Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses.

Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca(2+)-NFAT signaling and effector functions by repressing sarco/ER Ca(2+)-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.

Are methamphetamine users compulsive? Faulty reinforcement learning, not inflexibility, underlies decision making in people with methamphetamine use disorder.

Methamphetamine use disorder involves continued use of the drug despite negative consequences. Such 'compulsivity' can be measured by reversal learning tasks, which involve participants learning action-outcome task contingencies (acquisition-contingency) and then updating their behaviour when the contingencies change (reversal). Using these paradigms, animal models suggest that people with methamphetamine use disorder (PwMUD) may struggle to avoid repeating actions that were previously rewarded but are now punished (inflexibility). However, difficulties in learning task contingencies (reinforcement learning) may offer an alternative explanation, with meaningful treatment implications. We aimed to disentangle inflexibility and reinforcement learning deficits in 35 PwMUD and 32 controls with similar sociodemographic characteristics, using novel trial-by-trial analyses on a probabilistic reversal learning task. Inflexibility was defined as (a) weaker reversal phase performance, compared with the acquisition-contingency phases, and (b) persistence with the same choice despite repeated punishments. Conversely, reinforcement learning deficits were defined as (a) poor performance across both acquisition-contingency and reversal phases and (b) inconsistent postfeedback behaviour (i.e., switching after reward). Compared with controls, PwMUD exhibited weaker learning (odds ratio [OR] = 0.69, 95% confidence interval [CI] [0.63-0.77], p < .001), though no greater accuracy reduction during reversal. Furthermore, PwMUD were more likely to switch responses after one reward/punishment (OR = 0.83, 95% CI [0.77-0.89], p < .001; OR = 0.82, 95% CI [0.72-0.93], p = .002) but just as likely to switch after repeated punishments (OR = 1.03, 95% CI [0.73-1.45], p = .853). These results indicate that PwMUD's reversal learning deficits are driven by weaker reinforcement learning, not inflexibility.

Emotional and non-emotional facets of impulsivity in eating disorders: From anorexia nervosa to bulimic spectrum disorders.

OBJECTIVE: Impulsivity and difficulties in regulating emotions are considered to be transdiagnostic characteristics of patients with eating disorders (EDs). The study aimed to investigate trait impulsivity and inhibitory components of impulsivity, related or unrelated to emotions in patients with EDs. METHOD: A total of 17 patients with anorexia nervosa (AN), 16 patients with bulimic-spectrum EDs (BSD) and 20 healthy control (HC) participants completed an impulsivity scale (UPPS-P) before performing an emotional inhibitory control task during electroencephalography (EEG) acquisition. RESULTS: Higher trait impulsivity in EDs than HC (with higher scores among BSD patients) was observed. However, no differences in behavioural measures or neural indexes [event-related potential (ERP)] of emotional and non-emotional inhibitory control were observed between patients and HC. CONCLUSION: The present results highlighted negative urgency, an impulsive personality trait related to emotions, as a common feature of AN and BSD. Lack of perseverance, a trait which is less related to emotions, specifically characterises patients with BSD. On the other hand, behavioural and ERP data did not show altered inhibitory control in EDs, for either general or emotional-related response inhibition.

Types of Emotion Regulation and Their Associations with Gambling: A Cross-Sectional Study with Disordered and Non-problem Ecuadorian Gamblers.

