Plasticity of the Cullin-RING Ligase Repertoire Shapes Sensitivity to Ligand-Induced Protein Degradation.

Inducing protein degradation via small molecules is a transformative therapeutic paradigm. Although structural requirements of target degradation are emerging, mechanisms determining the cellular response to small-molecule degraders remain poorly understood. To systematically delineate effectors required for targeted protein degradation, we applied genome-scale CRISPR/Cas9 screens for five drugs that hijack different substrate receptors (SRs) of cullin RING ligases (CRLs) to induce target proteolysis. We found that sensitivity to small-molecule degraders is dictated by shared and drug-specific modulator networks, including the COP9 signalosome and the SR exchange factor CAND1. Genetic or pharmacologic perturbation of these effectors impairs CRL plasticity and arrests a wide array of ligases in a constitutively active state. Resulting defects in CRL decommissioning prompt widespread CRL auto-degradation that confers resistance to multiple degraders. Collectively, our study informs on regulation and architecture of CRLs amenable for targeted protein degradation and outlines biomarkers and putative resistance mechanisms for upcoming clinical investigation.

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders.

Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined 'functional hotspots'. Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. Intersection with deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets. Biophysical and structural validation suggests that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and widely accessible methodology to characterize small-molecule degraders and associated resistance mechanisms.

Permissive beliefs in the context of gaming, online shopping and alcohol drinking - Systematic development of a self-report measure.

BACKGROUND: The activation of permissive beliefs is a cognitive mechanism through which individuals permit themselves to engage in pleasurable, yet potentially unregulated activities. Existing measures are heterogenous, focusing either on specific behaviors or on particular licensing mechanisms. The new Permissive Beliefs Questionnaire (PBQ) seeks to integrate self-licensing mechanisms from various research domains and to be applicable to different behaviors. METHODS: Study 1 aimed at exploring the factor structure and reduce the number of items. In study 2, we used confirmatory factor analysis and tested convergent and discriminant validity in three subsamples of individuals playing videogames (n = 489), shopping online (n = 506), and drinking alcohol (n = 511). We tested the hypothesis whether individuals who experience a self-regulatory conflict show a greater expression of permissive beliefs. RESULTS: The final version of the PBQ consists of 12 items which represent two factors: Deserving Reward and Defensive Optimism. The PBQ exhibited robust model fit indices and internal consistencies in the three samples. Permissive beliefs were heightened among individuals intending to downregulate their gaming, shopping, or drinking behaviors as compared to individuals without this intention. CONCLUSION: The PBQ is a valid measure of permissive beliefs for gaming, online shopping, and drinking alcohol. It serves an ecologic and psychometrically valid tool to address empirical research questions regarding the functioning of permissive beliefs. Additionally, it may be used in clinical settings to measure and raise an understanding for permissive beliefs in clients.

Validation of the ACSID-11 for consistent screening of specific Internet-use disorders based on ICD-11 criteria for gaming disorder: A multitrait-multimethod approach.

