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1.  Response Inhibition during Cue Reactivity in Problem Gamblers: An fMRI Study 
PLoS ONE  2012;7(3):e30909.
Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).
Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.
PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.
This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.
PMCID: PMC3316530  PMID: 22479305
2.  Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study 
Addiction Biology  2010;15(4):491-503.
Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event-related cue reactivity paradigm, consisting of gambling, smoking-related and neutral pictures, was employed in 17 treatment-seeking non-smoking PRG, 18 non-gambling HSM, and 17 non-gambling and non-smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerström Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking-related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non-smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking-related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto-limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores.
PMCID: PMC3014110  PMID: 20840335
Addiction; cue reactivity; fMRI; impulse control disorder; nicotine dependence; pathological gambling
3.  Getting a grip on problem gambling: what can neuroscience tell us? 
In problem gamblers, diminished cognitive control and increased impulsivity is present compared to healthy controls. Moreover, impulsivity has been found to be a vulnerability marker for the development of pathological gambling (PG) and problem gambling (PrG) and to be a predictor of relapse. In this review, the most recent findings on functioning of the brain circuitry relating to impulsivity and cognitive control in PG and PrG are discussed. Diminished functioning of several prefrontal areas and of the anterior cingulate cortex (ACC) indicate that cognitive-control related brain circuitry functions are diminished in PG and PrG compared to healthy controls. From the available cue reactivity studies on PG and PrG, increased responsiveness towards gambling stimuli in fronto-striatal reward circuitry and brain areas related to attentional processing is present compared to healthy controls. At this point it is unresolved whether PG is associated with hyper- or hypo-activity in the reward circuitry in response to monetary cues. More research is needed to elucidate the complex interactions for reward responsivity in different stages of gambling and across different types of reward. Conflicting findings from basic neuroscience studies are integrated in the context of recent neurobiological addiction models. Neuroscience studies on the interface between cognitive control and motivational processing are discussed in light of current addiction theories.
Clinical implications: We suggest that innovation in PG therapy should focus on improvement of dysfunctional cognitive control and/or motivational functions. The implementation of novel treatment methods like neuromodulation, cognitive training and pharmacological interventions as add-on therapies to standard treatment in PG and PrG, in combination with the study of their effects on brain-behavior mechanisms could prove an important clinical step forward towards personalizing and improving treatment results in PG.
PMCID: PMC4033022  PMID: 24904328
pathological gambling; disordered gambling; reward sensitivity; impulsivity; cue reactivity; response inhibition; review; addictive behaviors
4.  Time course of attentional bias for gambling information in problem gambling 
There is a wealth of evidence showing enhanced attention towards drug-related information (i.e. attentional bias) in substance abusers. However, little is known about attentional bias in deregulated behaviors without substance use such as abnormal gambling. This study examined whether problem gamblers (PrG, as assessed through self-reported gambling-related craving and gambling dependence severity) exhibit attentional bias for gambling-related cues.
Forty PrG and 35 control participants performed a change detection task using the flicker paradigm, in which two images differing in only one aspect are repeatedly flashed on the screen until the participant is able to report the changing item. In our study, the changing item was either neutral or related to gambling. Eye movements were recorded, which made it possible to measure both initial orienting of attention as well as its maintenance on gambling information.
Direct (eye-movements) and indirect (change in detection latency) measures of attention in individuals with problematic gambling behaviors suggested the occurrence of both engagement and of maintenance attentional biases towards gambling-related visual cues. Compared to non-problematic gamblers, PrG exhibited (1) faster reaction times to gambling-cues as compared to neutral cues, (2) higher percentage of initial saccades directed toward gambling pictures; (3) an increased fixation duration and fixation count on gambling pictures. In the PrG group, measures of gambling-related attentional bias were not associated with craving for gambling and gambling dependence severity. Theoretical and clinical implications of these results are discussed.
PMCID: PMC3792789  PMID: 21688874
Gambling; Attentional bias; Dependence; Eye-tracking; Craving
5.  PTSD symptom severity is associated with increased recruitment of top-down attentional control in a trauma-exposed sample☆ 
NeuroImage : Clinical  2014;7:19-27.
Recent neuroimaging work suggests that increased amygdala responses to emotional stimuli and dysfunction within regions mediating top down attentional control (dorsomedial frontal, lateral frontal and parietal cortices) may be associated with the emergence of anxiety disorders, including posttraumatic stress disorder (PTSD). This report examines amygdala responsiveness to emotional stimuli and the recruitment of top down attention systems as a function of task demands in a population of U.S. military service members who had recently returned from combat deployment in Afghanistan/Iraq. Given current interest in dimensional aspects of pathophysiology, it is worthwhile examining patients who, while not meeting full PTSD criteria, show clinically significant functional impairment.
Fifty-seven participants with sub-threshold levels of PTSD symptoms completed the affective Stroop task while undergoing fMRI. Participants with PTSD or depression at baseline were excluded.
Greater PTSD symptom severity scores were associated with increased amygdala activation to emotional, particularly positive, stimuli relative to neutral stimuli. Furthermore, greater PTSD symptom severity was associated with increased superior/middle frontal cortex response during task conditions relative to passive viewing conditions. In addition, greater PTSD symptom severity scores were associated with: (i) increased activation in the dorsolateral prefrontal, lateral frontal, inferior parietal cortices and dorsomedial frontal cortex/dorsal anterior cingulate cortex (dmFC/dACC) in response to emotional relative to neutral stimuli; and (ii) increased functional connectivity during emotional trials, particularly positive trials, relative to neutral trials between the right amygdala and dmFC/dACC, left caudate/anterior insula cortex, right lentiform nucleus/caudate, bilateral inferior parietal cortex and left middle temporal cortex.