This cross-sectional study was aimed at investigating the role of emotional regulation in regular gambling in a sample of 197 disordered and non-problem gamblers from Ecuador. Two proxies were used as measures of behavioral signs of generalized emotion dysregulation (UPPS-P emotion-driven impulsivity) and intentional emotion regulation strategies (ERQ), and their associations with gambling cognitions (as measured by the GRCS questionnaire), gambling behavior (SOGS), and comorbid alcohol and drug misuse (MultiCAGE), were explored. For analyses, impulsivity traits, including emotion-driven impulsivity scores, were used as inputs to predict dispositional variables (ERQ strategies and GRCS cognitions), and clinically relevant behavioral outputs, while controlling for gambling severity. Hypotheses were based on previously published work, although the analysis has been improved (using hierarchical linear mixed-effects modelling), and homogenized in covariate control, and decision threshold stringency. Results were as follows: (1) After controlling for relevant covariates, UPPS-P sensation seeking was positively associated with gambling cognitions, whereas positive urgency was positively associated with cognitive biases (interpretative bias, control illusion, and predictive control) but not with other gambling cognitions. (2) Among emotion regulation strategies, reappraisal, but not suppression, was associated with gambling cognitions. (3) Negative urgency was distinctively associated with suppression, but not with reappraisal. And (4), no impulsivity dimensions significantly predicted drug or alcohol misuse, although negative urgency fell just below the decision threshold. These results reinforce the importance of emotion regulation processes in the cognitive and behavioral manifestations of gambling. Most importantly, they suggest a dissociation between the role of model-free dysregulation of negative emotions (as measured by UPPS-P negative urgency), as a key contributor to gambling complication and general psychopathology; and the one of strategic emotion regulation, in fueling gambling-related cognitive distortions.

Exploring the direct or inverse association of physical activity with behavioral addictions and other self-regulation problems. / ¿Protege o predispone la actividad física a las adicciones conductuales y otros problemas de autorregulación?

This cross-sectional survey study had the aim of clarifying the relationships between leisure time physical activity (LTPA) and non-drug-re-lated self-regulation problems (non-drug-related SRPs), including behavioral addictions, and the role of impulsive personality traits therein. Spanish university students (N = 329; Mage = 21.20) completed questionnaires for each of these constructs. Fitness and Bodybuilding LTPA was negatively associated with video gaming-related SRPs, r = -.13, p = .019, 95% CI (bootstrapped) [-.23, -.02], and positively associated with sex-related SRPs, r = .16, p = .005, 95% CI (bootstrapped) [.04,  .30]. Endurance LTPA was associated with higher scores in eating-related SRPs, r = .17, p = .003, 95% CI (bootstrapped) [.02,  .31]. The proportion of participants presenting scores above the clinically significant threshold in eating-related SRPs was 2.64 times higher for respondents in an Excessive Endurance LTPA cluster compared to the other respondents, Fisher's exact test, p = .017, OR = 3.10, 95% CI [1.26, 7.63], and the proportion of participants reporting vomiting to control weight was 2.12 times higher, Fisher's exact test, p = .040, OR = 2.43, 95% CI [1.06, 5.57]. The associations were largely independent of impulsive personality traits. We identified an elevated risk of eating pathology in a subgroup of participants with anomalously high participation in endurance physical activity. This overlap is consistent with the secondary dependence hypothesis of exercise addiction.

Este estudio tuvo como objetivo aclarar las relaciones entre la actividad física de ocio (AFO) y los problemas de autorregulación (PARs) no relacionados con drogas, incluyendo las adicciones conductuales, y el papel de los rasgos de personalidad impulsiva. Estudiantes universitarios españoles (N = 329, Mage = 21,20) completaron cuestionarios para cada uno de estos constructos.La AFO de gimnasio y musculación se asoció negativamente con los PARs relacionados con videojuegos, r = -0,13, p = 0,019, 95% CI (bootstrapped) [-0,23, -0,02], y positivamente con los PARs relacionados con sexo, r = 0,16, p = 0,005, 95% CI (bootstrapped) [0,04, -0,30]. La AFO de resistencia se asoció positivamente con los PARs relacionados con la alimentación, r = 0,17, p = 0,003, 95% CI (bootstrapped) [0,02,  0,31]. La probabilidad de presentar puntuaciones potencialmente clínicas en PARs de alimentación fue 2,64 veces mayor para los encuestados en un grupo de AFO de resistencia excesiva en comparación con los otros encuestados, prueba exacta de Fisher, p = 0,017, OR = 3,10, 95% CI [1,26, 7,63], y la probabilidad de vomitar para controlar el peso fue 2,12 veces mayor en ese mismo grupo, prueba exacta de Fisher, p = 0,040, OR = 2,43, 95% CI [1,06, 5,57]. Las asociaciones fueron en gran medida independientes de los rasgos de personalidad impulsiva.Identificamos un riesgo elevado de patología alimentaria potencialmente clínica en un subgrupo de participantes con niveles anormalmente altos de actividad física de resistencia. Esta superposición es consistente con la hipótesis de dependencia secundaria en la adicción al ejercicio.

