Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study

Background

Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations.

Methods

We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions.

Results

Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition.

Conclusions

During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.     

Response inhibition during cue reactivity in problem gamblers: an fMRI study

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.     

Pyroptosis‐related molecular classification and immune microenvironment infiltration in breast cancer: A novel therapeutic target

The underlying role of pyroptosis in breast cancer (BC) remains unknown. Herein, we investigated the correlations of 33 pyroptosis‐related genes (PRGs) with immune checkpoints and immune cell infiltrations in BC patients based on The Cancer Genome Atlas cohort (n = 996) and Gene Expression Omnibus cohort (n = 3,262). Enrichment analysis revealed that these PRGs mainly functioned in pyroptosis, inflammasomes and regulation of autophagy pathway. Four prognostic independent PRGs (CASP9, TIRAP, GSDMC and IL18) were identified. Then, cluster 1/2 was recognized using consensus clustering for these four PRGs. Patients from cluster 1 had a favourable prognosis and diverse immune cell infiltrations. A nomogram was developed based on age, TNM stage, tumour subtype and pyroptosis score. Patients with the high‐risk group exhibited worse 5‐year OS, and the result was consistent in the external cohort. Additionally, high‐risk group patients were associated with downregulated immune checkpoint expression. Further analysis suggested that the high‐risk group patients were associated with a higher IC50 of paclitaxel, doxorubicin, cisplatin, methotrexate and vinorelbine. In summarizing, the pyroptosis score‐based nomogram might serve as an independent prognostic predictor and could guide medication for chemotherapy. Additionally, it may bring novel insight into the regulation of tumour immune microenvironment in BC and help to achieve precision immunotherapy.     

Deciphering the onychophoran ‘segmentation gene cascade’: Gene expression reveals limited involvement of pair rule gene orthologs in segmentation,but a highly conserved segment polarity gene network

The hallmark of the arthropods is their segmented body, although origin of segmentation, however, is unresolved. In order to shed light on the origin of segmentation we investigated orthologs of pair rule genes (PRGs) and segment polarity genes (SPGs) in a member of the closest related sister-group to the arthropods, the onychophorans. Our gene expression data analysis suggests that most of the onychophoran PRGs do not play a role in segmentation. One possible exception is the even-skipped (eve) gene that is expressed in the posterior end of the onychophoran where new segments are likely patterned, and is also expressed in segmentation-gene typical transverse stripes in at least a number of newly formed segments. Other onychophoran PRGs such as runt (run), hairy/Hes (h/Hes) and odd-skipped (odd) do not appear to have a function in segmentation at all. Onychophoran PRGs that act low in the segmentation gene cascade in insects, however, are potentially involved in segment-patterning. Most obvious is that from the expression of the pairberry (pby) gene ortholog that is expressed in a typical SPG-pattern. Since this result suggested possible conservation of the SPG-network we further investigated SPGs (and associated factors) such as Notum in the onychophoran. We find that the expression patterns of SPGs in arthropods and the onychophoran are highly conserved, suggesting a conserved SPG-network in these two clades, and indeed also in an annelid. This may suggest that the common ancestor of lophotrochozoans and ecdysozoans was already segmented utilising the same SPG-network, or that the SPG-network was recruited independently in annelids and onychophorans/arthropods.     

Plasticity-related genes (PRGs/LRPs): a brain-specific class of lysophospholipid-modifying proteins

Recently, a set of five brain-specifically expressed membrane proteins, which define a novel subclass of the lipid phosphate phosphatases (LPP-)superfamily, has been identified, namely plasticity-related genes (PRGs/LRPs). The primary known significance of these genes is their involvement in regeneration processes and attenuation of effects induced by lysophosphatidic acid (LPA). LPA is key player in lysophospholipids, a hydrophilic group of lipids that have been recognized as important signaling molecules. It is a lipid mediator with a wide variety of biological actions, such as cell proliferation, migration and survival. Its extracellular effects are mediated through five distinct G-protein-coupled receptors (LPA(1-5)) and LPA therefore activates multiple signal transduction pathways. LPA signaling has been implicated in diverse processes, such as wound healing, brain development, vascular remodeling and tumor progression. LPA levels are controlled by enzymes that synthesize or degrade LPA and, thus, these enzymes also regulate many aspects of signaling transduction. Three LPPs and a splice variant have been demonstrated as deactivating LPA. Studies of PRGs indicate that this group of proteins may in fact serve as controllers of LPA and therefore opening the door to new therapeutic approaches.     

