Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.

Delayed memory for complex visual stimuli does not benefit from distraction during encoding.

The covert retrieval model (McCabe, Journal of Memory and Language 58(2), 480-494, 2008) postulates that delayed memory performance is enhanced when the encoding of memoranda in working memory (WM) is interrupted by distraction. When subjects are asked to remember stimuli for an immediate memory test, they usually remember them better when the items are presented without distraction, compared to a condition in which a distraction occurs following each item. In a delayed memory test, this effect has been shown to be reversed: Memory performance is better for items followed by distraction than without. Yet, this so-called McCabe effect has not been consistently replicated in the past. In an extensive replication attempt of a previous study showing the effect for complex visual stimuli, we investigated five potential boundary conditions of the predictions of the covert retrieval model: (1) Type of Stimuli (doors vs. faces), (2) type of distractor (pictures vs. math equations), (3) expectation about task difficulty (mixed vs. blocked lists), (4) memory load in WM (small vs. large), and (5) expectation about the long-term memory (LTM) test (intentional vs. incidental encoding). Across four experiments we failed to replicate the original findings and show that delayed memory for faces and other complex visual stimuli does not benefit from covert retrieval during encoding - as suggested as being induced by distractors. Our results indicate that the transfer of information from WM to LTM does not seem to be influenced by covert retrieval processes, but rather that a fixed proportion of information is laid down as a more permanent trace.

Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection.

BACKGROUND & AIMS: With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. A better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses in patients with different degrees of viral control. METHODS: We obtained blood from 124 HBV-infected individuals, including those with acute self-limiting HBV infection, chronic infection, and chronic infection with functional cure. We screened for HBV-specific T cell specificities by ELISpot, assessed the function of HBV-specific T cells using intracellular cytokine staining, and characterized HBV-specific CD4 T cells using human leukocyte antigen (HLA) class II tetramer staining, all directly ex vivo. RESULTS: ELISpot screening readily identified HBV-specific CD4 and CD8 T cell responses in acute resolving infection compared with more limited reactivity in chronic infection. Applying more sensitive assays revealed higher frequencies of functional HBV-specific CD4 T cells, but not CD8 T cells, in functional cure compared to chronic infection. Function independent analysis using HLA multimers also identified more HBV-specific CD4 T cell responses in functional cure compared to chronic infection, with the emergence of CD4 T cell memory both after acute and chronic infection. CONCLUSIONS: Functional cure is associated with higher frequencies of functional HBV-specific CD4 memory T cell responses. Thus, immunotherapeutic approaches designed to induce HBV functional cure should also aim to improve CD4 T cell responses. LAY SUMMARY: Immunotherapy is a form of treatment that relies on harnessing the power of an individual's immune system to target a specific disease or pathogen. Such approaches are being developed for patients with chronic HBV infection, in an attempt to mimic the immune response in patients who control HBV infection spontaneously, achieving a so-called functional cure. However, what exactly defines protective immune responses remains unclear. Herein, we show that functional cure is associated with robust responses by HBV-specific CD4 T cells (a type of immune cell).

Dissociating refreshing and elaboration and their impacts on memory.

Maintenance of information in working memory (WM) is assumed to rely on refreshing and elaboration, but clear mechanistic descriptions of these cognitive processes are lacking, and it is unclear whether they are simply two labels for the same process. This fMRI study investigated the extent to which refreshing, elaboration, and repeating of items in WM are distinct neural processes with dissociable behavioral outcomes in WM and long-term memory (LTM). Multivariate pattern analyses of fMRI data revealed differentiable neural signatures for these processes, which we also replicated in an independent sample of older adults. In some cases, the degree of neural separation within an individual predicted their memory performance. Elaboration improved LTM, but not WM, and this benefit increased as its neural signature became more distinct from repetition. Refreshing had no impact on LTM, but did improve WM, although the neural discrimination of this process was not predictive of the degree of improvement. These results demonstrate that refreshing and elaboration are separate processes that differently contribute to memory performance.

Repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex modulates value-based learning during sequential decision-making.