We suggest that these data may reflect two phenomena associated with increased PTSD symptomatology in combat-exposed, but PTSD negative, armed services members. First, these data indicate increased emotional responsiveness by: (i) the positive relationship between PTSD symptom severity and amygdala responsiveness to emotional relative to neutral stimuli; (ii) greater BOLD response as a function of PTSD symptom severity in regions implicated in emotion (striatum) and representation (occipital and temporal cortices) during emotional relative to neutral conditions; and (iii) increased connectivity between the amygdala and regions implicated in emotion (insula/caudate) and representation (middle temporal cortex) as a function of PTSD symptom severity during emotional relative to neutral trials. Second, these data indicate a greater need for the recruitment of regions implicated in top down attention as indicated by (i) greater BOLD response in superior/middle frontal gyrus as a function of PTSD symptom severity in task relative to view conditions; (ii) greater BOLD response in dmFC/dACC, lateral frontal and inferior parietal cortices as a function of PTSD symptom severity in emotional relative to neutral conditions and (iii) greater functional connectivity between the amygdala and inferior parietal cortex as a function of PTSD symptom severity during emotional relative to neutral conditions.
•Greater PTSD symptoms associated with increased amygdala activation to emotional stimuli•PTSD symptoms associated with greater top down attention response in task and emotion conditions•PTSD symptoms were associated with slower reaction times.•Increased top down attention recruitment may compensate for heightened emotional responses.
PMCID: PMC4299952  PMID: 25610763
Post-traumatic stress disorder; Emotion attention; Amygdala; Top down attention
6.  Abnormalities of functional brain networks in pathological gambling: a graph-theoretical approach 
Functional neuroimaging studies of pathological gambling (PG) demonstrate alterations in frontal and subcortical regions of the mesolimbic reward system. However, most investigations were performed using tasks involving reward processing or executive functions. Little is known about brain network abnormalities during task-free resting state in PG. In the present study, graph-theoretical methods were used to investigate network properties of resting state functional magnetic resonance imaging data in PG. We compared 19 patients with PG to 19 healthy controls (HCs) using the Graph Analysis Toolbox (GAT). None of the examined global metrics differed between groups. At the nodal level, pathological gambler showed a reduced clustering coefficient in the left paracingulate cortex and the left juxtapositional lobe (supplementary motor area, SMA), reduced local efficiency in the left SMA, as well as an increased node betweenness for the left and right paracingulate cortex and the left SMA. At an uncorrected threshold level, the node betweenness in the left inferior frontal gyrus was decreased and increased in the caudate. Additionally, increased functional connectivity between fronto-striatal regions and within frontal regions has also been found for the gambling patients. These findings suggest that regions associated with the reward system demonstrate reduced segregation but enhanced integration while regions associated with executive functions demonstrate reduced integration. The present study makes evident that PG is also associated with abnormalities in the topological network structure of the brain during rest. Since alterations in PG cannot be explained by direct effects of abused substances on the brain, these findings will be of relevance for understanding functional connectivity in other addictive disorders.
PMCID: PMC3784685  PMID: 24098282
fMRI; graph theory; network; connectivity; pathological gambling; reward; behavioral addiction; small world
7.  Striatal connectivity changes following gambling wins and near-misses: Associations with gambling severity 
NeuroImage : Clinical  2014;5:232-239.
Frontostriatal circuitry is implicated in the cognitive distortions associated with gambling behaviour. ‘Near-miss’ events, where unsuccessful outcomes are proximal to a jackpot win, recruit overlapping neural circuitry with actual monetary wins. Personal control over a gamble (e.g., via choice) is also known to increase confidence in one's chances of winning (the ‘illusion of control’).
Using psychophysiological interaction (PPI) analyses, we examined changes in functional connectivity as regular gamblers and non-gambling participants played a slot-machine game that delivered wins, near-misses and full-misses, and manipulated personal control. We focussed on connectivity with striatal seed regions, and associations with gambling severity, using voxel-wise regression.
For the interaction term of near-misses (versus full-misses) by personal choice (participant-chosen versus computer-chosen), ventral striatal connectivity with the insula, bilaterally, was positively correlated with gambling severity. In addition, some effects for the contrast of wins compared to all non-wins were observed at an uncorrected (p < .001) threshold: there was an overall increase in connectivity between the striatal seeds and left orbitofrontal cortex and posterior insula, and a negative correlation for gambling severity with the connectivity between the right ventral striatal seed and left anterior cingulate cortex.
These findings corroborate the ‘non-categorical’ nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling.
PMCID: PMC4110887  PMID: 25068112
Gambling; Connectivity; fMRI; Reward; Near-miss; Addiction
8.  An fMRI study of risk-taking following wins and losses: Implications for the gambler’s fallacy 
Human brain mapping  2011;32(2):271-281.
Human decision-making involving independent events is often biased and affected by prior outcomes. Using a controlled task that allows us to manipulate prior outcomes, the present study examined the effect of prior outcomes on subsequent decisions in a group of young adults. We found that participants were more risk-seeking after losing a gamble (Riskloss) than after winning a gamble (Riskwin), a pattern resembling the gambler’s fallacy. Functional MRI data revealed that decisions after Riskloss were associated with increased activation in the frontoparietal network, but decreased activation in the caudate and ventral striatum. The increased risk-seeking behavior after a loss showed a trend of positive correlation with activation in the frontoparietal network and the left lateral orbitofrontal cortex but a trend of negative correlation with activation in the amgydala and caudate. In addition, there was a trend of positive correlation between feedback-related activation in the left lateral frontal cortex and subsequent increased risk-seeking behavior. These results suggest that a strong cognitive control mechanism but a weak affective decision-making and reinforcement learning mechanism that usually contribute to flexible, goal-directed decisions can lead to decision biases involving random events. This has significant implications for our understanding of the gambler’s fallacy and human decision making under risk.