Insights into the antibiotic resistance dissemination in a wastewater effluent microbiome: bacteria,viruses and vesicles matter

Wastewater treatment plants effluents are considered as hotspots for the dispersion of antibiotic resistance genes (ARGs) into natural ecosystems. The bacterial resistome (ARG collection in a metagenome) analyses have provided clues on antibacterial resistance dynamics. However, viruses and vesicles are frequently ignored. Here, we addressed the bacterial, viral and vesicle resistomes from a representative wastewater effluent in natural conditions and amended with polymyxin, which is used as a last resort antibiotic. Metagenomics showed that the natural prokaryotic resistome was vast (9000 ARG hits/Gb metagenome) and diverse, while viral resistome was two orders of magnitude lower (50 ARG hits/Gb metagenome) suggesting that viruses rarely encoded ARGs. After polymyxin amendment, data showed no ARG enrichment – including to polymyxin – in the microbiome. Remarkably, microbiomes responded to polymyxin with a vast release of putative vesicles (threefold increase compared with the control), which might be used as 'traps' to decrease the antibiotic concentration. Intriguingly, although polymyxin resistance genes (PRGs) were rare in the microbiome (0.018% of total ARG found), in the viral and vesicle fractions, PRGs were more abundant (0.5%–0.8% of total ARG found). Our data suggest that vesicles could have a more active role in the context of transmission of antibiotic resistances.     

Inheritance analysis and identification of SNP markers associated with ZYMV resistance in <Emphasis Type="Italic">Cucurbita pepo</Emphasis>

Cucurbit crops are economically important worldwide. One of the most serious threats to cucurbit production is Zucchini yellow mosaic virus (ZYMV). Several resistant accessions were identified in Cucurbita moschata and their resistance was introgressed into Cucurbita pepo. However, the mode of inheritance of ZYMV resistance in C. pepo presents a great challenge to attempts at introgressing resistance into elite germplasm. The main goal of this work was to analyze the inheritance of ZYMV resistance and to identify markers associated with genes conferring resistance. An Illumina GoldenGate assay allowed us to assess polymorphism among nine squash genotypes and to discover six polymorphic single-nucleotide polymorphisms (SNPs) between two near-isogenic lines, “True French” (susceptible to ZYMV) and Accession 381e (resistant to ZYMV). Two F₂ and three BC₁ populations obtained from crossing the ZYMV-resistant Accession 381e with two susceptible ones, the zucchini True French and the cocozelle “San Pasquale,” were assayed for ZYMV resistance. Molecular analysis revealed an approximately 90% association between SNP1 and resistance, which was confirmed using High Resolution Melt (HRM) and a CAPS marker. Co-segregation up to 72% in populations segregating for resistance was observed for two other SNP markers that could be potentially linked to genes involved in resistance expression. A functional prediction of proteins involved in the resistance response was performed on genome scaffolds containing the three SNPs of interest. Indeed, 16 full-length pathogen recognition genes (PRGs) were identified around the three SNP markers. In particular, we discovered that two nucleotide-binding site leucine-rich repeat (NBS-LRR) protein-encoding genes were located near the SNP1 marker. The investigation of ZYMV resistance in squash populations and the genomic analysis performed in this work could be useful for better directing the introgression of disease resistance into elite C. pepo germplasm.     

AU-rich transient response transcripts in the human genome: expressed sequence tag clustering and gene discovery approach

Transient response genes regulate critical biological responses that include cell proliferation, signal transduction events, and responses to exogenous agents such as inflammatory stimuli, microbes, and radiation. An important feature that ensures a timely response is the short half-life of the messenger RNA (mRNA), which is thought to be predominantly mediated by adenylate uridylate-rich sequence elements (AREs) in the 3' untranslated region (3' UTR). The repertoire and extent of transient response genes in the human genome are not known. We used a computational approach to delineate those genes that code for transient ARE mRNAs. We utilized a 3' UTR-specific ARE motif to retrieve and cluster 3'-end ESTs using a refined extraction protocol. With the availability of the entire human genome, we were able to utilize ARE EST clusters for further mining and computational prediction of ARE genes. The described approaches led to the finding of more than 1500 ARE genes in the human genome. In particular, "hidden" ARE mRNAs and alternative forms due to 3'UTR completeness, variant polyadenylation, and splicing were uncovered.     

Prediction of auxin response elements based on data fusion in <Emphasis Type="Italic">Arabidopsis thaliana</Emphasis>

The plant hormone “auxin” is a key regulator of plant development and environmental responses. Many genes in Arabidopsis thaliana are known to be up-regulated in response to auxin. Auxin response factors activate or repress the expression of genes by binding at their promoter regions within auxin response elements (AuxRE) that are key regulatory cis-acting motives. Therefore, the identification of auxin-response elements is among the most important issues to understand the auxin regulation mechanisms. Thus, searching the TGTCTC motif is an unreliable method to identify AuxRE because many AuxRE variants may also be functional. In the present study, we perform an In-silico prediction of AuxREs in promoters of primary auxin responsive genes. We exploit microarray data of auxin response in Arabidopsis thaliana seedlings, in order to provide biological annotation to AuxRE. We apply a data fusion method based on the combined use of evidence theory and fuzzy sets to scan upstream sequences of response genes.     