Impulsivity and problem awareness predict therapy compliance and dropout from treatment for gambling disorder. / Impulsividad y conciencia del problema predicen la adherencia terapéutica y el abandono del tratamiento en el trastorno por juego de azar.

This study investigates the predictive value of impulsivity traits (as measured by the UPPS-P impulsive behaviour scale) and relevant covariates (sociodemographics, gambling severity, dysphoric mood, other potentially addictive behaviours, and non-verbal intelligence) with regard to treatment dropout and level of adherence to therapy guidelines and instructions in patients with gambling disorder. Sixty-six patients seeking treatment for gambling disorder, and recruited to participate in a larger protocol (G-Brain), were initially assessed in impulsivity traits and relevant covariates in the first six months after admission. Of these, 24 patients dropped out (DO) and 42 patients remained in therapy (NDO) during the subsequent 6-month follow-up period. A multivariate analysis of impulsivity subscales suggested prospective differences between DO and NDO, with affect-driven dimensions (positive and negative urgency) seemingly driving these differences. Among these, only positive urgency independently predicted a slight increase in the drop-out probability. In the NDO group, a higher degree of adherence to therapy was independently predicted by lower sensation-seeking scores and stronger awareness of gambling-related problems. Results suggest the presence of affect-driven impulsivity traits as dropout predictors in patients with gambling disorder. Awareness of gambling-related problems and lower sensation-seeking enhanced compliance with therapeutic guidelines and instructions.

Este estudio investiga el valor predictivo de la impulsividad como rasgo (evaluada con la escala de conducta impulsiva UPPS-P) y de covariados relevantes (variables sociodemográficas, severidad del juego de azar, estado de ánimo disfórico, otras conductas adictivas e inteligencia no verbal), con respecto al abandono del tratamiento y los niveles de cumplimiento de las prescripciones terapéuticas en pacientes con trastorno por juego de azar. Sesenta y seis pacientes con este trastorno, participantes del proyecto G-Brain, fueron evaluados inicialmente en impulsividad rasgo y en los covariados mencionados. Dicha evaluación se realizó durante los seis primeros meses desde el inicio de su tratamiento. En el seguimiento realizado a los 6 meses, 24 pacientes habían abandonado (grupo ABD) y 42 continuaban el tratamiento (grupo NABD). Los análisis multivariados con las subescalas de impulsividad mostraron diferencias prospectivas entre ambos grupos. Aparentemente, estas diferencias son atribuibles a las dimensiones afectivas de impulsividad (urgencias positiva y negativa). Entre ambas dimensiones, solo la urgencia positiva fue un predictor independiente de un ligero incremento en la probabilidad de abandono. Dentro del grupo NABD, un mayor grado de adherencia terapéutica vino predicho, de manera independiente, tanto por una baja búsqueda de sensaciones como por una mayor conciencia de los problemas vinculados al juego. Estos resultados sugieren que los rasgos de impulsividad de origen afectivo son predictores de abandono del tratamiento en pacientes con trastorno por juego. La conciencia de problemas asociados al juego de azar y una baja búsqueda de sensaciones predisponen a una mayor adherencia a las prescripciones terapéuticas.

A test-retest assessment of the effects of mental load on ratings of affect, arousal and perceived exertion during submaximal cycling.

This study aimed to test the effects of mental (i.e. executive) load during a dual physical-mental task on ratings of perceived exertion (RPE), affective valence, and arousal. The protocol included two dual tasks with matched physical demands but different executive demands (2-back and oddball), carried out on different days. The procedure was run twice to assess the sensitivity and stability of RPE, valence and arousal across the two trials. Linear mixed-effects analyses showed less positive valence (-0.44 points on average in a 1-9 scale; Rß2 = 0.074 [CI90%, 0.052-0.098]), and heightened arousal (+0.13 points on average in a 1-9 scale; Rß2 = 0.006 [CI90%, 0.001-0.015]), for the high executive load condition, but showed no effect of mental load on RPE. Separated analyses for the two task trials yielded best-fitting models that were identical across trials for RPE and valence, but not for arousal. Model fitting was improved by assuming a 1-level autoregressive covariance structure for all analyses. In conclusion, executive load during a dual physical-mental task modulates the emotional response to effort, but not RPE. The autoregressive covariance suggests that people tend to anchor estimates on prior ones, which imposes certain limits on scales' usability.