INTRODUCTION: With the inclusion of gaming disorder in the ICD-11, diagnostic criteria were introduced for this relatively new disorder. These criteria may be applied to other potential specific Internet-use disorders. The 11-item Assessment of Criteria for Specific Internet-use Disorders (ACSID-11) was developed for consistent screening of gaming disorder, online buying-shopping disorder, online pornography-use disorder, social networks-use disorder, and online gambling disorder. This study tested the construct validity of the ACSID-11, including convergent and divergent measures. METHODS: The ACSID-11 measures five behavioral addictions with the same set of items by following the principles of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). The ACSID-11 was administered to a convenience sample of active Internet users (N = 1597) together with validated and established measures of each specific Internet-use disorder along with screeners for mental health. Included are the Ten-Item Internet Gaming Disorder Test (IGDT-10), the Bergen Shopping Addiction Scale (BSAS), the Problematic Pornography Consumption Scale (PPCS), the Bergen Social Media Addiction Scale (BSMAS) and the Berlin Inventory of Gambling behavior - Screening (BIG-S). The ACSID-11 was compared convergently and divergently through a multitrait-multimethod approach along with contingency tables with the other Internet-use disorder screeners. RESULTS: The multitrait-multimethod results shows that each behavior assessed with the ACSID-11 has moderate to strong correlations (r's from 0.462 to 0.609) with the scores of the corresponding established measures and, furthermore, positive correlations (r's from 0.122 to 0.434) with measures of psychological distress and further shows that the ACSID-11 can be used for a comprehensive assessment of different behaviors. The contingency tables reveal large divergences between the ACSID-11 and other screening instruments concerning the classification of problematic specific Internet use based on the given cut-off values. CONCLUSION: The current work provides additional validation for the ACSID-11. Accordingly, this tool can be considered as reliable and valid for the simultaneous assessment of different Internet-use disorders: gaming disorder, online buying-shopping disorder, online pornography use disorder, social networks use disorder, and online gambling disorder. With a subsequent clinical validation of the scale and the proposed cut-off score, the ACSID-11 will be a thoroughly validated useful screening tool for clinical practice.

Stress and compulsive buying-shopping disorder: A scoping review.

INTRODUCTION: Theoretical frameworks of behavioral addictions mostly acknowledge the role of stress in the development and maintenance of these disorders, models of compulsive buying-shopping disorder (CBSD) however rarely incorporated stress. The association between stress and CBSD has not been reviewed yet. METHODS: A scoping review was conducted to evaluate empirical results on the association between stress and CBSD. A comprehensive search string was employed in three databases. RESULTS: 16 studies were included. Correlative studies suggested significant correlations between general perceived stress and CBSD symptom severity. Studies involving mean comparisons found higher general perceived stress levels in persons with problematic buying-shopping behavior/CBSD compared to control participants (large effects). Mixed results were found in studies involving regression/structural equation models and ecological momentary assessments. One study with a stress/negative mood induction observed more CBSD symptoms in a high stress group compared to a low stress group. DISCUSSION: The studies are heterogeneous concerning design, samples and measures. Only very few studies surpass the level of cross-sectional correlative data which limits the ability to draw clear conclusions. Future research should study the impact of experimentally induced stress on CBSD symptoms, examine the relationship between stress and CBSD longitudinally and assess objective stress markers.

Cue-reactivity to distal cues in individuals at risk for gaming disorder.

BACKGROUND: Gaming disorder (GD) is a disorder due to addictive behaviors (ICD-11). Cue-reactivity and craving are relevant mechanisms in the development and maintenance of addictive behaviors. When confronted with cues showing in-game content (proximal cues) individuals with higher symptom severity show increased cue-reactivity. Based on conditioning and addiction theories on incentive sensitization, cue-reactivity responses may generalize to more distal cues, e.g. when individuals at risk of developing a GD are confronted with a starting page of an online game. In cue-reactivity paradigms so far, only proximal gaming cues have been used. METHODS: We investigated the effect of distal gaming cues compared to gaming-unrelated control cues on cue-reactivity and craving in 88 individuals with non-problematic use of online games (nPGU) and 69 individuals at risk for GD (rGD). The distal cues showed the use of an electronic device (e.g., desktop PC or smartphone) whose screen showed starting pages of either games (target cues), shopping- or pornography sites (control cues) from a first-person perspective. FINDINGS: We found significantly higher urge and arousal ratings as well as longer viewing times for gaming-related compared to gaming-unrelated control cues in rGD compared to nPGU. Valence ratings did not differ between groups. INTERPRETATION: The results demonstrate that already distal gaming-specific cues lead to cue-reactivity and craving in rGD. This finding indicates that based on conditioning processes, cue-reactivity and craving develop during the course of GD and generalize to cues that are only moderately related to the specific gaming activity.

Rational discovery of molecular glue degraders via scalable chemical profiling.

Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.

The experience of gratification and compensation in addictive behaviors: How can these experiences be measured systematically within and across disorders due to addictive behaviors?

