Identification of an HLA-DQ2 peptide binding motif and HLA-DPw3-bound self-peptide by pool sequencing

Molecules of the major histocompatibility complex (MHC) present antigenic peptides to T cells. Sequencing peptide pools eluted from MHC class I molecules has established allele-specific peptide binding motifs. We applied pool sequencing to analyze human MHC class II-bound peptides and found that HLA-DQ2-eluted peptides predominantly contained lysine, isoleucine, and phenylalanine at relative position i, i + 3 and i + 8, respectively. These residues putatively represent anchor residues for MHC binding. Analysis of a heterogeneous HLA-DPw3/DPw4-eluted peptide pool yielded a sequence matching an epitope from the endogeneous enzyme glyceraldehyde-3-phosphate dehydrogenase. This self-peptide and a partially identical, known allo-epitope bound specifically to DPw3 and DR13 molecules, suggesting the sharing of a binding motif. In particular, the presence of an arginine at relative position 4 appeared important for binding to these HLA class II specificities. Thus, pool sequencing is applicable for the analysis of MHC class II-eluted peptides.     

Alcohol-related effects on automaticity due to experimentally manipulated conditioning

Background: The use of alcohol is associated with various forms of automatic processing, such as approach tendencies and attentional biases, which may play a role in addictive behavior. The development of such automaticity has generally occurred well before subjects perform tasks designed to detect them. Although it seems plausible that this development involves some form of alcohol‐related conditioning, this process is not usually included in the experimental procedure. Methods: The development of automaticity involving alcoholic or nonalcoholic stimuli was experimentally manipulated via a conditioning task. Subjects were presented with pairs of stimuli from a set of 4 stimuli: 2 pictures of alcoholic beverages, and 2 pictures of nonalcoholic beverages. One of the alcoholic and 1 of the nonalcoholic beverages was associated with reward, the other stimuli with punishment. Subjects had to learn to select the rewarded stimuli from pairs of 1 rewarded and 1 punished stimulus. The task, thus experimentally established reward versus punishment stimulus–response–outcome associations, for alcoholic and for nonalcoholic stimuli. Subsequently, a cued reversal task was used to test automaticity involving alcoholic versus nonalcoholic, and rewarded versus punished stimuli. Results: An association was found between heavier drinking and an alcohol‐related conditioning bias: heavier drinkers had more difficulty overcoming a conditioned response when it involved selecting a previously punished nonalcoholic stimulus over a previously rewarded alcoholic stimulus. Conclusions: The study provided novel information on secondary reinforcement involving alcoholic stimuli: heavier drinkers may more easily develop automaticity related to alcohol‐reward contingencies. This may have implications for interventions and the interpretation of findings concerning alcohol‐related automatic processing.     

The moderating role of working memory capacity and alcohol-specific rule-setting on the relation between approach tendencies and alcohol use in young adolescents

Background: Dual process models of alcohol addiction propose that the transition from normative alcohol consumption to heavy drinking is the result of an imbalance in interplay between relatively impulsive or automatic and reflective or controlled processes. The current study examines whether impulsive and reflective processes are also detectable in a sample of adolescents with limited alcohol use. Methods: Specifically, we tested the interaction between alcohol approach tendencies and 2 types of reflective processes, working memory capacity (WMC) and alcohol‐specific rule‐setting, on changes in alcohol use of 238 young adolescents (mean age: 13.82 years). Gender differences in these associations were also explored. Results: Results showed that WMC did not moderate the relation between approach tendencies and subsequent alcohol use, whereas rule‐setting did, with stronger associations between approach tendencies and alcohol use for male adolescents reporting more permissive parents than male adolescents with parents enforcing stricter rules involving alcohol use. Associations between approach tendencies and subsequent alcohol use did not emerge for female adolescents. Conclusions: Results indicate that even in a sample of adolescents with limited drinking experience, automatic processes are positively associated with alcohol use for male adolescents that are not motivated by parents to control their drinking.     

Predicting alcohol dependence from multi-site brain structural measures

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.     

BCG-induced trained immunity in NK cells: Role for non-specific protection to infection

Adaptive features of innate immunity, also termed ‘trained immunity’, have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination.     