Electroencephalographic Evidence of Abnormal Anticipatory Uncertainty Processing in Gambling Disorder Patients.

Putting money at stake produces anticipatory uncertainty, a process that has been linked to key features of gambling. Here we examined how learning and individual differences modulate the stimulus preceding negativity (SPN, an electroencephalographic signature of perceived uncertainty of valued outcomes) in gambling disorder patients (GDPs) and healthy controls (HCs), during a non-gambling contingency learning task. Twenty-four GDPs and 26 HCs performed a causal learning task under conditions of high and medium uncertainty (HU, MU; null and positive cue-outcome contingency, respectively). Participants were asked to predict the outcome trial-by-trial, and to regularly judge the strength of the cue-outcome contingency. A pre-outcome SPN was extracted from simultaneous electroencephalographic recordings for each participant, uncertainty level, and task block. The two groups similarly learnt to predict the occurrence of the outcome in the presence/absence of the cue. In HCs, SPN amplitude decreased as the outcome became predictable in the MU condition, a decrement that was absent in the HU condition, where the outcome remained unpredictable during the task. Most importantly, GDPs' SPN remained high and insensitive to task type and block. In GDPs, the SPN amplitude was linked to gambling preferences. When both groups were considered together, SPN amplitude was also related to impulsivity. GDPs thus showed an abnormal electrophysiological response to outcome uncertainty, not attributable to faulty contingency learning. Differences with controls were larger in frequent players of passive games, and smaller in players of more active games. Potential psychological mechanisms underlying this set of effects are discussed.

Causal Learning in Gambling Disorder: Beyond the Illusion of Control.

Causal learning is the ability to progressively incorporate raw information about dependencies between events, or between one's behavior and its outcomes, into beliefs of the causal structure of the world. In spite of the fact that some cognitive biases in gambling disorder can be described as alterations of causal learning involving gambling-relevant cues, behaviors, and outcomes, general causal learning mechanisms in gamblers have not been systematically investigated. In the present study, we compared gambling disorder patients against controls in an instrumental causal learning task. Evidence of illusion of control, namely, overestimation of the relationship between one's behavior and an uncorrelated outcome, showed up only in gamblers with strong current symptoms. Interestingly, this effect was part of a more complex pattern, in which gambling disorder patients manifested a poorer ability to discriminate between null and positive contingencies. Additionally, anomalies were related to gambling severity and current gambling disorder symptoms. Gambling-related biases, as measured by a standard psychometric tool, correlated with performance in the causal learning task, but not in the expected direction. Indeed, performance of gamblers with stronger biases tended to resemble the one of controls, which could imply that anomalies of causal learning processes play a role in gambling disorder, but do not seem to underlie gambling-specific biases, at least in a simple, direct way.

Increased corticolimbic connectivity in cocaine dependence versus pathological gambling is associated with drug severity and emotion-related impulsivity.

Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine-targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting-state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co-morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed-based analyses to characterize the connectivity of regions displaying between-group differences. We examined the relationships between seed-based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large-scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed-based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision-making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus-outcome learning. Orbitofrontal-subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large-scale ventral corticostriatal-amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect.

Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor cell adaptation to nutrient availability.

Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), encoded by the nuclear PCK2 gene, links TCA cycle intermediates and glycolytic pools through the conversion of mitochondrial oxaloacetate into phosphoenolpyruvate. In the liver PEPCK-M adjoins its profusely studied cytosolic isoform (PEPCK-C) potentiating gluconeogenesis and TCA flux. However, PEPCK-M is present in a variety of non-gluconeogenic tissues, including tumors of several origins. Despite its potential relevance to cancer metabolism, the mechanisms responsible for PCK2 gene regulation have not been elucidated. The present study demonstrates PEPCK-M overexpression in tumorigenic cells as well as the mechanism for the modulation of PCK2 abundance under several stress conditions. Amino acid limitation and ER stress inducers, conditions that activate the amino acid response (AAR) and the unfolded protein response (UPR), stimulate PCK2 gene transcription. Both the AAR and UPR lead to increased synthesis of ATF4, which mediates PCK2 transcriptional up-regulation through its binding to a putative ATF/CRE composite site within the PCK2 promoter functioning as an amino acid response element. In addition, activation of the GCN2-eIF2α-ATF4 and PERK-eIF2α-ATF4 signaling pathways are responsible for increased PEPCK-M levels. Finally, PEPCK-M knockdown using either siRNA or shRNA were sufficient to reduce MCF7 mammary carcinoma cell growth and increase cell death under glutamine deprivation or ER stress conditions. Our data demonstrate that this enzyme has a critical role in the survival program initiated upon stress and shed light on an unexpected and important role of mitochondrial PEPCK in cancer metabolism.

Cocaine use severity and cerebellar gray matter are associated with reversal learning deficits in cocaine-dependent individuals.

Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning-sensitive regions. Cocaine-targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine-dependent individuals (CDIs) varying on levels of cocaine exposure in comparison with healthy controls (HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task (PRLT) and were subsequently scanned in a 3-Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and then must learn to respond according to the opposite, previously irrelevant, stimulus-reward pairing. Performance measures were errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel-based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter.

Nonmonetary Decision-Making Indices Discriminate Between Different Behavioral Components of Gambling.

Recent research has proposed that altered reward and punishment sensitivity, heightened impulsivity, and faulty dynamic decision-making are at the core of disordered gambling. However, each of these traits and cognitive aspects dimensionally vary in the normal population, such that the link between individual differences in these dimensions and gambling use can be ultimately informative to explain disordered gambling. The main aim of the present study was to investigate the contribution of such decision-making-related indices to gambling use parameters in a community sample of college students. Assessment included punishment and reward sensitivity (as measured by the shortened Sensitivity to Punishment and Sensitivity to Reward Questionnaire), impulsivity (as measured by the UPPS-P model and a motor inhibition Go/No-go task), and dynamic decision-making [as measured by the probabilistic reversal learning task (PRLT)]. A structured interview was conducted to explore quantitative aspects of the participants gambling habits (gambling presence, gambling frequency, and average amount of money spent in gambling per unit of time). Our results showed the existence of a decision-making profile of gambling, as it naturally occurs in college students, in which sensation seeking is directly and specifically related to gambling presence (gambling, or not gambling at all), punishment sensitivity is inversely related to gambling frequency, and inflexibility in the PRLT specifically predicts the losses accrued because of gambling. These results are compatible with the idea that sensation seeking and punishment insensitivity could increase exposure to gambling activities, whereas reversal learning inflexibility, in people who already gamble, could boost the risk to accumulate losses.

The hidden cost of coaching: intentional training of shot adequacy discrimination in basketball hampers utilization of informative incidental cues.

The goal was to identify the advantages and disadvantages of using intentional guidance to teach to discriminate between good and bad circumstances to shoot in basketball. A simulated shot-adequacy learning task was developed, in which participants were asked to decide, in each trial, whether the player in possession of the ball should shoot or not. After each decision, they received feedback on their response (determined by five cues: Opposition, Rebound, Balance, Alternative, and Distance). 65 naïve participants (M age = 18.6 yr., SD = 1.3) were divided into two groups. The Incidental group received no guiding instructions. The Intentional group was instructed to utilize four of the five cues. The Distance cue was kept incidental for both groups. Participants effectively incorporated the cues into their decisions. Guidance had a markedly different effect across cues. The Intentional group utilized Distance less efficiently than the Incidental group, i.e., intentional instructions on the other four cues nearly blocked the utilization of Distance.

Psychometric Properties of the Spanish Motives for Online Gaming Questionnaire in a Sample of College Students.