BACKGROUND: Beyond gaming disorder and gambling disorder, pornography-use disorder, buying-shopping disorder, and social-networksuse disorders are discussed as further disorders due to addictive behaviors. For addictive behaviors, it is assumed that the experience of gratification and the experience of compensation due to the specific behavior represent reinforcing processes involved in the development and maintenance of the problematic behaviors. We aimed to develop two questionnaires that capture the experienced gratification and experienced compensation while using online activities. We additionally assume significant relationships with further addiction-related constructs such as symptom severity, use expectancies, and craving experiences. METHODS: We conducted three studies for the development of the "Experience of Gratification Scale" (EGS) and the "Experience of Compensation Scale" (ECS). In each study, participants answered the questionnaires modified for their preferred online activity (gaming, gambling, buying-shopping, social-networks use, pornography use). Additional questionnaires were used, assessing further addiction-related constructs. RESULTS: The results of the gradual approach by using exploratory and confirmatory factor analyses indicated for both scales a two-factor solution resulting in "gratification of needs" and "experience of pleasure" for the EGS, and "compensation of needs" and "experience of relief from negative feelings" for the ECS. The factors were significantly correlated with each other as well as with craving experiences, use expectancies, and symptom severity. Moreover, we found significant differences in the experienced gratification and experienced compensation for specific online behaviors. CONCLUSION: The theoretically plausible specific factors for experienced gratification and experienced compensation could be identified and were related to constructs considered important in addictive online behaviors. Further studies should investigate the relevance of these constructs for different types of addictive behaviors, but also within the addiction process addressing specific needs and motives as well as further positive and negative reinforcement mechanisms.

Advances in problematic usage of the internet research - A narrative review by experts from the European network for problematic usage of the internet.

Global concern about problematic usage of the internet (PUI), and its public health and societal costs, continues to grow, sharpened in focus under the privations of the COVID-19 pandemic. This narrative review reports the expert opinions of members of the largest international network of researchers on PUI in the framework of the European Cooperation in Science and Technology (COST) Action (CA 16207), on the scientific progress made and the critical knowledge gaps remaining to be filled as the term of the Action reaches its conclusion. A key advance has been achieving consensus on the clinical definition of various forms of PUI. Based on the overarching public health principles of protecting individuals and the public from harm and promoting the highest attainable standard of health, the World Health Organisation has introduced several new structured diagnoses into the ICD-11, including gambling disorder, gaming disorder, compulsive sexual behaviour disorder, and other unspecified or specified disorders due to addictive behaviours, alongside naming online activity as a diagnostic specifier. These definitions provide for the first time a sound platform for developing systematic networked research into various forms of PUI at global scale. Progress has also been made in areas such as refining and simplifying some of the available assessment instruments, clarifying the underpinning brain-based and social determinants, and building more empirically based etiological models, as a basis for therapeutic intervention, alongside public engagement initiatives. However, important gaps in our knowledge remain to be tackled. Principal among these include a better understanding of the course and evolution of the PUI-related problems, across different age groups, genders and other specific vulnerable groups, reliable methods for early identification of individuals at risk (before PUI becomes disordered), efficacious preventative and therapeutic interventions and ethical health and social policy changes that adequately safeguard human digital rights. The paper concludes with recommendations for achievable research goals, based on longitudinal analysis of a large multinational cohort co-designed with public stakeholders.

[Centralization, Specialization, and Outpatient Care for Head and Neck Tumor Patients]. / Zentralisierung, Spezialisierung und Ambulantisierung der Versorgung von Kopf-Hals-Tumorpatienten.