PMCID: PMC3429350  PMID: 21229615
Amygdala; Decision Making; Emotion; Frontal Cortex; functional MRI; Gambler’s Fallacy; Orbitofrontal Cortex; Reinforcement Learning; Striatum
9.  In Vivo and In Vitro Analyses of Regulation of the Pheromone-Responsive prgQ Promoter by the PrgX Pheromone Receptor Protein 
Journal of Bacteriology  2012;194(13):3386-3394.
Expression of conjugative transfer and virulence functions of the Enterococcus faecalis antibiotic resistance plasmid pCF10 is regulated by the interaction of the pheromone receptor protein PrgX with two DNA binding operator sites (XBS1 and XBS2) upstream from the transcription start site of the prgQ operon (encoding the pCF10 transfer machinery) and by posttranscriptional mechanisms. Occupancy of both binding sites by PrgX dimers results in repression of the prgQ promoter. Structural and genetic studies suggest that the peptide pheromone cCF10 functions by binding to PrgX and altering its oligomerization state, resulting in reduced occupancy of XBSs and increased prgQ transcription. The DNA binding activity of PrgX has additional indirect regulatory effects on prgQ transcript levels related to the position of the convergently transcribed prgX operon. This has complicated interpretation of previous analyses of the control of prgQ expression by PrgX. We report here the results of in vivo and in vitro experiments examining the direct effects of PrgX on transcription from the prgQ promoter, as well as quantitative correlation between the concentrations of XBSs, PrgX protein, and prgQ promoter activity in vivo. The results of electrophoretic mobility shift assays and quantitative analysis of prgQ transcription in vitro and in vivo support the predicted roles of the PrgX DNA binding sites in prgQ transcription regulation. The results also suggest the existence of other factors that impede PrgX repression or enhance its antagonism by cCF10 in vivo.
PMCID: PMC3434730  PMID: 22544272
10.  Cyclic loading increases friction and changes cartilage surface integrity in lubricin-mutant mouse knees 
Arthritis and Rheumatism  2012;64(2):465-473.
To investigate the effects of lubricin gene dosage and cyclic loading on whole joint coefficient of friction and articular cartilage surface integrity in mouse knee joints.
Joints from mice with 2 (Prg4+/+), 1 (Prg4+/−), or no (Prg4−/−) functioning lubricin alleles were subjected to 26 hours of cyclic loading using a custom-built pendulum. Coefficient of friction values were measured at multiple time points. Contralateral control joints were left unloaded. Following testing, joints were examined for histologic evidence of damage and cell viability.
At baseline, the coefficient of friction values in Prg4−/− mice were significantly higher than those in Prg4+/+ and Prg4+/− mice (P < 0.001). Cyclic loading continuously increased the coefficient of friction in Prg4−/− mouse joints. In contrast, Prg4+/− and Prg4+/+ mouse joints had no coefficient of friction increases during the first 4 hours of loading. After 26 hours of loading, joints from all genotypes had increased coefficient of friction values compared to baseline and unloaded controls. Significantly greater increases occurred in Prg4−/− and Prg4+/− mouse joints compared to Prg4+/+ mouse joints. The coefficient of friction values were not significantly associated with histologic evidence of damage or loss of cell viability.
Our findings indicate that mice lacking lubricin have increased baseline coefficient of friction values and are not protected against further increases caused by loading. Prg4+/− mice are indistinguishable from Prg4+/+ mice at baseline, but have significantly greater coefficient of friction values following 26 hours of loading. Lubricin dosage affects joint properties during loading, and may have clinical implications in patients for whom injury or illness alters lubricin abundance.
PMCID: PMC3252402  PMID: 21905020
11.  Binding of Porphyromonas gingivalis Fimbriae to Proline-Rich Glycoproteins in Parotid Saliva via a Domain Shared by Major Salivary Components 
Infection and Immunity  1998;66(5):2072-2077.
Porphyromonas gingivalis, a putative periodontopathogen, can bind to human saliva through its fimbriae. We previously found that salivary components from the submandibular and sublingual glands bind to P. gingivalis fimbriae and that acidic proline-rich protein (PRP) and statherin function as receptor molecules for fimbriae. In this study, we investigated the fimbria-binding components in parotid saliva. Fractionated human parotid saliva by gel-filtration chromatography was immobilized onto nitrocellulose membranes for the overlay assay following sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The salivary components on the membrane were allowed to interact with fimbriae purified from P. gingivalis ATCC 33277, and the interacted fimbriae were probed with anti-fimbria antibodies. The fimbriae were shown to bind to two forms of proline-rich glycoproteins (PRGs) as well as to acidic PRPs and statherin. Moreover, fimbriae bound to several components of smaller molecular size which appeared to be acidic PRP variants and basic PRPs. Fimbriae bound strongly to the purified PRGs adsorbed onto hydroxyapatite (HAP) beads. In contrast, PRGs in solution failed to inhibit the fimbrial binding to the immobilized PRGs on the HAP beads. These findings suggest that the appearance of binding site(s) of PRGs can be ascribed to their conformational changes. We previously identified the distinct segments within PRP and statherin molecules that are involved in fimbrial binding. The peptides analogous to the binding regions of PRP and statherin (i.e., PRP-C and STN-C) markedly inhibit the binding of fimbriae to PRP and statherin immobilized on the HAP beads, respectively. The PRP-C significantly inhibited the binding of fimbriae to PRG-coated HAP beads as well as to PRP on HAP beads. The peptide did not affect the binding of fimbriae to statherin, whereas the STN-C showed no effect on the fimbrial binding to PRPs or PRGs. In the overlay assay, the PRP-C clearly diminished the interactions between the fimbriae and the various salivary components, including PRPs, the PRGs, and the components with smaller molecular sizes but not statherin. These results strongly suggest that fimbriae bind to salivary components (except statherin) via common peptide segments. It is also suggested that fimbriae bind to saliva through the two distinct binding domains of receptory salivary components: (i) PRGs and PRPs and (ii) statherin.