Adaptive behavior in daily life often requires the ability to acquire and represent sequential contingencies between actions and the associated outcomes. Although accumulating evidence implicates the role of dorsolateral prefrontal cortex (dlPFC) in complex value-based learning and decision-making, direct evidence for involvements of this region in integrating information across sequential decision states is still scarce. Using a 3-stage deterministic Markov decision task, here we applied offline, inhibitory low-frequency 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the left dlPFC in young male adults (n = 31, mean age = 23.8 years, SD = 2.5 years) in a within-subject cross-over design to study the roles of this region in influencing value-based sequential decision-making. In two separate sessions, each participant received 1-Hz rTMS stimulation either over the left dlPFC or over the vertex. The results showed that transiently inhibiting the left dlPFC impaired choice accuracy, particularly in situations in which the acquisition of sequential transitions between decision states and temporally lagged action-outcome contingencies played a greater role. Estimating parameters of a diffusion model from behavioral choices, we found that the diffusion drift rate, which reflects the efficiency of information integration, was attenuated by the stimulation. Moreover, the effects of rTMS interacted with session: individuals who could not efficiently integrate information across sequential states in the first session due to disrupted dlPFC function also could not catch up in performance during the second session with those individuals who could learn sequential transitions with intact dlPFC function in the first session. Taken together, our findings suggest that the left dlPFC is crucially involved in the acquisition of complex sequential relations and in the potential of such learning.

The effects of refreshing and elaboration on working memory performance, and their contributions to long-term memory formation.

Refreshing and elaboration are cognitive processes assumed to underlie verbal working-memory maintenance and assumed to support long-term memory formation. Whereas refreshing refers to the attentional focussing on representations, elaboration refers to linking representations in working memory into existing semantic networks. We measured the impact of instructed refreshing and elaboration on working and long-term memory separately, and investigated to what extent both processes are distinct in their contributions to working as well as long-term memory. Compared with a no-processing baseline, immediate memory was improved by repeating the items, but not by refreshing them. There was no credible effect of elaboration on working memory, except when items were repeated at the same time. Long-term memory benefited from elaboration, but not from refreshing the words. The results replicate the long-term memory benefit for elaboration, but do not support its beneficial role for working memory. Further, refreshing preserves immediate memory, but does not improve it beyond the level achieved without any processing.

When Load is Low, Working Memory is Shielded From Long-Term Memory's Influence.

Previous studies found that episodic long-term memory (eLTM) enhances working memory (WM) performance when both novel and previously learnt word pairs must be retained on a short-term basis. However, there is uncertainty regarding how and when WM draws on eLTM. Three possibilities are (a) that people draw on eLTM only if WM capacity is exceeded; (b) that there is always a contribution of eLTM to WM performance, irrespective of whether prior knowledge is helpful or not; or (c) benefits of prior knowledge are specific to comparisons between conditions which are similarly ambiguous concerning whether LTM may be useful. We built on the assumption that under conditions of a contribution from LTM, these LTM traces of memoranda could benefit or hamper performance in WM tasks depending on the match between the traces stored in LTM and the ones to-be stored in WM in the current trial, yielding proactive facilitation (PF) and proactive interference (PI), respectively. Across four experiments, we familiarized participants with some items before they completed a separate WM task. In accordance with possibility (a) we show that there are indeed conditions in which only WM contributes to performance. Performance deteriorated with the addition of stimuli from eLTM when WM load was low, but not when it was high; and an exchange of information between LTM and WM occurred only when WM capacity was exceeded, with PI and PF effects affecting immediate memory performance in verbal and visual tasks only at higher set sizes.

Grouping in working memory guides chunk formation in long-term memory: Evidence from the Hebb effect.