Demographically, the German population is aging and becoming more morbid. At the same time, urbanization trends, medical overcapacities, and increasing care costs are being observed in association with a tight healthcare budget. Centralization, specialization, and outpatient care are intended to provide a remedy and can be controlled by modifications to remuneration. This upheaval poses new challenges for patients and physicians, which were analyzed exemplarily at the Head and Neck Tumor (HNC) Center of the University Hospital Ulm. This is a retrospective, monocentric cohort study on the development of patient volume, catchment area, treatment modality, and demographics including 2070 HNC patients at the ENT clinic between the years 2011 and 2020. It was observed that the number (new diagnoses 2011: 134 vs. 2020: 204) and the average age (2011: 61.5 years vs. 2020: 65.8 years; p < 0.0001) of HNC patients increased over time. In addition, patients tended to travel longer distances (2011: 54.4 km vs. 2020: 64.4 km; p = 0.05). At the same time, the mean number of consultations and treatments per patient per 5-year follow-up interval grew (at initial diagnosis in 2011: 7.8 vs. 2016: 10.4; p = 0.0003), with the proportion of outpatient contacts increasing from 58.9 % to 62.4 % (p = 0.09) from 2011 to 2020. Accordingly, clinical centers are expected to become more important in the care of HNC patients as the healthcare system becomes more specialized, and centralized with a growing outpatient setting. The following consequences for patient care should be considered in restructuring strategies.

Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative conventional therapy of head and neck squamous cell carcinoma (HNSCC).

Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled "Immune Response Evaluation to Curative conventional Therapy" (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy.

Deficits in executive functions but not in decision making under risk in individuals with problematic social-network use.

BACKGROUND: The tendency to strive for immediate gratification by neglecting potential negative long-term outcomes characterizes addictive behaviors, such as substance use or gaming disorder. Problematic social-network use is currently discussed as another potential addictive behavior, which is considered to result from an imbalance between affective and cognitive processes, indicated by traits such as increased impulsivity and/or decreased executive functions and decision-making abilities. METHODS: This study investigates the respective functions in social-network users by use of the Cards and Lottery Task (CLT) - a decision-making task under risk conditions in which options contain conflicting immediate and long-term outcomes at the same time. A sample of German and Spanish participants (N = 290) performed the CLT as well as the Modified Card Sorting Test (MCST), Barratt Impulsiveness Scale (BIS), the short Internet Addiction Test specified for social-networking (sIAT-SNS), and screeners on other potentially problematic behaviors. RESULTS: Comparing extreme groups based on sIAT-SNS scores (1SD above/below mean), individuals with problematic social-network use (n = 56), as compared to those with non-problematic social-network use (n = 50), showed increased attentional impulsivity and reduced executive functions. No differences were observed in decision-making performance. CONCLUSION: The findings indicate that problematic social-network use is related to attentional rather than general decision-making deficits. Furthermore, problematic social-network use is likely to co-occur with other problematic Internet-use behaviors, particularly gaming or shopping.

Dorsal and ventral striatum activity in individuals with buying-shopping disorder during cue-exposure: A functional magnetic resonance imaging study.

BACKGROUND AND AIMS: Buying-shopping disorder (BSD) is a clinical condition in which individuals lose control over their buying behaviour and continue buying despite negative consequences such as indebtedness, loss of family and friends. BSD has been considered a behavioural addiction and first studies provide evidence for cue-reactivity and craving as potential pathomechanisms. The current study aimed at investigating neural correlates of cue-reactivity and craving in individuals with BSD using functional magnetic resonance imaging (fMRI). METHODS: A cue-reactivity paradigm comprising individualised shopping-related and control cues was applied in n = 18 individuals diagnosed with BSD and n = 18 gender, age, and handedness matched control participants using fMRI. Outside the scanner, symptoms of BSD and craving reactions towards shopping (before and after the cue-reactivity paradigm) were assessed via questionnaires. FINDINGS: Higher subjective craving reactions towards shopping, prior and after exposure to shopping cues, were observed in individuals with BSD compared to control participants. Consistent with studies in addiction research, we found increased activations in the dorsal striatum for individuals with BSD compared to control participants during exposure to shopping cues. Activity in the ventral striatum was associated with symptoms of BSD in affected individuals, but not in control participants. CONCLUSIONS: Consistent with studies investigating cue-reactivity in substance-use and behavioural addictions, the association between cue-exposure and activities in reward-related brain structures such as the dorsal and ventral striatum in BSD participants may contribute to a neural explanation of why individuals experience irresistible urges to buy and lose control over their behaviour.