PMCID: PMC108165  PMID: 9573091
12.  Characterization of the Sequence Specificity Determinants Required for Processing and Control of Sex Pheromone by the Intramembrane Protease Eep and the Plasmid-Encoded Protein PrgY▿  
Journal of Bacteriology  2007;190(4):1172-1183.
Conjugative transfer of the Enterococcus faecalis plasmid pCF10 is induced by the peptide pheromone cCF10 when recipient-produced cCF10 is detected by donors. cCF10 is produced by proteolytic processing of the signal sequence of a chromosomally encoded lipoprotein (CcfA). In donors, endogenously produced cCF10 is carefully controlled to prevent constitutive expression of conjugation functions, an energetically wasteful process, except in vivo, where endogenous cCF10 induces a conjugation-linked virulence factor. Endogenous cCF10 is controlled by two plasmid-encoded products; a membrane protein PrgY reduces pheromone levels in donors, and a secreted inhibitor peptide iCF10 inhibits the residual endogenous pheromone that escapes PrgY control. In this study we genetically determined the amino acid specificity determinants within PrgY, cCF10, and the cCF10 precursor that are necessary for cCF10 processing and for PrgY-mediated control. We showed that amino acid residues 125 to 241 of PrgY are required for specific recognition of cCF10 and that PrgY recognizes determinants within the heptapeptide cCF10 sequence, supporting a direct interaction between PrgY and mature cCF10. In addition, we found that a regulated intramembrane proteolysis (RIP) family pheromone precursor-processing protein Eep recognizes amino acids N-terminal to cCF10 in the signal sequence of CcfA. These results support a model where Eep directly targets pheromone precursors for RIP and PrgY interacts directly with the mature cCF10 peptide during processing. Despite evidence that both PrgY and Eep associate with cCF10 in or near the membrane, results presented here indicate that these two proteins function independently.
PMCID: PMC2238190  PMID: 18083822
13.  RNA-Mediated Reciprocal Regulation between Two Bacterial Operons Is RNase III Dependent 
mBio  2011;2(5):e00189-11.
In bacteria, RNAs regulate gene expression and function via several mechanisms. An RNA may pair with complementary sequences in a target RNA to impact transcription, translation, or degradation of the target. Control of conjugation of pCF10, a pheromone response plasmid of Enterococcus faecalis, is a well-characterized system that serves as a model for the regulation of gene expression in bacteria by intercellular signaling. The prgQ operon, whose products mediate conjugation, is negatively regulated by two products of the prgX operon, Anti-Q, a small RNA, and PrgX, the transcriptional repressor of the prgQ promoter. Here we show that Qs, an RNA from the 5′ end of the prgQ operon, represses expression of PrgX by targeting prgX mRNA for cleavage by RNase III. Our results demonstrate that the prgQ and prgX operons each use RNAs to negatively regulate gene expression from the opposing operon by different mechanisms. Such reciprocal regulation between two operons using RNAs has not been previously demonstrated. Furthermore, these results show that Qs is an unusually versatile RNA, serving three separate functions in the regulation of conjugation. Understanding the potential versatility of RNAs and their various roles in gene regulatory networks will allow us to better understand how cells regulate complex behavior.
Importance Bacteria use RNA to regulate gene expression by a variety of mechanisms. The prgQ and prgX operons of pCF10, a conjugative plasmid of Enterococcus faecalis, have been shown to negatively regulate one another by a variety of mechanisms. One of these mechanisms involves Anti-Q, a small RNA from the prgX operon that prevents gene expression from the prgQ operon. In this work, we find that Qs, an RNA from the prgQ operon, negatively regulates gene expression from the prgX operon. These findings have a number of implications. (i) The Anti-Q and Qs RNAs act by different mechanisms, highlighting the variety of ways in which bacteria can regulate gene expression using RNAs. (ii) Reciprocal regulation between operons mediated by small RNAs has not been previously described, deepening our understanding of how bacteria regulate complex behavior. (iii) Additional roles for Qs have been described, demonstrating the versatility of this RNA.
Bacteria use RNA to regulate gene expression by a variety of mechanisms. The prgQ and prgX operons of pCF10, a conjugative plasmid of Enterococcus faecalis, have been shown to negatively regulate one another by a variety of mechanisms. One of these mechanisms involves Anti-Q, a small RNA from the prgX operon that prevents gene expression from the prgQ operon. In this work, we find that Qs, an RNA from the prgQ operon, negatively regulates gene expression from the prgX operon. These findings have a number of implications. (i) The Anti-Q and Qs RNAs act by different mechanisms, highlighting the variety of ways in which bacteria can regulate gene expression using RNAs. (ii) Reciprocal regulation between operons mediated by small RNAs has not been previously described, deepening our understanding of how bacteria regulate complex behavior. (iii) Additional roles for Qs have been described, demonstrating the versatility of this RNA.
PMCID: PMC3181467  PMID: 21954305
14.  Genetic analysis of a region of the Enterococcus faecalis plasmid pCF10 involved in positive regulation of conjugative transfer functions. 
Journal of Bacteriology  1995;177(8):2107-2117.
