Positive biases and psychological functioning during the coronavirus disease 2019 pandemic.

Many individuals have experienced a multitude of chronic stressors and diminished psychological functioning during COVID-19. The current study examined whether biases towards positive social media or positive autobiographical memories was related to increases in psychological functioning during COVID-19. Participants were 1071 adults (Mage = 46.31; 58% female; 78% White) recruited from MTurk. Participants reported on their social media consumption and autobiographical recall, positive and negative affect, and dysphoria symptoms. Results indicated that, at the first assessment collected in the spring and summer of 2020, positively biased social media consumption was cross-sectionally related to higher levels of positive affect, and positively biased autobiographical recall was cross-sectionally related to lower levels of negative affect and dysphoria symptoms. Sensitivity analyses examined cross-sectional relations from a second assessment collected in fall 2020, and prospective cross-lagged analyses. The findings point to potential psychological benefits of positive biases during chronic stressors.

Associations between positive memory count and hazardous substance use in a trauma-exposed sample: Examining the moderating role of emotion dysregulation.

OBJECTIVES: Research has demonstrated links between autobiographical memory retrieval and hazardous substance use. However, limited work has examined relations between positive autobiographical memories and hazardous substance use, as well as moderating factors influencing these relations. Thus, we examined the potential moderating roles of negative and positive emotion dysregulation in the relations between count of retrieved positive memories and hazardous substance use (alcohol and drug use separately). METHODS: Participants were 333 trauma-exposed students (Mage = 21.05; 85.9% women) who completed self-report measures assessing positive memory count, hazardous alcohol and drug use, negative emotion dysregulation, and positive emotion dysregulation. RESULTS: Positive emotion dysregulation significantly moderated the association between positive memory count and hazardous alcohol use (b = 0.04, 95% confidence interval [CI] [0.01, 0.06], p = 0.019), as well as the association between positive memory count and hazardous drug use (b = 0.02, 95% CI [0.01, 0.03], p = 0.002). Individuals with more positive emotion dysregulation had stronger associations between increases in positive memory count and increased hazardous substance use. CONCLUSION: Findings indicate that trauma-exposed individuals who retrieve more positive memories and experience difficulties regulating positive emotions report greater hazardous substance use. Positive emotion dysregulation may be an important target for memory-based interventions among trauma-exposed individuals who report hazardous substance use.

Structure of a patient-derived antibody in complex with allergen reveals simultaneous conventional and superantigen-like recognition.

Antibodies classically bind antigens via their complementarity-determining regions, but an alternative mode of interaction involving V-domain framework regions has been observed for some B cell "superantigens." We report the crystal structure of an antibody employing both modes of interaction simultaneously and binding two antigen molecules. This human antibody from an allergic individual binds to the grass pollen allergen Phl p 7. Not only are two allergen molecules bound to each antibody fragment (Fab) but also each allergen molecule is bound by two Fabs: One epitope is recognized classically, the other in a superantigen-like manner. A single allergen molecule thus cross-links two identical Fabs, contrary to the one-antibody-one-epitope dogma, which dictates that a dimeric allergen at least is required for this to occur. Allergens trigger immediate hypersensitivity reactions by cross-linking receptor-bound IgE molecules on effector cells. We found that monomeric Phl p 7 induced degranulation of basophils sensitized solely with this monoclonal antibody expressed as an IgE, demonstrating that the dual specificity has functional consequences. The monomeric state of Phl p 7 and two structurally related allergens was confirmed by size-exclusion chromatography and multiangle laser light scattering, and the results were supported by degranulation studies with the related allergens, a second patient-derived allergen-specific antibody lacking the nonclassical binding site, and mutagenesis of the nonclassically recognized allergen epitope. The antibody dual reactivity and cross-linking mechanism not only have implications for understanding allergenicity and allergen potency but, importantly, also have broader relevance to antigen recognition by membrane Ig and cross-linking of the B cell receptor.

Prior Emotional Context Modulates Early Event-Related Potentials to Neutral Retrieval Cues.