Addiction Research Unit: Affective and cognitive mechanisms of specific Internet-use disorders.

In the eleventh International Classification of Diseases (ICD-11) of the World Health Organization, gambling disorder and gaming disorder are included in the category 'disorders due to addictive behaviours', which can be specified further as occurring either predominantly offline or predominantly online. Other specific problematic behaviours may be considered for the category 'other specified disorders due to addictive behaviours'. The Research Unit FOR 2974, funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), focuses on the most prominent online addictive behaviours: gaming, pornography use, buying-shopping and social-networks use. The main goal of the Research Unit is to contribute to a better understanding of the common and differential psychological as well as neurobiological mechanisms involved in these specific types of Internet-use disorders. We aim to investigate theoretically argued (bio)psychological processes with a focus on concepts coming from research of substance-use disorders, for example, cue reactivity and craving, executive functions and specific inhibitory control, coping, implicit cognitions, and decision making. One central characteristic of the Research Unit is that we will investigate all participants using a comprehensive core battery of experimental paradigms, neuropsychological tasks, questionnaires, biomarkers, ambulatory assessment, and a 6-month follow-up survey. Beyond the anticipated contributions to the scientific understanding of the mechanisms involved in the development and maintenance of respective online addictive behaviours, we also expect contributions to clinical practice by showing which affective and cognitive mechanisms may be addressed more intensively to optimize treatment.

Associations of Buying-Shopping Disorder Symptoms with Identity Confusion, Materialism, and Socially Undesirable Personality Features in a Community Sample.

INTRODUCTION: While identity problems and materialistic value endorsement have been described as predisposing factors for buying-shopping disorder (BSD) in the literature, little empirical data are available on the role of socially undesirable personality features that may contribute to financial misconduct and manipulative interpersonal behaviors in BSD. The dark triad of personality refers to such offensive yet non-pathological personality traits and has been applied to addictive behaviors in the past. The aim of the present study was to investigate whether the "dark triad" dimensions Machiavellianism, subclinical narcissism, and subclinical psychopathy predict symptoms of BSD above and beyond identity confusion and materialism, or moderate the relationship between materialism and symptoms of BSD. METHOD: The participants comprised a convenience sample (N = 272, 72.4% women) aged between 18 and 67 years. Assessment included standard questionnaires for BSD, identity problems, materialism, and the dark triad of personality. RESULTS: Zero-order correlations indicate a weak association between BSD and the dark triad dimensions Machiavellianism and narcissism, but not psychopathy. Results of a moderated regression analysis with BSD symptoms as a dependent variable revealed significant main effects for materialism, female gender, and a significant "narcissism by materialism" effect, after accounting for identity confusion/synthesis and the single dark triad traits. CONCLUSION: The findings suggest that individuals with BSD attempt to address their narcissistic deficits via materialistic possessions. This assumption warrants further investigation in a clinical sample.

Exploring the Associations Between Self-reported Tendencies Toward Smartphone Use Disorder and Objective Recordings of Smartphone, Instant Messaging, and Social Networking App Usage: Correlational Study.