The Hebb effect refers to the improvement in immediate memory performance on a repeated list compared to unrepeated lists. That is, participants create a long-term memory representation over repetitions, on which they can draw in working memory tests. These long-term memory representations are likely formed by chunk acquisition: The whole list becomes integrated into a single unified representation. Previous research suggests that the formation of such chunks is rather inflexible and only occurs when at least the beginning of the list repeats across trials. However, recent work has shown that repetition learning strongly depends on participants recognizing the repeated information. Hence, successful chunk formation may depend on the recognizability of the repeated part of a list, and not on its position in the list. Across six experiments, we compared these two alternatives. We tested immediate serial recall of eight-letter lists, some of which partially repeated across trials. We used different partial-repetition structures, such as repeating only the first half of a list, or only every second item. We manipulated the salience of the repeating structure by spatially grouping and coloring the lists according to the repetition structure. We found that chunk formation is more flexible than previously assumed: Participants learned contiguous repeated sequences regardless of their position within the list, as long as they were able to recognize the repeated structure. Even when the repeated sequence occurred at varying positions over repetitions, learning was preserved when the repeated sequence was made salient by the spatial grouping. These findings suggest that chunk formation requires recognition of which items constitute a repeating group, and demonstrate a close link between grouping of information in working memory, and chunk formation in long-term memory.

The benefits of memory control processes in working memory: Comparing effects of self-reported and instructed strategy use.

Working memory performance is often assumed to benefit from different maintenance control strategies such as rehearsal, refreshing, elaboration, and grouping. In studies assessing strategy self-reports, some strategies were indeed associated with better recall. Nevertheless, experimental studies assessing the effect of instructing maintenance strategies compared to a no-instruction baseline lend no evidence for the effectiveness of these strategies for working memory. Explanations for this contradiction could be that instruction implementation engenders dual-task costs or that strategy instructions reduce adaptive strategy switching. Across two experiments, we investigated the frequency and variability of strategy use with trial-wise self-reports in serial recall of word lists. Furthermore, we examined potential instruction costs by comparing performance in trials with self-reported versus instructed use of the same strategies. Self-reported strategy use varied from trial to trial, with elaboration and rehearsal being the most frequent. Self-reported elaboration was correlated with better performance than reading and rehearsal. For the most prevalent strategies-elaboration and rehearsal-there were no costs of instructed strategy implementation. Our results speak against dual-task costs and for the advantage of adaptively choosing one's own strategy from trial to trial. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The contribution of episodic long-term memory to working memory for bindings.

The present experiments support two conclusions about the capacity limit of working memory (WM). First, they provide evidence for the Binding Hypothesis, WM capacity is limited by interference between bindings but not items. Second, they show that episodic LTM contributes substantially to binding memory when the capacity of WM is stretched to the limit by larger set sizes. We tested immediate memory for sets of word-picture pairs. With increasing set size, memory for bindings declined more precipitously than memory for items, as predicted from the binding hypothesis. Yet, at higher set sizes performance was more stable than expected from a capacity limited memory, suggesting a contribution of episodic long-term memory (LTM) to circumvent the WM capacity limit. In support of that hypothesis, we show a double dissociation of contributions of WM and episodic LTM to binding memory: Performance at set sizes larger than 3 was specifically affected by proactive interference - but were immune to influences from a distractor-filled delay. In contrast, performance at set size 2 was unaffected by proactive interference but harmed by a distractor-filled delay.

Chunking, boosting, or offloading? Using serial position to investigate long-term memory's enhancement of verbal working memory performance.

Individuals can use information stored in episodic long-term memory (LTM) to optimize performance in a working memory (WM) task, and the WM system negotiates the exchange of information between WM and LTM depending on the current memory load. In this study, we assessed the ability of different accounts of interactions between LTM and WM to explain these findings, by investigating whether the position of pre-learnt information within a memory list encoded into WM affects the benefit it provides to immediate memory. In two experiments we varied the input position of previously learned word-word pairs within a set of four to-be-remembered pairs. We replicated previous findings of superior performance when these LTM pairs were included in the WM task and show that the position in the list in which these LTM pairs were included not seem to matter. These results are most consistent with the idea that having access to information in LTM reduces or removes the need to rely on WM for its storage, implying that people "offload" information in conditions containing LTM pairs.

When Does Episodic Memory Contribute to Performance in Tests of Working Memory?