The prgB gene encodes the surface protein Asc10, which mediates cell aggregation resulting in high-frequency conjugative transfer of the pheromone-inducible tetracycline resistance plasmid pCF10 in Enterococcus faecalis. Previous Tn5 insertional mutagenesis and sequencing analysis of a 12-kb fragment of pCF10 indicated that a region containing prgX, -Q, -R, -S, and -T, located 3 to 6 kb upstream of prgB, is required to activate the expression of prgB. Complementation studies showed that the positive regulatory region functions in cis in an orientation-dependent manner (J. W. Chung and G. M. Dunny, Proc. Natl. Acad. Sci. USA 89:9020-9024, 1992). In order to determine the involvement of each gene in the activation of prgB, Tn5 insertional mutagenesis and exonuclease III deletion analyses of the regulatory region were carried out. The results indicate that prgQ and -S are required for the expression of prgB, while prgX, -R, and -T are not required. Western blot (immunoblot) analysis of these mutants shows that prgQ is also essential for the expression of prgA (encoding the surface exclusion protein Sec10), which is located between prgB and the positive-control region. Complementation analysis demonstrates that a cis-acting regulatory element is located in the prgQ region and that pCF10 sequences in an untranslated region 3' from prgQ are an essential component of the positive-control system. Analyses of various Tn5 insertions in pCF10 genes suggest that transcription reading into this transposon is terminated in E. faecalis but that outward-reading transcripts may initiate from within the ends of Tn5 or from the junction sequences.
PMCID: PMC176855  PMID: 7721703
15.  Analysis of the Amino Acid Sequence Specificity Determinants of the Enterococcal cCF10 Sex Pheromone in Interactions with the Pheromone-Sensing Machinery▿  
Journal of Bacteriology  2006;189(4):1399-1406.
The level of expression of conjugation genes in Enterococcus faecalis strains carrying the pheromone-responsive transferable plasmid pCF10 is determined by the ratio in the culture medium of two types of signaling peptides, a pheromone (cCF10) and an inhibitor (iCF10). Recent data have demonstrated that both peptides target the cytoplasmic receptor protein PrgX. However, the relative importance of the interaction of these peptides with the pCF10 protein PrgZ (which enhances import of cCF10) versus PrgX is not fully understood, and there is relatively little information about specific amino acid sequence determinants affecting the functional interactions of cCF10 with these proteins in vivo. To address these issues, we used a pheromone-inducible reporter gene system where various combinations of PrgX and PrgZ could be expressed in an isogenic host background to examine the biological activities of cCF10, iCF10, and variants of cCF10 isolated in a genetic screen. The results suggest that most of the amino acid sequence determinants of cCF10 pheromone activity affect interactions between the peptide and PrgX, although some sequence variants that affected peptide/PrgZ interactions were also identified. The results provide functional data to complement ongoing structural studies of PrgX and increase our understanding of the functional interactions of cCF10 and iCF10 with the pheromone-sensing machinery of pCF10.
PMCID: PMC1797347  PMID: 17098891
16.  Catechol-O-methyltransferase (COMT) influences the connectivity of the prefrontal cortex at rest 
Neuroimage  2013;68(C):49-54.
Catechol-O-methyltransferase (COMT) modulates dopamine in the prefrontal cortex (PFC) and influences PFC dopamine-dependent cognitive task performance. A human COMT polymorphism (Val158Met) alters enzyme activity and is associated with both the activation and functional connectivity of the PFC during task performance, particularly working memory. Here, we used functional magnetic resonance imaging and a data-driven, independent components analysis (ICA) approach to compare resting state functional connectivity within the executive control network (ECN) between young, male COMT Val158 (n = 27) and Met158 (n = 28) homozygotes. COMT genotype effects on grey matter were assessed using voxel-based morphometry. COMT genotype significantly modulated functional connectivity within the ECN, which included the head of the caudate, and anterior cingulate and frontal cortical regions. Val158 homozygotes showed greater functional connectivity between a cluster within the left ventrolateral PFC and the rest of the ECN (using a threshold of Z > 2.3 and a family-wise error cluster significance level of p < 0.05). This difference occurred in the absence of any alterations in grey matter. Our data show that COMT Val158Met affects the functional connectivity of the PFC at rest, complementing its prominent role in the activation and functional connectivity of this region during cognitive task performance. The results suggest that genotype-related differences in prefrontal dopaminergic tone result in neuroadaptive changes in basal functional connectivity, potentially including subtle COMT genotype-dependent differences in the relative coupling of task-positive and task-negative regions, which could in turn contribute to its effects on brain activation, connectivity, and behaviour.
► We studied the impact of COMT Val158Met genotype on resting state connectivity. ► We compared resting state functional connectivity in Val/Val vs. Met/Met men. ► We focussed on the predominantly prefrontal (PFC) executive control network (ECN). ► The ECN was identified using a group ICA approach. ► We found greater resting PFC functional connectivity in Val/Val vs. Met/Met men.
PMCID: PMC3566589  PMID: 23228511
Resting state network; Dopamine; Working memory; Prefrontal cortex; Polymorphism; fMRI
17.  Pharmacotherapy Impacts Functional Connectivity Among Affective Circuits During Response Inhibition in Pediatric Mania 
Behavioural Brain Research  2011;226(2):493-503.
The aim of the current study was to determine the influence of implicated affective circuitry disturbance in pediatric bipolar disorder (PBD) on behavioral inhibition. The differential influence of an antipsychotic and an anti-epileptic medication on the functional connectivity across affective and cognitive neural operations in PBD was examined..
This was a six-week double blind randomized fMRI trial of risperidone plus placebo vs. divalproex plus placebo for patients with mania (n=22; 13.6±2.5 years). Healthy controls (HC; n=14, 14.5±2.8 years) were also scanned for normative comparison. Participants performed a response inhibition fMRI task where a motor response, already ‘on the way’ to execution, had to be voluntarily inhibited on trials where a stop signal was presented. Independent component analysis was used to map functional connectivity across the whole brain.