BACKGROUND: Social communication via instant messaging (IM) and social networking (SN) apps makes up a large part of the time that smartphone users spend on their devices. Previous research has indicated that the excessive use of these apps is positively associated with problematic smartphone use behaviors. In particular, image-based SN apps, such as Instagram (Facebook Inc) and Snapchat (Snap Inc), have been shown to exert stronger detrimental effects than those exerted by traditional apps, such as Facebook (Facebook Inc) and Twitter (Twitter Inc). OBJECTIVE: In this study, we investigated the correlation between individuals' tendencies toward smartphone use disorder (SmUD) and objective measures of the frequency of smartphone usage. Additionally, we put to test the hypothesis that the pathway linking the frequency of actual smartphone usage to self-reported tendencies toward SmUD was mediated by the increased frequency of IM and SN app usage. METHODS: We recruited a sample of 124 adult smartphone users (females: 78/124, 62.9%; age: mean 23.84 years, SD 8.29 years) and collected objective information about the frequency of smartphone and SN app usage over 1 week. Participants also filled in a self-report measure for assessing the multiple components of tendencies toward SmUD. Bivariate associations were investigated by using Spearman correlation analyses. A parallel mediation analysis was conducted via multiple regression analysis. RESULTS: The frequency of smartphone usage, as well as the use of IM apps (Messenger, Telegram, and WhatsApp [Facebook Inc]), Facebook, and image-based apps (Instagram and Snapchat), had significant positive associations with at least 1 component of SmUD, and the cyberspace-oriented relationships factor exhibited the strongest associations overall. We found support for an indirect effect that linked actual smartphone usage to SmUD tendencies via the frequency of the use of image-based SN apps. CONCLUSIONS: Our novel results shed light on the factors that promote SmUD tendencies and essentially indicate that image-based SN apps seem to be more strongly associated with problematic smartphone behaviors compared to IM apps and traditional SN apps, such as Facebook.

Decision-making, cognitive functions, impulsivity, and media multitasking expectancies in high versus low media multitaskers.

In several studies, individuals who reported to frequently multitask with different media displayed reduced cognitive performance, for example in fluid intelligence and executive functioning. These cognitive functions are relevant for making advantageous decisions under both objective risk (requiring reflection and strategical planning) and ambiguous risk (requiring learning from feedback). Thus, compared to low media multitaskers (LMMs), high media multitaskers (HMMs) may perform worse in both types of decision situations. The current study investigated HMMs and LMMs in a laboratory setting with the Game of Dice Task (GDT; objective risk), the Iowa Gambling Task (IGT; ambiguous risk), various tests quantifying cognitive functions (logical reasoning, working memory, information processing, general executive functions), and self-report measures of impulsivity, media multitasking expectancies, and problematic Internet use. From 182 participants, 25 HMMs and 19 LMMs were identified using the Media Multitasking Index. Results show that HMMs compared to LMMs performed weaker on the IGT but not on the GDT. Furthermore, HMMs had slightly decreased performance in tests of logical reasoning and working memory capacity. HMMs tended to increased information processing speed but this difference was not significant. Furthermore, HMMs have more positive expectancies regarding media multitasking and reported higher tendencies toward problematic Internet use. HMMs and LMMs did not differ significantly with respect to impulsivity and executive functions. The results give a first hint that HMMs may have difficulties in decision-making under ambiguous but not under objective risk. HMMs may be more prone to errors in tasks that require feedback processing. However, HMMs appear not to be impaired in aspects of long-term strategic decision-making.

[The Pathological Buying Screener: Validation in a Clinical Sample]. / Der Pathological Buying Screener: Validierung in einer klinischen Stichprobe.

AIM: The aim of the study was to evaluate the psychometric properties of the 13-item Pathological Buying Screener (PBS, [1]) in a clinical sample. METHOD: The PBS was administered to a total sample of 413 treatment-seeking patients (buying-shopping disorder n=151, gambling disorder n=59, alcohol dependency n=60, other mental disorders [anxiety, depressive, eating, somatoform disorders] n=143). Factor structure was tested in the total sample using confirmatory factor analysis (CFA), reliability was determined by means of Cronbach's α. Group comparisons were used to determine to which degree the PBS discriminates between patients with BSD and other clinical groups. The BSD-group completed a battery of other measures to explore convergent and divergent validity. A subgroup (n=29) answered the PBS before and after psychotherapy to investigate sensitivity to change. A receiver operating characteristic (ROC) curve analysis with PBS data of patients with buying-shopping disorder and those from a previous community sample 1 was performed to define a cut-off point for buying-shopping disorder. RESULTS: The CFA showed a good model fit for both a one-factor and a two-factor structure with the subscales "loss of control/consequences" (10 items) and "excessive buying behavior" (3 items). The subscales were highly intercorrelated (r=0.92). A hierarchical regression analysis with another BSD measure as dependent variable did not indicate an own incremental validity of the subscale "excessive buying behavior". Good convergent, divergent and discriminative capacity was obtained for the PBS total score. At its recommended cut-off point of ≥29 the PBS has a sensitivity of 98% and a specificity of 94.7%. CONCLUSION: The findings indicate good psychometric properties of the PBS and suggest that the PBS total score can be used in clinical settings.