Both the experimental and the psychometric investigation of the WM capacity limit depend critically on the assumption that performance in our tests of WM reflects that capacity limit to a good approximation. Most tasks to measure WM rely on testing memory after a short time during which participants are asked to maintain information in WM. In these tests, episodic long-term memory is likely to also lay down a trace of the memory set. Therefore, participants can draw on two sources of information when memory is tested, making it difficult to separate the contributions of WM and episodic LTM to the performance on immediate-memory tests. Here we use proactive interference to distinguish between these two sources of remembered information, building on the fact that episodic memory is vulnerable to proactive interference, whereas WM is protected against it. We use a release-from-PI paradigm to determine the extent to which commonly used WM tasks reflect contributions from episodic LTM. We focus on memory for serial order of verbal lists, but also include visual and spatial WM tasks. The results of five experiments demonstrate that although some tasks used to investigate WM are heavily contaminated by episodic LTM, other popular paradigms such as serial and probed recall, and the standard version of the continuous color-reproduction task, are not. Measuring proactive interference can help researchers determine the extent to which WM and episodic LTM contribute to performance in immediate-memory tasks.

To be or not to be relevant: Comparing short- and long-term consequences across working memory prioritization procedures.

Priority-based allocation of attentional resources has shown robust effects in working memory (WM) with both cue-based and reward-based prioritization. However, direct comparisons between these effects in WM are needed. Additionally, the consequences of WM prioritization for remembering in the long term remain unclear for both prioritization procedures. Here, we tested and compared the immediate and long-term memory (LTM) effects of cue-based versus reward-based retrospective prioritization of WM content. Participants encoded four memory items and were then indicated to prioritize one of the items through the presentation of either a retro-cue or a reward pattern. We then tested their immediate and delayed memory. The results of the first experiment showed better memory for prioritized than for unprioritized information in WM and LTM, but the WM effect was driven solely by the retro-cue, making it difficult to interpret any reward-based effects in LTM. In the second experiment, using a more explicit and meaningful reward-based manipulation, the results showed a prioritization benefit in WM for both prioritization procedures. In LTM, however, the prioritization effect was predominantly driven by the retro-cue manipulation. Taken together, we found that (1) the way in which attention is directed in WM impacts the size of the prioritization benefit in WM, (2) WM prioritization generally results in a prioritization effect in LTM, and (3) that the effect in LTM is more robust for cue-based prioritization. Exploratory analyses indicated that the LTM effect of cue-based prioritization reflected a cost in performance for noncued items rather than a benefit for cued items.

Effects of stress beliefs on the emotional and biological response to acute psychosocial stress in healthy men.

BACKGROUND: Negative beliefs about stress (e.g., "stress is bad") constitute an independent risk factor for increased morbidity and mortality. One potential underlying mechanism are altered responses to acute psychosocial stress. The aim of this study was to investigate whether beliefs about stress are associated with physiological and endocrine stress response patterns. METHODS: A total of N = 77 healthy adults were randomised to an experimental and a placebo control group and were subsequently exposed to the Trier Social Stress Test (TSST). Stress beliefs were measured before and after a psychological manipulation aiming at fostering more balanced stress beliefs or a placebo manipulation. Self-reported stress was measured four times before/after the TSST, heart rate was assessed continuously, and cortisol was assessed eight times before/after the TSST. RESULTS: There was a significant decrease in negative stress beliefs (p < .001) and increase in positive stress beliefs (p < .001) in participants in the experimental condition, which was absent in participants in the placebo condition. The participants in the experimental group had more pronounced self-reported stress reactions (p = .028) while at the same time also showing more pronounced stress recoveries (p = .036). The findings regarding cortisol were mixed. CONCLUSIONS: More balanced stress beliefs appeared to be associated with more efficient subjective responses to acute psychosocial stress. These findings attest to a potential mechanism translating negative stress beliefs into ill health while at the same time outlining targets for psychological interventions.

Freeing capacity in working memory (WM) through the use of long-term memory (LTM) representations.