Differential expression of poplar <Emphasis Type="Italic">sucrose nonfermenting1-related protein kinase 2</Emphasis> genes in response to abiotic stress and abscisic acid

Knowledge on the responses of woody plants to abiotic stress can inform strategies to breed improved tree varieties and to manage tree species for environmental conservation and the production of lignocellulosic biomass. In this study, we examined the expression patterns of poplar (Populus trichocarpa) genes encoding members of the sucrose nonfermenting1-related protein kinase 2 (SnRK2) family, which are core components of the abiotic stress response. The P. trichocarpa genome contains twelve SnRK2 genes (PtSnRK2.1- PtSnRK2.12) that can be divided into three subclasses (I–III) based on the structures of their encoded kinase domains. We found that PtSnRK2s are differentially expressed in various organs. In MS medium-grown plants, all of the PtSnRK2 genes were significantly upregulated in response to abscisic acid (ABA) treatment, whereas osmotic and salt stress treatments induced only some (four and seven, respectively) of the PtSnRK2 genes. By contrast, soil-grown plants showed increased expression of most PtSnRK2 genes under drought and salt treatments, but not under ABA treatment. In soil-grown plants, drought stress induced SnRK2 subclass II genes in all tested organs (leaves, stems, and roots), whereas subclass III genes tended to be upregulated in leaves only. These results suggest that the PtSnRK2 genes are involved in abiotic stress responses, are at least partially activated by ABA, and show organ-specific responses.     

Identification of genes differentially expressed in husk tomato (<Emphasis Type="Italic">Physalis philadelphica</Emphasis>) in response to whitefly (<Emphasis Type="Italic">Trialeurodes vaporariorum</Emphasis>) infestation

Plants respond to phloem-feeding whiteflies by extensive changes in gene expression. To identify differentially expressed genes in husk tomato plants (Physalis philadelphica) infested with Trialeurodes vaporariorum, young plants were challenged with adult whiteflies, and forward and reverse subtractive libraries were constructed from infested leaves at 5 and 15 days after infestation. Several genes were identified as up-regulated; these included a diversity of genes involved in plant defense responses, protein synthesis or degradation, and cell wall fortification or modification. Genes required for amino acid biosynthesis, lipid metabolism and synthesis, including cell surface components such as suberin, responses to stress, photosynthesis and other functions, were similarly induced. Down-regulated genes were also identified, most prominently kinases and aquaporin genes. Similarities in defense responses between tomato and P. philadelphica were noted regarding the expression of certain genes in response to nematode, aphid, or whitefly. A role for abscisic acid, brassinosteroids, and cytokinins in the regulated response to whitefly infestation in P. philadelphica was also implied by the expression pattern of phytohormone-associated genes, including genes coding for proteins containing F-box motifs. Differential expression of selected genes was validated by quantitative real-time PCR. The possible role played by some of these genes during whitefly infestation is discussed.     

Genetic dissection of the maize (<Emphasis Type="Italic">Zea mays</Emphasis> L.) MAMP response

Key message

Loci associated with variation in maize responses to two microbe-associated molecular patterns (MAMPs) were identified. MAMP responses were correlated. No relationship between MAMP responses and quantitative disease resistance was identified.

Abstract

Microbe-associated molecular patterns (MAMPs) are highly conserved molecules commonly found in microbes which can be recognized by plant pattern recognition receptors. Recognition triggers a suite of responses including production of reactive oxygen species (ROS) and nitric oxide (NO) and expression changes of defense-related genes. In this study, we used two well-studied MAMPs (flg22 and chitooctaose) to challenge different maize lines to determine whether there was variation in the level of responses to these MAMPs, to dissect the genetic basis underlying that variation and to understand the relationship between MAMP response and quantitative disease resistance (QDR). Naturally occurring quantitative variation in ROS, NO production, and defense genes expression levels triggered by MAMPs was observed. A major quantitative traits locus (QTL) associated with variation in the ROS production response to both flg22 and chitooctaose was identified on chromosome 2 in a recombinant inbred line (RIL) population derived from the maize inbred lines B73 and CML228. Minor QTL associated with variation in the flg22 ROS response was identified on chromosomes 1 and 4. Comparison of these results with data previously obtained for variation in QDR and the defense response in the same RIL population did not provide any evidence for a common genetic basis controlling variation in these traits.