Neural Mechanisms for Accepting and Rejecting Artificial Social Partners in the Uncanny Valley.

Artificial agents are becoming prevalent across human life domains. However, the neural mechanisms underlying human responses to these new, artificial social partners remain unclear. The uncanny valley (UV) hypothesis predicts that humans prefer anthropomorphic agents but reject them if they become too humanlike-the so-called UV reaction. Using fMRI, we investigated neural activity when subjects evaluated artificial agents and made decisions about them. Across two experimental tasks, the ventromedial prefrontal cortex (VMPFC) encoded an explicit representation of subjects' UV reactions. Specifically, VMPFC signaled the subjective likability of artificial agents as a nonlinear function of humanlikeness, with selective low likability for highly humanlike agents. In exploratory across-subject analyses, these effects explained individual differences in psychophysical evaluations and preference choices. Functionally connected areas encoded critical inputs for these signals: the temporoparietal junction encoded a linear humanlikeness continuum, whereas nonlinear representations of humanlikeness in dorsomedial prefrontal cortex (DMPFC) and fusiform gyrus emphasized a human-nonhuman distinction. Following principles of multisensory integration, multiplicative combination of these signals reconstructed VMPFC's valuation function. During decision making, separate signals in VMPFC and DMPFC encoded subjects' decision variable for choices involving humans or artificial agents, respectively. A distinct amygdala signal predicted rejection of artificial agents. Our data suggest that human reactions toward artificial agents are governed by a neural mechanism that generates a selective, nonlinear valuation in response to a specific feature combination (humanlikeness in nonhuman agents). Thus, a basic principle known from sensory coding-neural feature selectivity from linear-nonlinear transformation-may also underlie human responses to artificial social partners.SIGNIFICANCE STATEMENT Would you trust a robot to make decisions for you? Autonomous artificial agents are increasingly entering our lives, but how the human brain responds to these new artificial social partners remains unclear. The uncanny valley (UV) hypothesis-an influential psychological framework-captures the observation that human responses to artificial agents are nonlinear: we like increasingly anthropomorphic artificial agents, but feel uncomfortable if they become too humanlike. Here we investigated neural activity when humans evaluated artificial agents and made personal decisions about them. Our findings suggest a novel neurobiological conceptualization of human responses toward artificial agents: the UV reaction-a selective dislike of highly humanlike agents-is based on nonlinear value-coding in ventromedial prefrontal cortex, a key component of the brain's reward system.

Adenosine-producing regulatory B cells in head and neck cancer.

BACKGROUND: Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (Breg). Recently, we have shown that Breg suppress T cell function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of Breg in head and neck cancer remains unclear. METHODS: Blood (n = 42) and tumor tissue (n = 39) of head and neck cancer patients and healthy donors (n = 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca2+ influx and ADO production was analyzed in Breg and effector B cells (Beff) by FACS, luminescence and mass spectrometry. The blockage of the ADO receptor A2A was analyzed in a murine head and neck cancer model. RESULTS: ADO-producing Breg were found in tumor tissue and peripheral blood. ADO inhibited the intracellular Bruton's tyrosine kinase (BTK) and Ca2+ influx only in Beff. The inhibition of BTK by ibrutinib mimicked the effect of ADO, and ibrutinib reduced the production of ADO by downregulation of CD39 in vitro. The inhibition of ADO receptor A2A significantly reduced tumor mass and increased B cell infiltration, in vivo. CONCLUSION: Our data demonstrate the presence of a novel ADO-producing Breg population within the tumor microenvironment in mice and humans. A new model is proposed on how ADO-producing Breg can influence the function of Beff cells in healthy donors and cancer patients. Thus, the modulation of the ADO pathway in B cells may serve as a therapeutic approach for cancer patients.