Memory retrieval is thought to involve the reactivation of encoding processes. Previous fMRI work has indicated that reactivation processes are modulated by the residual effects of the prior emotional encoding context; different spatial patterns emerge during retrieval of memories previously associated with negative compared with positive or neutral context. Other research suggests that event-related potential (ERP) indicators of memory retrieval processes, like the left parietal old/new effect, can also be modulated by emotional context, but the spatial distribution and temporal dynamics of these effects are unclear. In the current study, we examined "when" emotion affects recognition memory and whether that timing reflects processes that come before and may guide successful retrieval or postrecollection recovery of emotional episodic detail. While recording EEG, participants (n = 25) viewed neutral words paired with negative, positive, or neutral pictures during encoding, followed by a recognition test for the words. Analyses focused on ERPs during the recognition test. In line with prior ERP studies, we found an early positive-going parietally distributed effect starting around 200 msec after retrieval-cue onset. This effect emerged for words that had been encoded in an emotional compared with neutral context (no valence differences), before the general old/new effect. This emotion-dependent effect occurred in an early time window, suggesting that emotion-related reactivation is a precursor to successful recognition.

Increased IgA production by B-cells in COPD via lung epithelial interleukin-6 and TACI pathways.

Despite their relevance to mucosal defense, production of IgA and the function of lung B-cells remain unknown in chronic obstructive pulmonary disease (COPD). We assessed IgA synthesis in the lungs of COPD (n=28) and control (n=21) patients, and regulation of B-cells co-cultured with in vitro-reconstituted airway epithelium. In COPD lung tissue, synthesis of IgA1 was increased, which led to its accumulation in subepithelial areas. In vitro, the COPD bronchial epithelium imprinted normal human B-cells for increased production of IgA (mainly IgA1) and maturation into CD38(+) plasma cells. These effects were associated with upregulation of TACI (transmembrane activator and CAML interactor) and were observed under resting conditions, while being partly inhibited upon stimulation with cigarette smoke extract. Interleukin (IL)-6 and BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) were upregulated in the COPD epithelium and lung tissue, respectively; the IgA-promoting effect of the COPD bronchial epithelium was inhibited by targeting IL-6 and, to a lower extent, by blocking TACI. These data show that in COPD, the bronchial epithelium imprints B-cells with signals promoting maturation into IgA-producing plasma cells through the action of two epithelial/B-cell axes, namely the IL-6/IL-6 receptor and BAFF-APRIL/TACI pathways, while cigarette smoke partly counteracts this IgA-promoting effect.

Untangling the threads of motivated memory: Independent influences of reward and emotion.

Motivational and emotional influences on memory have been studied extensively; however, despite the link between these constructs, they have been studied in separate lines of research, with very little work examining their effects concurrently. The current study takes a novel approach to manipulate motivational and emotional influences orthogonally, and within the same task, to test their interplay on intentional memory formation. If emotion and reward motivation are tightly linked, they may rely on overlapping cognitive mechanisms, thus we would not expect emotion and reward to interact in memory. Alternatively, they could be distinct constructs and therefore would boost memory when both are included in the same experimental trial, above and beyond additive effects. To test these competing predictions, in Experiment 1, participants (n = 180) completed an old/new recognition memory task with emotional (negative, positive) and neutral words intentionally encoded with high or low reward anticipation cues. In Experiment 2, participants (n = 159) encoded emotional and neutral words with a high or low reward cue, but memory was tested with free recall using study-test blocks. The findings from both experiments converged. There were main effects of emotion and reward in generally hypothesized directions, but no evidence of an interaction between these factors. This is in line with the prediction that emotion and reward motivation are similar constructs. Their combination within a trial does not boost memory above and beyond either of these factors alone perhaps indicating these constructs have similar cognitive mechanisms.

Individual Differences in Older Adult Frontal Lobe Function Relate to Memory and Neural Activity for Self-Relevant and Emotional Content.