Previous research indicates that long-term memory (LTM) may contribute to performance in working memory (WM) tasks. Across 3 experiments, we investigated the extent to which active maintenance in WM can be replaced by relying on information stored in episodic LTM, thereby freeing capacity for additional information in WM. First, participants encoded word pairs into LTM, and then completed a WM task, also involving word pairs. Crucially, the pairs presented in each WM trial comprised varying numbers of new pairs and the previously learned LTM pairs. Experiment 1 showed that recall performance in the WM task was unaffected when memory set size increased through the addition of LTM pairs, but that it deteriorated when set size increased through adding new pairs. In Experiment 2, we investigated the robustness of this effect, orthogonally manipulating the number of new and LTM pairs used in the WM task. When WM load was low, performance declined with the addition of LTM pairs but remained superior to performance with the matched set size comprising only new pairs. By contrast, when WM load was higher, adding LTM pairs did not affect performance. In Experiment 3, we found that the benefit of LTM representations arises from retrieving these during the WM test, leading them to suffer from typical interference effects. We conclude that individuals can outsource workload to LTM to optimize performance, and that the WM system negotiates the exchange of information between WM and LTM depending on the current memory load. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Expression of IGF-1 receptor and GH receptor in hepatic tissue of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

OBJECTIVE: The GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC). DESIGN: GEA (n = 318) and IHC (n = 30) cohorts were identified from the Massachusetts General Hospital NAFLD Tissue Repository. GEA subjects were categorized based on histopathology as normal liver histology (NLH), steatosis only (Steatosis), nonalcoholic steatohepatitis (NASH) without fibrosis (NASH F0), and NASH with fibrosis (NASH F1-4) with GEA by the Nanostring nCounter assay. IHC subjects were matched for age, body mass index (BMI), sex, and diabetic status across three groups (n = 10 each): NLH, Steatosis, and NASH with fibrosis (NASH F1-3). IHC for IGF-1R, IGF-1 and GHR was performed on formalin-fixed, paraffin-embedded hepatic tissue samples. RESULTS: IGF-1R gene expression did not differ across NAFLD severity while IGF-1 gene expression decreased with increasing NAFLD severity, including when controlled for BMI and age. GHR expression did not differ by severity of NAFLD based on GEA or IHC. CONCLUSIONS: IGF-1R and GHR expression levels were not significantly different across NAFLD disease severity. However, expression of IGF-1 was lower with increasing severity of NAFLD. Additional research is needed regarding the contribution of the GH/IGF-1 axis to the pathophysiology of NAFLD and NASH.

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance.

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin's role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.

Distinct Hepatic Gene-Expression Patterns of NAFLD in Patients With Obesity.

Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene-expression patterns associated with different patterns of liver injury in a high-risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1-4 (NASH F1-F4). One hundred twenty-five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma-interferon-inducible lysosomal thiol reductase (IFI30) and chemokine (C-X-C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1-F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high-risk individuals.

Reactivated Visual Masks Do Not Disrupt Serial Recall.

The process of spontaneous refreshing plays a central role in current models of working memory but is yet to be observed directly. In a recent study, Rey, Versace, and Plancher (2018) introduced a novel approach to investigate the mechanisms underlying refreshing: They presented tones previously associated with a visual mask during the free time of a complex span task and found that this impaired memory, presumably because reactivation of the masks disrupts refreshing. Here, we aimed to replicate their finding under more controlled settings with more observations per participant. We failed to replicate the previous findings, thereby questioning the robustness of the original effect.

Intrahepatic TH17/TReg Cells in Homeostasis and Disease-It's All About the Balance.

Both acute and chronic hepatic inflammation likely result from an imbalance in the TH1/TH2 cell response and can lead to liver fibrosis and end-stage liver disease. More recently, a novel CD4+ T helper cell subset was described, characterized by the production of IL-17 and IL-22. These TH17 cells 50were predominantly implicated in host defense against infections and in autoimmune diseases. Interestingly, studies over the last 10 years revealed that the development of TH17 cells favors pro-inflammatory responses in almost all tissues and there is a reciprocal relationship between TH17 and TReg cells. The balance between TH17and TReg cells is critical for immune reactions, especially in injured liver tissue and the return to immune homeostasis. The pathogenic contribution of TH17 and TReg cells in autoimmunity, acute infection, and chronic liver injury is diverse and varies among disease etiologies. Understanding the mechanisms underlying TH17 cell development, recruitment, and maintenance, along with the suppression of TReg cells, will inform the development of new therapeutic strategies in liver diseases. Active manipulation of the balance between pathogenic and regulatory processes in the liver may assist in the restoration of homeostasis, especially in hepatic inflammation.