While there were no behavioral differences between the groups at pre- or post-drug trial, there was significant improvement on manic symptoms in the patient groups. All participants engaged an Evaluative Affective Circuit (EAC: bilateral inferior frontal gyrus, middle frontal gyrus, anterior cingulate cortex (ACC), middle temporal gyrus, insulae, caudate and putamen) and a Reactive Affective Circuit (RAC: bilateral occipital cortex, amygdala, medial frontal gyrus and insula) during task performance. Within the EAC, post treatment and relative to HC, greater engagement was seen in left insula in risperidone group and left subgenual ACC in divalproex group. Within the RAC, greater baseline amygdala connectivity in patients did not alter with treatment.
EAC and RAC are two key circuits that moderate emotional influence on response inhibition in PBD. Risperidone and divalproex differentially engage the EAC. Limited change in amygdala activity with treatment in all patients indicates a likely trait deficit in PBD.
PMCID: PMC3253527  PMID: 22004983
Functional connectivity; bipolar disorder; pediatric; response inhibition; affect
18.  Insula and striatum activity in effort-related monetary reward processing in gambling disorder: The role of depressive symptomatology 
NeuroImage : Clinical  2014;6:243-251.
The neurobiological underpinnings of effort-related monetary reward processing of gambling disorder have not been previously studied. To date neuroimaging studies lack in large sample sizes and as a consequence less attention has been given to brain reward processing that could potentially be attributed to comorbid conditions such as depressive mood state. We assessed monetary reward processing using an effort-dependent task during 3 tesla functional magnetic resonance imaging. We investigated a large sample of male, right-handed, slot-machine-playing disordered gamblers (DGs; N = 80) as well as age- and smoking-matched male healthy controls (HCs; N = 89). Depressive symptoms were assessed using the Beck Depression Inventory (BDI). DGs and HCs were divided into subgroups (“high” and “low”) based on their BDI scores. Effort-related monetary reward processing did not differ between the complete groups of HCs and DGs. Brain activation during receipt of monetary reward though revealed a significant Group × BDI interaction: DGs with higher BDI scores compared to DGs with lower BDI scores showed greater brain activity in the right insula cortex and dorsal striatum while no differences were observed for HCs with higher versus lower BDI scores. Our results suggest that effort-related aspects of monetary motivation, i.e. when monetary output is tied to performance, are not altered in DG. Additionally, our findings strengthen the need for subgroup comparisons in future investigations of the disorder as part of a personalized medicine approach.
•We studied effort-related monetary reward processing in disordered gamblers (DGs).•Anticipatory and feedback-related activity did not differ between DGs and controls.•Impact of depressive symptoms on feedback-related brain activity in DGs.•DGs with higher BDI scores showed increased insula and dorsal striatum activity.•Results highlight the need of subgroup comparisons in gambling disorder.
PMCID: PMC4215467  PMID: 25379437
Gambling disorder; Depressive mood; Monetary reward; Dorsal striatum; Insula; fMRI
19.  Interactions of the Transmembrane Polymeric Rings of the Salmonella enterica Serovar Typhimurium Type III Secretion System 
mBio  2010;1(3):e00158-10.
The type III secretion system (T3SS) is an interspecies protein transport machine that plays a major role in interactions of Gram-negative bacteria with animals and plants by delivering bacterial effector proteins into host cells. T3SSs span both membranes of Gram-negative bacteria by forming a structure of connected oligomeric rings termed the needle complex (NC). Here, the localization of subunits in the Salmonella enterica serovar Typhimurium T3SS NC were probed via mass spectrometry-assisted identification of chemical cross-links in intact NC preparations. Cross-links between amino acids near the amino terminus of the outer membrane ring component InvG and the carboxyl terminus of the inner membrane ring component PrgH and between the two inner membrane components PrgH and PrgK allowed for spatial localization of the three ring components within the electron density map structures of NCs. Mutational and biochemical analysis demonstrated that the amino terminus of InvG and the carboxyl terminus of PrgH play a critical role in the assembly and function of the T3SS apparatus. Analysis of an InvG mutant indicates that the structure of the InvG oligomer can affect the switching of the T3SS substrate to translocon and effector components. This study provides insights into how structural organization of needle complex base components promotes T3SS assembly and function.
Many biological macromolecular complexes are composed of symmetrical homomers, which assemble into larger structures. Some complexes, such as secretion systems, span biological membranes, forming hydrophilic domains to move substrates across lipid bilayers. Type III secretion systems (T3SSs) deliver bacterial effector proteins directly to the host cell cytoplasm and allow for critical interactions between many Gram-negative pathogenic bacterial species and their hosts. Progress has been made towards the goal of determining the three-dimensional structure of the secretion apparatus by determination of high-resolution crystal structures of individual protein subunits and low-resolution models of the assembly, using reconstructions of cryoelectron microscopy images. However, a more refined picture of the localization of periplasmic ring structures within the assembly and their interactions has only recently begun to emerge. This work localizes T3SS transmembrane rings and identifies structural elements that affect substrate switching and are essential to the assembly of components that are inserted into host cell membranes.
PMCID: PMC2932509  PMID: 20824104
20.  Specific functional connectivity alterations of the dorsal striatum in young people with depression 
NeuroImage : Clinical  2014;7:266-272.
Altered basal ganglia function has been implicated in the pathophysiology of youth Major Depressive Disorder (MDD). Studies have generally focused on characterizing abnormalities in ventral “affective” corticostriatal loops supporting emotional processes. Recent evidence however, has implicated alterations in functional connectivity of dorsal “cognitive” corticostriatal loops in youth MDD. The contribution of dorsal versus ventral corticostriatal alterations to the pathophysiology of youth MDD remains unclear.