OBJECTIVES: Older adults show memory benefits for self-relevant and emotional content, but there are individual differences in this effect. It has been debated whether processing of self-relevant and emotional information relies on similar processes to one another. We examined whether variation in frontal lobe (FL) function among older adults related similarly to the processing of self-relevant information as it did to emotional information, or whether these relations diverged. METHODS: While undergoing fMRI, participants (ages 60-88) viewed positive, negative, and neutral objects, and imagined placing those objects in either their home or a stranger's home. Participants completed a surprise memory test outside of the MRI. In a separate session, a cognitive battery was collected and composite scores measuring FL and medial temporal lobe function were computed and related to the behavioral memory performance and the neural engagement during fMRI. RESULTS: Behaviorally, FL function related to memory for self-relevant, but not emotional content. Older adults with higher FL function demonstrated reduced self-bias in memory performance. During the processing of self-relevant stimuli, independent of emotion, levels of activity in the middle frontal gyrus showed positive associations with FL function. This relationship was not driven by compensatory activity or disruptions to nonself-relevant neutral content. DISCUSSION: These findings point to divergence in the cognitive functions relating to memory enhancements for self- and emotional-relevance. The results further suggest self-relevance as a mnemonic device for older adults, especially in those with lower FL function.

IL-2 regulates expression of C-MAF in human CD4 T cells.

Blockade of IL-2R with humanized anti-CD25 Abs, such as daclizumab, inhibits Th2 responses in human T cells. Recent murine studies have shown that IL-2 also plays a significant role in regulating Th2 cell differentiation by activated STAT5. To explore the role of activated STAT5 in the Th2 differentiation of primary human T cells, we studied the mechanisms underlying IL-2 regulation of C-MAF expression. Chromatin immunoprecipitation studies revealed that IL-2 induced STAT5 binding to specific sites in the C-MAF promoter. These sites corresponded to regions enriched for markers of chromatin architectural features in both resting CD4 and differentiated Th2 cells. Unlike IL-6, IL-2 induced C-MAF expression in CD4 T cells with or without prior TCR stimulation. TCR-induced C-MAF expression was significantly inhibited by treatment with daclizumab or a JAK3 inhibitor, R333. Furthermore, IL-2 and IL-6 synergistically induced C-MAF expression in TCR-activated T cells, suggesting functional cooperation between these cytokines. Finally, both TCR-induced early IL4 mRNA expression and IL-4 cytokine expression in differentiated Th2 cells were significantly inhibited by IL-2R blockade. Thus, our findings demonstrate the importance of IL-2 in Th2 differentiation in human T cells and support the notion that IL-2R-directed therapies may have utility in the treatment of allergic disorders.

Human T(H)2 cells respond to cysteinyl leukotrienes through selective expression of cysteinyl leukotriene receptor 1.

BACKGROUND: Allergic asthma is characterized by reversible airway obstruction and bronchial hyperresponsiveness associated with T(H)2 cell-mediated inflammation. Cysteinyl leukotrienes (CysLTs) are potent lipid mediators involved in bronchoconstriction, mucus secretion, and cell trafficking in asthmatic patients. Recent data have implicated CysLTs in the establishment and amplification of T(H)2 responses in murine models, although the precise mechanisms are unresolved. OBJECTIVES: Preliminary microarray studies suggested that human T(H)2 cells might selectively express cysteinyl leukotriene receptor 1 (CYSLTR1) mRNA. We sought to establish whether human T(H)2 cells are indeed a CysLT target cell type. METHODS: We examined the expression of CYSLTR1 using real-time PCR in human T(H)1 and T(H)2 cells. We functionally assessed cysteinyl leukotriene receptor 1 protein (CysLT(1)) expression using calcium flux, cyclic AMP, and chemotaxis assays. RESULTS: We show that human T(H)2 cells selectively express CYSLTR1 mRNA at high levels compared with T(H)1 cells after in vitro differentiation from naive precursors. Human T(H)2 cells are selectively responsive to CysLTs in a calcium flux assay when compared with T(H)1 cells with a rank order of potency similar to that described for CysLT(1) (leukotriene [LT] D(4) > LTC(4) > LTE(4)). We also show that LTD(4)-induced signaling in T(H)2 cells is mediated through CysLT(1) coupled to G(α)q and G(α)i proteins, and both pathways can be completely inhibited by selective CysLT(1) antagonists. LTD(4) is also found to possess potent chemotactic activity for T(H)2 cells at low nanomolar concentrations. CONCLUSIONS: These findings suggest a novel mechanism of action for CysLTs in the pathogenesis of asthma and provide a potential explanation for the anti-inflammatory effects of CysLT(1) antagonists.