This study investigates the psychometric properties of the Spanish version of the Motives for Online Gaming Questionnaire (MOGQ). We explored the factor structure and construct validity of the MOGQ through its relationships with gaming disorder symptoms (IGD-20) and impulsivity traits. We also analyzed if sociodemographic variables and gaming habits were related to gaming motives. An online cross-sectional survey was completed by 845 college students. Structure validity was examined using a combination of exploratory and confirmatory factor analyses, which supported a bifactor model composed of a general motivation factor and six uncorrelated factors (a mixed factor composed of escape and coping, competition, recreation, skill, social, and fantasy). Omega-hierarchical and omega coefficients were used to determine reliability of the MOGQ. The scale presented acceptable reliability for the general factor (ωh = .79) and the specific factor scores (social ω = .79, escape/coping ω = .81, competition ω = .79, skill ω = .84, fantasy ω = .82, and recreation ω = .70). Positive associations were observed between the MOGQ and the IGD-20 symptoms, with escape/coping (r = .48) and fantasy (r =.40) showing the strongest ones. Null or low correlations were observed with impulsivity traits. Motives to play varied significantly across genders. These findings provide evidence that the Spanish version of the MOGQ is a reliable and valid tool to assess motives to play online games.

PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis.

BACKGROUND & AIMS: Hepatic gluconeogenesis helps maintain systemic energy homeostasis by compensating for discontinuities in nutrient supply. Liver-specific deletion of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) abolishes gluconeogenesis from mitochondrial substrates, deregulates lipid metabolism and affects TCA cycle. While the mouse liver almost exclusively expresses PEPCK-C, humans equally present a mitochondrial isozyme (PEPCK-M). Despite clear relevance to human physiology, the role of PEPCK-M and its gluconeogenic potential remain unknown. Here, we test the significance of PEPCK-M in gluconeogenesis and TCA cycle function in liver-specific PEPCK-C knockout and WT mice. METHODS: The effects of the overexpression of PEPCK-M were examined by a combination of tracer studies and molecular biology techniques. Partial PEPCK-C re-expression was used as a positive control. Metabolic fluxes were evaluated in isolated livers by NMR using (2)H and (13)C tracers. Gluconeogenic potential, together with metabolic profiling, was investigated in vivo and in primary hepatocytes. RESULTS: PEPCK-M expression partially rescued defects in lipid metabolism, gluconeogenesis and TCA cycle function impaired by PEPCK-C deletion, while ∼10% re-expression of PEPCK-C normalized most parameters. When PEPCK-M was expressed in the presence of PEPCK-C, the mitochondrial isozyme amplified total gluconeogenic capacity, suggesting autonomous regulation of oxaloacetate to phosphoenolpyruvate fluxes by the individual isoforms. CONCLUSIONS: We conclude that PEPCK-M has gluconeogenic potential per se, and cooperates with PEPCK-C to adjust gluconeogenic/TCA flux to changes in substrate or energy availability, hinting at a role in the regulation of glucose and lipid metabolism in the human liver.

Functionally enhanced siRNA targeting TNFα attenuates DSS-induced colitis and TLR-mediated immunostimulation in mice.

Tumor necrosis factor (TNFα) is a proinflammatory cytokine involved in the pathogenesis of inflammatory bowel disease (IBD). Although TNFα has been extensively targeted using systemic drugs, the use of antisense and small interfering RNA (siRNA) to drive down its expression at the site of inflammation should provide important advantages. In this study, native and chemically modified siRNA against TNFα was developed and characterized using a murine model of IBD. siRNA with 2'-O-methyl and propanediol modifications (siTNF-OMe-P) were resistant to nuclease degradation and provided better silencing efficacy in vitro as compared to unmodified siRNA. Every modification reduced nonspecific Toll-like receptor (TLR)-mediated immunomodulation in human peripheral blood mononuclear cells (PBMC) cells. Intrarectal administration of siTNF-OMe-P significantly ameliorated the clinical endpoints and histopathological severity in 5% dextran sulphate sodium (DSS)-treated mice as compared to unmodified and other chemically modified siRNAs. Differential gene expression assessed in siTNF-OMe-P-treated animals correlated with improved colon integrity and reduced TLR activation as compared to all treatment groups. All in all, this study demonstrates that propanediol and 2'-O-methyl modifications have profound functional consequences for siRNA efficacy in vivo. Consequently, this strategy has potential implications for therapeutic intervention in IBD and other diseases.