Twenty-one medication-free patients with moderate-to-severe MDD between the ages of 15 and 24 years old were matched with 21 healthy control participants. Using resting-state functional connectivity magnetic resonance imaging we systematically investigated connectivity of eight dorsal and ventral subdivisions of the striatum. Voxelwise statistical maps of each subregion's connectivity with other brain areas were compared between the depressed and control groups.
Depressed youths showed alterations in functional connectivity that were confined to the dorsal corticostriatal circuit. Compared to controls, depressed patients showed increased connectivity between the dorsal caudate nucleus and ventrolateral prefrontal cortex bilaterally. Increased depression severity correlated with the magnitude of dorsal caudate connectivity with the right dorsolateral prefrontal cortex. There were no significant between-group differences in connectivity of ventral striatal regions.
The results provide evidence that alterations in corticostriatal connectivity are evident at the early stages of the illness and are not a result of antidepressant treatment. Increased connectivity between the dorsal caudate, which is usually associated with cognitive processes, and the more affectively related ventrolateral prefrontal cortex may reflect a compensatory mechanism for dysfunctional cognitive-emotional processing in youth depression.
•We systematically examine dorsal and ventral striatal connectivity in youth MDD.•Alterations in functional connectivity in youth MDD are confined to the dorsal circuit.•Youths with MDD show increased dorsal caudate connectivity with the VLPFC.•Altered dorsal caudate–VLPFC connectivity in MDD may reflect a compensatory response.
PMCID: PMC4300014  PMID: 25610789
Major Depressive Disorder; Youth; Functional magnetic resonance imaging; Striatum; Functional connectivity
21.  Differential psychophysiological interactions of insular subdivisions during varied oropharyngeal swallowing tasks 
Physiological Reports  2013;2(3):e00239.
The insula is a highly integrated cortical region both anatomically and functionally. It has been shown to have cognitive, social–emotional, gustatory, and sensorimotor functions. Insular involvement in both normal and abnormal swallowing behavior is well established, yet its functional connectivity is unclear. Studies of context‐dependent connectivity, or the connectivity during different task conditions, have the potential to reveal information about synaptic function of the insula. The goal of this study was to examine the functional connectivity of specific insular regions (ventral anterior, dorsal anterior, and posterior) with distant cortical regions during four swallowing conditions (water, sour, e‐stim, and visual biofeedback) using generalized psychophysiological interactions (gPPI). In 19 healthy adults, we found that the visual biofeedback condition was associated with the most and strongest increases in functional connectivity. The posterior insula/rolandic operculum regions had the largest clusters of increases in functional connectivity, but the ventral anterior insula was functionally connected to a more diverse array of cortical regions. Also, laterality assessments showed left lateralized increases in swallowing functional connectivity. Our results are aligned with reports about the insula's interconnectivity and extensive involvement in multisensory and cognitive tasks.
The goal of this study was to examine the functional connectivity of specific insular regions (ventral anterior, dorsal anterior, and posterior) with distant cortical regions during four swallowing conditions (water, sour, e‐stim, and visual biofeedback) using generalized psychophysiological interactions (gPPI). In 19 healthy adults, we found that the visual biofeedback condition was associated with the most functional connectivity increases. The posterior insula/rolandic operculum regions had the largest clusters of functional connectivity, but the ventral anterior insula was functionally connected to a more diverse array of cortical regions.
PMCID: PMC4002228  PMID: 24760502
Biofeedback; connectivity; deglutition; gPPI; laterality; psychophysiological interactions; taste
22.  Plasticity-related Gene 5 (PRG5) Induces Filopodia and Neurite Growth and Impedes Lysophosphatidic Acid– and Nogo-A–mediated Axonal Retraction 
Molecular Biology of the Cell  2010;21(4):521-537.
The authors have cloned a novel member of the PRG family that induces filopodia growth in a Cdc42-independent manner. Hence, studies in primary neurons revealed that PRG5 impedes RhoA-mediated axon collapse induced by LPA and Nogo-A. These data reveal a new function of PRG5 with impact on neurite growth in an axonal growth inhibitory environment.
Members of the plasticity-related gene (PRG1-4) family are brain-specific integral membrane proteins and implicated in neuronal plasticity, such as filopodia formation and axon growth after brain lesion. Here we report on the cloning of a novel member of the PRG family, PRG5, with high homologies to PRG3. PRG5 is regulated during brain and spinal cord development and is exclusively allocated within the nervous system. When introduced in neurons, PRG5 is distributed in the plasma membrane and induces filopodia as well as axon elongation and growth. Conversely, siRNA mediated knockdown of PRG5 impedes axon growth and disturbs filopodia formation. Here we show that PRG5 induces filopodia growth independently of Cdc42. Moreover, axon collapse and RhoA activation induced by LPA and myelin-associated neurite inhibitor Nogo-A is attenuated in the presence of PRG5, although direct activation of the RhoA-Rho-PIP5K kinase pathway abolishes PRG5 -formed neurites. Thus, we describe here the identification of a novel member of the PRG family that induces filopodia and axon elongation in a Cdc42-independent manner. In addition, PRG5 impedes brain injury-associated growth inhibitory signals upstream of the RhoA-Rho kinase pathway.
PMCID: PMC2820418  PMID: 20032306
23.  Characteristics and Help-Seeking Behaviors of Internet Gamblers Based on Most Problematic Mode of Gambling 
Previous studies of problem Internet gamblers have failed to distinguish whether their problem gambling relates to Internet or land-based gambling modes. Therefore, characteristics and help-seeking behaviors of people whose gambling problems relate specifically to Internet gambling are unknown, but could inform the optimal alignment of treatment and support services with the needs and preferences of problem gamblers.