Allergen specificity of IgG(4)-expressing B cells in patients with grass pollen allergy undergoing immunotherapy.

BACKGROUND: Serum IgG(4) responses to allergen immunotherapy are well documented as blocking allergen binding to receptor-bound IgE on antigen-presenting cells and effector cells, but the molecular characteristics of treatment-induced IgG(4), particularly in relation to expressed antibody, are poorly defined. OBJECTIVES: We aimed to clone and express recombinant IgG(4) from patients receiving grass pollen immunotherapy using single B cells to obtain matched heavy- and light-chain pairs. METHODS: IgG(4)(+) B cells were enriched from blood samples taken from 5 patients receiving grass pollen immunotherapy. Matched heavy- and light-chain variable-region sequences were amplified from single IgG(4)(+) B cells. Variable regions were cloned and expressed as recombinant IgG(4). Binding analysis of grass pollen-specific IgG(4) was performed by using surface plasmon resonance. Functional assays were used to determine IgE blocking activity. In a separate experiment grass pollen-specific antibodies were depleted from serum samples to determine the proportion of grass pollen-specific IgG(4) within total IgG(4). RESULTS: Depletion of grass pollen-specific antibodies from serum led to a modest reduction in total IgG(4) levels. Matched heavy- and light-chain sequences were cloned from single IgG(4)(+) B cells and expressed as recombinant IgG(4). We identified an IgG(4) that binds with extremely high affinity to the grass pollen allergen Phl p 7. Furthermore, we found that a single specific mAb can block IgE-mediated facilitated allergen presentation, as well as IgE-mediated basophil activation. CONCLUSION: Although increases in IgG(4) levels cannot be wholly accounted for within the allergen-specific fraction, allergen immunotherapy might result in the production of high-affinity allergen-specific blocking IgG(4).

Reward motivation more consistently modulates memory for younger compared to older adults in a directed forgetting task.

Remembering and forgetting are both important processes of a healthy memory system, but both processes can show age-related decline. Reward anticipation is effective at improving remembering in both younger and older adults, but little is known about the effects of incentives on forgetting. In four online experiments, we examined whether reward motivation modulates intentional remembering and forgetting in younger and older adults, and systematically varied the presentation of reward cues during encoding to test whether the temporal dynamics of reward anticipation are important for directed forgetting performance. Both age groups showed directed forgetting effects such that participants remembered more items they were instructed to remember than instructed to forget, but across experiments, we found no evidence that reward incentives improved forgetting in either age group. Younger adults consistently exhibited reward-modulated memory across experiments and varying the timing of the reward cue had little impact on performance. Older adults displayed inconsistent effects of reward on memory, only when reward anticipation was elicited closer to the middle of the experimental trial did it enhance memory in this task. Overall, the findings from the current set of experiments indicate that reward anticipation improved memory, but not forgetting, and most consistently for younger adults, compared to older adults. Further, older adults' cognitive performance may be more sensitive to the placement and timing of reward anticipation in the experimental trial perhaps due to the time course of reward anticipation and interactions with the hippocampus that may show age-related change. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cognitive biases in perceptions of posttraumatic growth: A systematic review and meta-analysis.