Gaming passion contributes to the definition and identification of problematic gaming.

Even if for most people playing video games is a healthy leisure activity, a minority of vulnerable users present an excessive use associated to negative consequences (e.g., psychosocial maladjustment, sleep interference) and functional impairment. The current study first aims to identify psychological factors that contribute to discriminate highly involved (but healthy) gamers from problematic gamers. For that purpose, we used a cluster analysis approach to identify different groups of gamers based on their profiles of passion towards gaming (using the Dualistic Model of Passion). Another objective of the present study is to explore, using supervised machine-learning, how gaming disorder symptoms, assessed within the substance use disorder framework (e.g., tolerance, withdrawal), might be linked to harmonious and/or an obsessive passion for gaming. Three distinct clusters of gamers were identified based on their passion profiles, including risky gamers, engaged gamers, and casual gamers. Supervised machine-learning algorithms identified that specific gaming disorder symptoms (salience, mood modification, tolerance, low level of conflict) were predominantly related to harmonious passion, whereas others (withdrawal, high level of conflict, relapse) were more directly related to obsessive passion. Our results support the relevance of person-centered approaches to the treatment of problematic gaming.

The associative learning roots of affect-driven impulsivity and its role in problem gambling: A replication attempt and extension of Quintero et al. (2020).

Background and aims: Negative/positive urgency (NU/PU) refers to the proneness to act rashly under negative/positive emotions. These traits are proxies to generalized emotion dysregulation, and are well-established predictors of gambling-related problems. We aimed to replicate a previous work (Quintero et al., 2020) showing NU to be related to faulty extinction of conditioned stimuli in an emotional conditioning task, to extend these findings to PU, and to clarify the role of urgency in the development of gambling-related craving and problems. Methods: 81 gamblers performed an acquisition-extinction task in which neutral, disgusting, erotic and gambling-related images were used as unconditioned stimuli (US), and color patches as conditioned stimuli (CS). Trial-by-trial predictive responses were analyzed using generalized linear mixed-effects models (GLME). Results: PU was more strongly related than NU to craving and severity of gambling problems. PU did not influence acquisition in the associative task, whereas NU slightly slowed it. Extinction was hampered in individuals with high PU, and a follow-up analysis showed this effect to depend on relative preference for skill-based and casino games. Discussion and conclusions: Results suggest that resistance to extinction of emotionally conditioned cues is a sign of malfunctioning emotion regulation in problematic gambling. In our work, the key effect was driven by PU (instead of NU), and gambling craving and symptoms were also more closely predicted by it. Future research should compare the involvement of PU and NU in emotion regulation and gambling problems, for gamblers with preference for different gambling modalities (e.g., pure chance vs skill games).

Operationalization and measurement of compulsivity across video gaming and gambling behavioral domains.

BACKGROUND: Compulsivity is the hallmark of addiction progression and, as a construct, has played an important role in unveiling the etiological pathways from learning mechanisms underlying addictive behavior to harms resulting from it. However, a sound use of the compulsivity construct in the field of behavioral addictions has been hindered to date by the lack of consensus regarding its definition and measurement. Here we capitalize on a previous systematic review and expert appraisal to develop a compulsivity scale for candidate behavioral addictions (the Granada Assessment for Cross-domain Compulsivity, GRACC). METHODS: The initial scale (GRACC90) consisted of 90 items comprising previously proposed operationalizations of compulsivity, and was validated in two panel samples of individuals regularly engaging in gambling and video gaming, using exploratory structural equation modeling (ESEM) and convergence analyses. RESULTS: The GRACC90 scale is unidimensional and structurally invariant across samples, and predicted severity of symptoms, lower quality of life, and negative affect, to similar degrees in the two samples. Additionally, poorer quality of life and negative affect were comparably predicted by compulsivity and by severity of symptoms. A shorter version of the scale (GRACC18) is proposed, based on selecting the 18 items with highest factor loadings. CONCLUSIONS: Results support the proposal that core symptoms of behavioral addictions strongly overlap with compulsivity, and peripheral symptoms are not essential for their conceptualization. Further research should clarify the etiology of compulsive behavior, and whether pathways to compulsivity in behavioral addictions could be common or different across domains.