This study aimed to compare (1) characteristics of problem Internet gamblers and problem land-based gamblers and (2) uptake of different types and modes of help between problem Internet gamblers and problem land-based gamblers. Hypothesis 1 was that problem Internet gamblers are less likely to seek help. Hypothesis 2 was that problem Internet gamblers are more likely to use online modes of help.
A sample of 620 respondents meeting criteria for problem gambling was drawn from an online survey of 4594 Australian gamblers. Respondents were recruited through advertisements on gambling and gambling help websites, Facebook, and Google. Measures consisted of gambling participation; proportion of gambling on the Internet; most problematic mode of gambling; help seeking from 11 different sources of formal help, informal help, and self-help for gambling problems; psychological distress (Kessler 6); problem gambling severity (Problem Gambling Severity Index, PGSI); and demographics.
Problem Internet gamblers were significantly more likely than problem land-based gamblers to be male (χ2 1=28.3, P<.001, φ=0.21), younger (t 616.33=4.62, P<.001, d=0.37), have lower psychological distress (χ2 1=5.4, P=.02, φ=0.09), and experience problems with sports and race wagering (χ2 4=228.5, P<.001, φ=0.61). Uptake of help was significantly lower among problem Internet compared to problem land-based gamblers (χ2 1=6.9, P<.001, φ=0.11), including from face-to-face services, gambling helplines, online groups, self-exclusion from land-based venues, family or friends, and self-help strategies. Both problem Internet and problem land-based gamblers had similarly low use of online help. However, problem land-based gamblers (37.6%, 126/335) were significantly more likely to have sought land-based formal help compared to problem Internet gamblers (23.5%, 67/285; χ2 1=14.3, P<.001, φ=0.15).
The findings suggest that more targeted and innovative efforts may be needed to increase use of gambling help by problem Internet gamblers. Alternatively, their lower PGSI and K6 scores suggest Internet problem gamblers may have less need for gambling-related help. This is the first known study to classify problem Internet gamblers as those whose problem gambling specifically relates to Internet gambling. Further research is needed to better understand why help-seeking rates are lower among Internet problem gamblers.
PMCID: PMC4296092  PMID: 25567672
gambling; Internet; pathological gambling; treatment
24.  Specific Control of Endogenous cCF10 Pheromone by a Conserved Domain of the pCF10-Encoded Regulatory Protein PrgY in Enterococcus faecalis 
Journal of Bacteriology  2005;187(14):4830-4843.
Conjugative transfer of Enterococcus faecalis plasmid pCF10 is induced by the heptapeptide pheromone cCF10. cCF10 produced by plasmid-free recipient cells is detected by pCF10-containing donor cells, which respond by induction of plasmid-encoded transfer functions. The pCF10-encoded membrane protein PrgY is essential to prevent donor cells from responding to endogenously produced pheromone while maintaining the ability to respond to pheromone from an exogenous source; this function has not been identified in any nonenterococcal prokaryotic signaling system. PrgY specifically inhibited endogenous cCF10 and cPD1 (a pheromone that induces transfer of closely related plasmid pPD1) but not cAD1 (which is specific for less-related plasmid pAD1). Ectopic expression of PrgY in plasmid-free recipient cells reduced pheromone activity in culture supernatants and reduced the ability of these cells to acquire pCF10 by conjugation but did not have any effect on the interaction of these cells with exogenously supplied cCF10. The cloned prgY gene could complement a pCF10 prgY null mutation, and complementation was used to identify point mutations impairing PrgY function. Such mutations also abolished the inhibitory effect of PrgY expression in recipients on pheromone production and on acquisition of pCF10. Most randomly generated point mutations identified in the genetic screen mapped to a predicted extracellular domain in the N terminus of PrgY that is conserved in a newly identified family of related proteins from disparate species including Borrelia burgdorferi, Archaeoglobus fulgidus, Arabidopsis thaliana, and Homo sapiens. The combined genetic and physiological data suggest that PrgY may sequester or inactivate cCF10 as it is released from the membrane.
PMCID: PMC1169508  PMID: 15995198
25.  Gambling severity predicts midbrain response to near-miss outcomes 
Gambling is a common recreational activity that becomes dysfunctional in a subset of individuals, with DSM ‘pathological gambling’ regarded as the most severe form. During gambling, players experience a range of cognitive distortions that promote an over-estimation of the chances of winning. Near-miss outcomes are thought to fuel these distortions. We observed previously that near-misses recruited overlapping circuitry to monetary wins in a study in healthy volunteers (Clark et al. 2009). The present study sought to extend these observations in regular gamblers and relate brain responses to an index of gambling severity. Twenty regular gamblers, who varied in their involvement from recreational players to probable pathological gamblers, were scanned whilst performing a simplified slot-machine task that delivered occasional monetary wins, as well as near-miss and full-miss non-win outcomes. In the overall group, near-miss outcomes were associated with a significant response in the ventral striatum, which was also recruited by monetary wins. Gambling severity, measured with the South Oaks Gambling Screen, predicted a greater response in the dopaminergic midbrain to near-miss outcomes. This effect survived controlling for clinical co-morbidities that were present in the regular gamblers. Gambling severity did not predict win-related responses in the midbrain or elsewhere. These results demonstrate that near-miss events during gambling recruit reward-related brain circuitry in regular players. An association with gambling severity in the midbrain suggests that near-miss outcomes may enhance dopamine transmission in disordered gambling, which extends neurobiological similarities between pathological gambling and drug addiction.
PMCID: PMC2929454  PMID: 20445043
Gambling; Cognitive; Addiction; Dopamine; Striatum; Midbrain

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