Posttraumatic growth (PTG) has captivated the attention of clinicians and researchers over the past three decades. However, accumulating evidence suggests that individuals' self-reports of PTG may be cognitively biased. In the current systematic review and meta-analysis, we aimed to investigate the relation between cognitive biases and perceived PTG. In line with existing theory on cognitive biases that may lead to illusory perceived PTG, we examined the following cognitive biases: defensiveness, memory bias, downward comparison bias, social desirability bias, positive attention bias, and growth beliefs. Forty-seven studies met criteria for inclusion in this review and 66 separate effects were coded for meta-analyses. Results indicated that cognitive biases were related to perceived PTG, with variation by type of cognitive bias. Moderator analyses revealed that downward comparison bias, positive attention bias, and growth beliefs exhibited stronger relations with perceived PTG than did defensiveness, memory bias, and social desirability bias. Further, subgroup analyses explored effects by type of cognitive bias and characteristics of cognitive bias measurements. The current study suggests that cognitive biases may have a role in individuals' perceptions of their PTG. This contributes to theory on the origins of illusory perceptions of PTG and provides direction for improvements to the measurement of PTG and clinical approaches to PTG.

An ERP investigation of age differences in the negativity bias for self-relevant and non-self-relevant stimuli.

As we age, we show increased attention and memory for positive versus negative information, and a key event-related potential (ERP) marker of emotion processing, the late positive potential (LPP), is sensitive to these changes. In young adults the emotion effect on the LPP is also quite sensitive to the self-relevance of stimuli. Here we investigated whether the shift toward positive stimuli with age would be magnified by self-relevance. Participants read 2-sentence scenarios that were either self-relevant or non-self-relevant with a neutral, positive, or negative critical word in the second sentence. The LPP was largest for self-relevant negative information in young adults, with no significant effects of emotion for non-self-relevant scenarios. In contrast, older adults showed a smaller negativity bias, and the effect of emotion was not modulated by self-relevance. The 3-way interaction of age, emotion, and self-relevance suggests that the presence of self-relevant stimuli may reduce or inhibit effects of emotion for non-self-relevant stimuli on the LPP in young adults, but that older adults do not show this effect to the same extent.

Influence of Reward Motivation on Directed Forgetting in Younger and Older Adults.

An important feature of the memory system is the ability to forget, but aging is associated with declines in the ability to intentionally forget potentially due to declines in cognitive control. Despite cognitive deficits, older adults are sensitive to affective manipulations, such as reward motivation, and reward anticipation can improve older adults' memory performance. The goal of the current studies was to examine the effect of reward motivation on directed remembering and forgetting. Participants were healthy CloudResearch/Turk Prime workers aged 18-35 and 60-85. In Experiment 1, we conducted a typical item-method directed forgetting task using neutral words presented one at a time followed by a to-be-remembered (TBR) or to-be-forgotten (TBF) cue. A recognition memory test followed that included all words from the encoding task, as well as new words. We replicated prior findings of better memory for TBR compared to TBF items, but not typical age-related differences in recognition of TBF items. In Experiments 2-4, we repeated this paradigm except that in the second block of trials, each word was presented with a high ($0.75) or low ($0.01) reward cue indicating the value that could be earned if the item was successfully Remembered or Forgotten (depending on cue). During recognition, correct responses to target items (both TBR and TBF) resulted in the associated reward, but incorrect "old" responses resulted in a loss of $0.50. In three experiments, high rewards led to better memory for younger and older adults compared to low rewards, regardless of the directed cue to remember or forget the word. In Experiments 3 and 4, older adults showed typical deficits in directed forgetting, but this was across reward conditions. For older adults, there was no evidence that including reward motivation improved cognitive control abilities as high value reward anticipation did not improve directed forgetting. Instead, in line with hypotheses, high compared to low value reward anticipation leads to engagement of processes that result in better memory regardless of the TBR or TBF cue, and reward anticipation bolsters memory in a relatively automatic, rather than strategic, fashion that overrides one's ability to cognitively control encoding processes.

Reward motivation influences response bias on a recognition memory task.