Retraining automatic action‐tendencies to approach alcohol in hazardous drinkers

Aims The main aim of this study was to test whether automatic action‐tendencies to approach alcohol can be modified, and whether this affects drinking behaviour. Design and participants Forty‐two hazardous drinkers were assigned randomly to a condition in which they were implicitly trained to avoid or to approach alcohol, using a training variety of the alcohol Approach Avoidance Test (AAT). Participants pushed or pulled a joystick in response to picture‐format (landscape or portrait). The pictures depicted alcoholic or non‐alcoholic drinks. Participants in the avoid‐alcohol condition pushed most alcoholic and pulled most non‐alcoholic drinks. For participants in the approach‐alcohol condition these contingencies were reversed. After the implicit training, participants performed a taste test, including beers and soft drinks. Automatic action tendencies at post‐test were assessed with the AAT, including both trained and untrained pictures, and with a different test (Implicit Association Test, IAT). We further tested effects on subjective craving. Results Action tendencies for alcohol changed in accordance with training condition, with the largest effects in the clinically relevant avoid‐alcohol condition. These effects occurred outside subjective awareness and generalized to new pictures in the AAT and to an entirely different test using words, rather than pictures (IAT). In relatively heavy drinking participants who demonstrated changed action tendencies in accordance with their training condition, effects were found on drinking behaviour, with participants in the approach‐alcohol condition drinking more alcohol than participants in the avoid‐alcohol condition. No effect was found on subjective craving. Conclusions Retraining automatic processes may help to regain control over addictive impulses, which points to new treatment possibilities.     

Implicit and explicit alcohol-related cognitions

This article presents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada organized by Reinout W. Wiers and Alan W. Stacy. The purpose of the symposium was to present recent applications of implicit cognitive processing theory to alcohol research. Basic cognitive research has demonstrated that implicit cognition influences memory and behavior without explicit recall or introspection. The presentations from this symposium show that implicit cognition approaches yield new insights into understanding drinking motivation. The presentations were: (1) An introduction by Alan W. Stacy; (2) Implicit cognition and alcohol use. Involvement of other variables? (Susan L. Ames); (3) Alcohol expectancies and the art of implicit priming (Jane A. Noll); (4) Parental alcoholism and the effects of alcohol on semantic priming (Michael A. Sayette); (5) Implicit arousal and explicit liking of alcohol in heavy drinkers (Reinout W. Wiers); and (6) Negative affective cues and associative cognition in problem drinkers (Martin Zack). Comments were provided by the discussant Marvin Krank. The presented studies demonstrated that: (1) implicit memories of alcohol associations are powerful predictors and cross‐sectional correlates of alcohol use; (2) implicit retrieval processes influence alcohol outcome expectancies and alcohol consumption; (3) alcohol consumption influences implicit memory processing; (4) heavy drinkers reveal different affective responses in implicit and explicit tasks; and (5) negative affect exerts an implicit priming effect for alcohol associations in problem drinkers. These findings illustrate the importance of implicit cognition in understanding alcohol abuse and demonstrate the potential of the theoretical framework for more widespread application across a variety of areas of alcohol research, including diagnostics for the risk of alcohol abuse, treatment, and prevention.     

Selective cognitive processing of drug cues in heroin dependence

Previous studies provide evidence for the selective processing of disorder related stimuli on anxiety, depression, and eating disorders. There exist some preliminary indications that selective processing of drug cues may be involved in drug craving and relapse that deserve further investigation. In order to investigate the role of processing bias in an abnormal motivational system, the attentional bias for drug related stimuli was studied in a heroin dependent population. Heroin dependent participants (n = 21) and control participants (n = 30) performed a supra- and subliminal heroin Stroop task and heroin craving was assessed. Heroin dependent participants showed a considerable attentional bias for supraliminally presented heroin cues. However, there was no evidence for a preattentive bias on the subliminal presented cues. Reaction time on heroin cues was significantly predicted by heroin craving-levels. Results indicate that selective processing may be related to motivational induced states in general. The finding are discussed in the context of selective information processing in general psychopathology and in motivational processes as addiction specifically.