weight fragments usually requires highly sensitive biophysical methods, because of the generally low affinity of the identified ligands. Here, we developed a cell-based fragment screening assay (cellFy) that allows sensitive identification of fragment hits in a physiologically more relevant environment, in contrast to isolated target screenings in solution. For this, a fluorescently labeled multivalent reporter was employed, enabling direct measurement of displacement by low-molecular-weight fragments without requiring enzymatic reactions or receptor activation. We applied this technique to identify hits against two challenging targets of the C-type lectin receptor (CLR) family: Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN) and Langerin. Both receptors are involved in pathogen recognition and initiation of an immune response, which renders them attractive targets for immune modulation. Because of their shallow and hydrophilic primary binding site, hit identification for CLRs is challenging and druglike ligands for CLRs are sparse. Screening of a fragment library followed by hit validation identified several promising candidates for further fragment evolution for DC-SIGN. In addition, a multiplexed assay format was developed for simultaneous screening against multiple CLRs, allowing a selectivity counterscreening. Overall, this sensitive cell-based fragment screening assay provides a powerful tool for rapid identification of bioactive fragments, even for difficult targets.

The SRP-Sec61 targeting/translocation pathway of eukaryotic cells targets nascent protein chains to the membrane of the endoplasmic reticulum. Using this machinery, secretory proteins are translocated across this membrane whereas membrane proteins are integrated into the lipid bilayer. One of the key players of the pathway is the protein-conducting Sec61 (translocon) complex of the endoplasmic reticulum. The Sec61 complex has no enzymatic activity, is expressed only intracellularly and is difficult to purify and to reconstitute. Screening for small molecule inhibitors impairing its functions is thus notoriously difficult. Such inhibitors may not only be valuable tools for cell biology, they may also represent novel anti-tumor drugs. Here we have developed a two-step, sequential screening assay for inhibitors of the whole SRP-Sec61 targeting/translocation pathway which might include molecules affecting Sec61 complex functions. The resulting hit compounds were analyzed using a whole cell biosynthesis assay and a cell free transcription/translation/translocation assay. Using this methodology, we identified novel compounds inhibiting this pathway. Following structure-based back screening, one of these substances was analyzed in more detail and we could show that it indeed impairs translocation at the level of the Sec61 complex. A slightly modified methodology may be used in the future to screen for substances affecting SecYEG, the bacterial ortholog of the Sec61 complex in order to derive novel antibiotic drugs., Competing Interests: The authors have declared that no competing interests exist.

Installation art is one of the most important and provocative developments in the visual arts during the last half century and has become a key focus of artists and of contemporary museums. It is also seen as particularly challenging or even disliked by many viewers, and-due to its unique in situ , immersive setting-is equally regarded as difficult or even beyond the grasp of present methods in empirical aesthetic psychology. In this paper, we introduce an exploratory study with installation art, utilizing a collection of techniques to capture the eclectic, the embodied, and often the emotionally-charged viewing experience. We present results from an investigation of two pieces, both part of Olafur Eliasson's exhibition "Baroque, Baroque" held at the Belvedere museum in Vienna. These were assessed by pre- and post-viewing questionnaires focusing on emotion, meaning-making, and appraisals, in tandem with mobile eye tracking to consider viewers' attention to both installed artworks and/or to the museum environment. The data showed differences in participants' emotional states, appraisals, and visual exploration, which together paint a picture of the aesthetic reactions to the works. These differences also showed how viewers' appraisal strategies, meaning making, and physical actions facilitated relatively more or less deep engagement with, and enjoyment of, the art. The results are discussed in terms of their implications for museum studies, art education, and theory in empirical aesthetics.

The present study investigates the hypothesis that brightness of colors is associated with positivity, postulating that this is an automatic and universal effect. The Implicit Association Test (IAT; Greenwald, McGhee, & Schwartz, 1998) was used in all studies. Study 1 used color patches varying on brightness, Study 2 used achromatic stimuli to eliminate the potential confounding effects of hue and saturation. Study 3 replicated Study 2 in a different cultural context (Japan vs. Austria), both studies also included a measure of explicit association. All studies confirmed the hypothesis that brightness is associated with positivity, at a significance level of p < .001 and Cohen's D varying from 0.90 to 3.99. Study 1-3 provided support for the notion that this is an automatic effect. Additionally, Study 2 and Study 3 showed that people also have an explicit association of brightness with positivity. However, as expected, our results also show that the implicit association was stronger than the explicit association. Study 3 shows clear support for the universality of our effects. In sum, our results support the idea that brightness is associated with positivity and that these associations are automatic and universal., (Copyright © 2018 Elsevier B.V. All rights reserved.)