Reward-motivated memory has been studied extensively in psychology and neuroscience. Many recognition studies follow the same type of paradigm: stimuli are cued at encoding with high or low reward values which indicate the amount the stimulus is worth if successfully recognized on a subsequent memory test. Each incorrect endorsement of a lure at retrieval is penalized with an arbitrary value between the high and low reward value, resulting in a single false alarm rate. Studies employing this type of paradigm have reported higher hit rates for high value items compared to low value items, but generally hit rate is the only measure of memory that is reported as a function of reward value. It is currently not clear what aspects of the experimental design lead to these memory effects, and other measures, like discriminability and response bias, cannot be properly calculated when there is only a single false alarm rate, but we hypothesize that these are also susceptible to motivational manipulations. To test how reward anticipation might influence memory and response bias in this type of task, we created a novel paradigm that allowed us to calculate both by associating rewards with categories (indoor vs. outdoor scenes), thus calculating separate false alarm rate as well as hit rate at each level of reward. We report results of three experiments that varied rewards and penalties for correct and error responses for the category items. In two experiments, we replicated prior findings of higher hit rates for high compared to low reward items, but consistently across three experiments, when d' was calculated, we found no difference in memory discriminability as a function of reward. Further, Experiment 1 we found that response bias was more conservative for low reward items: participants were more likely to endorse a 'new' response to low compared to high reward items. This effect was significantly reduced in Experiment 2 and eliminated in Experiment 3 when the reward-penalty structure was manipulated to reduce bias. Our findings reveal that reward motivation can influence decisional biases thought to be independent of memory processes. The amount of the reward value for correct responses and the amount of the penalty for incorrect responses should be considered when designing experimental paradigms to study motivation-cognition interactions.

Frontostriatal functional connectivity supports reward-enhanced memory in older adults.

Both younger and older adults prioritize reward-associated stimuli in memory, but there has been little research on possible age differences in the neural mechanisms mediating this effect. In the present study, we examine neural activation and functional connectivity in healthy younger and older adults to test the hypothesis that older adults would engage prefrontal regions to a greater extent in the service of reward-enhanced memory. While undergoing MRI, target stimuli were presented after high- or low-reward cues. The cues indicated the reward value for successfully recognizing the stimulus on a memory test 24 hours later. We replicated prior findings that both older and younger adults had better memory for high- compared to low-reward stimuli. Critically, in older but not younger adults, this enhanced subsequent memory for high-reward items was supported by greater connectivity between the caudate and bilateral inferior frontal gyrus. The findings add to the growing literature on motivation-cognition interactions in healthy aging and provide novel findings of the neural underpinnings of reward-motivated encoding.

Neural mechanisms supporting emotional and self-referential information processing and encoding in older and younger adults.

Emotion and self-referential information can both enhance memory, but whether they do so via common mechanisms across the adult lifespan remains underexplored. To address this gap, the current study directly compared, within the same fMRI paradigm, the encoding of emotionally salient and self-referential information in older adults and younger adults. Behavioral results replicated the typical patterns of better memory for emotional than neutral information and for self-referential than non-self-referential materials; these memory enhancements were present for younger and older adults. In neural activity, young and older adults showed similar modulation by emotion, but there were substantial age differences in the way self-referential processing affected neural recruitment. Contrary to our hypothesis, we found little evidence for overlap in the neural mechanisms engaged for emotional and self-referential processing. These results reveal that-just as in cognitive domains-older adults can show similar performance to younger adults in socioemotional domains even though the two age groups engage distinct neural mechanisms. These findings demonstrate the need for future research delving into the neural mechanisms supporting older adults' memory benefits for socioemotional material.

The glucocorticoid receptor beta isoform can mediate transcriptional repression by recruiting histone deacetylases.

BACKGROUND: The glucocorticoid receptor (GR) is able to participate in regulation of transcription by a variety of mechanisms, one of which involves DNA binding and recruitment of regulatory cofactors. The best-studied forms of the receptor are the 777-amino-acid alpha and the 742-amino-acid beta variants. The beta isoform, which does not bind cortisol in human subjects, has been proposed to be a dominant-negative inhibitor of the transcriptional activation-competent GRalpha isoform. OBJECTIVE: GRalpha has roles in both transcriptional activation and repression. We wished to determine the influence of GRbeta on genes that are normally transcriptionally repressed by glucocorticoids. We studied IL5 and IL13, which both contribute to the asthmatic phenotype. METHODS: We used transient transfection systems and coimmunoprecipitation experiments to determine whether GRbeta has repressive activity on the promoters of the human IL5 and IL13 genes. RESULTS: GRbeta is able to act as a transcriptional repressor of cytokine genes and mediates its function through the recruitment of histone deacetylase complexes. CONCLUSION: GRalpha and GRbeta act in a similar manner on IL5 and IL13 promoters, serving to repress transcription. In this circumstance GRbeta does not act as a dominant-negative inhibitor of GRalpha.

Age differences in the neural response to negative feedback.

Affective processing is one domain that remains relatively intact in healthy aging. Investigations into the neural responses associated with reward anticipation have revealed that older and younger adults recruit the same midbrain reward regions, but other evidence suggests this recruitment may differ depending on the valence (gain, loss) of the incentive cue. The goal of the current study was to examine functional covariance during gain and loss feedback in younger and healthy older adults. A group of 15 older adults (mean age = 68.5) and 16 younger adults (mean age = 25.4) completed a revised Monetary Incentive Delay task (rMID; Knutson, Westdorp, Kaiser, & Hommer, 2000) while in the fMRI scanner. The rMID is a reaction time task where successful performance, either gaining a reward or avoiding a loss, is defined by hitting a button during the brief presentation of a visual target. Participants receive gain and loss anticipation cues before each trial and feedback after each trial with four possible outcomes: +$5.00, +0.00, -$5.00, and -$0.00. Using seed-voxel partial least squares analyses, with seed voxels in the caudate and ventromedial prefrontal cortex, whole-brain functional covariance revealed that younger and older adults engage the same network of regions to support general feedback processing. However, older adults engaged two additional networks to support processing of negative feedback, gain_miss (+0), loss_miss (-$5), and loss_hit (-0), specifically. These findings are in line with theories of a positivity effect in aging and may have implications for reward-stimulus learning and decision making following performance-contingent negative feedback.

Transcriptional Analysis of the Human IgE-Expressing Plasma Cell Differentiation Pathway.

IgE is secreted by plasma cells (PCs) and is central to allergic disease. Using an ex vivo tonsil B cell culture system, which mimics the Th2 responses in vivo, we have recently characterized the development pathway of human IgE-expressing PCs. In this system, as in mice, we reported the predisposition of IgE-expressing B cells to differentiate into PCs. To gain a comprehensive understanding of the molecular events involved in the differentiation of human IgE+ B cells into PCs we have used the Illumina HumanHT-12 v4 Expression BeadChip array to analyse the gene expression profile of ex vivo generated human IgE+ B cells at various stages of their differentiation into PCs. We also compared the transcription profiles of IgE+ and IgG1+ cells to discover isotype-specific patterns. Comparisons of IgE+ and IgG1+ cell transcriptional profiles revealed molecular signatures specific for IgE+ cells, which diverge from their IgG1+ cell counterparts upon differentiation into PCs. At the germinal center (GC) stage of development, unlike in some mouse studies of IgE biology, we observed similar rates of apoptosis and no significant differences in the expression of apoptosis-associated genes between the IgE+ and IgG1+ B cells. We identified a gene interaction network associated with early growth response 1 (EGR1) that, together with the up-regulated IRF4, may account for the predisposition of IgE+ B cells to differentiate into PCs. However, despite their swifter rates of PC differentiation, the transcription profile of IgE+ PCs is more closely related to IgE+ and IgG1+ plasmablasts (PBs) than to IgG1+ PCs, suggesting that the terminal differentiation of IgE+ cells is impeded. We also show that IgE+ PCs have increased levels of apoptosis suggesting that the IgE+ PCs generated in our in vitro tonsil B cell cultures, as in mice, are short-lived. We identified gene regulatory networks as well as cell cycle and apoptosis signatures that may explain the diverging PC differentiation programme of these cells. Overall, our study provides a detailed analysis of the transcriptional pathways underlying the differentiation of human IgE-expressing B cells and points to molecular signatures that regulate IgE+ PC differentiation and function.