Priming Of Responses Research Articles

Deleted in malignant brain tumors 1 (DMBT1) gene relate to immune priming and phagocytosis modulation in the small abalone Haliotis diversicolor.

The small abalone (Haliotis diversicolor) is an economic shellfish cultured in the south coast of China. In recent years, the frequent occurrence of the disease has led to significant mortality in abalone farms. Deleted in malignant brain tumors 1 (DMBT1), a member of the scavenger receptor cysteine-rich (SRCR) protein family, plays an important role in host defense. However, its function in H. diversicolor remains unknown. In order to evaluate the immune priming effect after secondary infection and elucidate possible regulatory mechanism, a novel DMBT1 from the small abalone H. diversicolor (designated as HdDMBT1) was cloned and characterized in this study. The open reading frame of HdDMBT1 was 2331 bp encoding 776 amino acids with a molecular weight of 84.73 kDa. HdDMBT1 contained conserved active sites with DMBT1 from other species, detected in all tested tissues and had higher expression levels in hepatopancreas. The temporal expression profiles of HdDMBT1 after two challenges of Vibrio harveyi were examined to evaluate priming response in the small abalone. The expression level of HdDMBT1 mRNA in hepatopancreas increased significantly after V. harveyi challenge. Meanwhile, the expression level of HdDMBT1 after the second challenge was significantly higher than that after the first challenge (4.23-fold). RNA interference (RNAi) experiments were conducted to examine the role of HdDMBT1 in response to V. harveyi infection. Knocking down HdDMBT1 decreased the hemocytes phagocytosis (0.48-fold). In addition, the bacterial density in hemolymph and the mortality of abalone raised, when infected with V. harveyi after dsHdDMBT1 injection. These results indicated that HdDMBT1 might play an important role in tolerance to bacterial infection.

Chemical disruption of ABA signaling overcomes high-temperature inhibition of seed germination and enhances seed priming responses.

Seed germination is critical to agricultural productivity because low germination rates and/or asynchronous germination negatively affect stand establishment and subsequent yields. Exposure to high temperatures during seed imbibition can decrease both germination synchrony and rates through an ABA-mediated process called thermoinhibition. Methods to reduce thermoinhibition would be agriculturally valuable, particularly with increasing global mean temperatures. Lettuce seed germination is particularly sensitive to high temperatures and is a classic system for studying thermoinhibition. Extensive evidence using mutants and carotenoid biosynthetic inhibitors (e.g. fluridone) has demonstrated that endogenous abscisic acid (ABA) biosynthesis is required for thermoinhibition in lettuce and Arabidopsis. Although fluridone and related carotenoid biosynthetic inhibitors block thermoinhibition, they are not well-suited for this application due to their herbicidal effects. Here we explore the potential of ABA receptor antagonism to disrupt thermoinhibition using antabactin (ANT), a broad-spectrum high-affinity receptor antagonist. We show low μM ANT treatments (10 μM) during lettuce seed imbibition reduces thermoinhibition at temperatures of up to 40°C, demonstrating that ABA signaling is required for thermoinhibition and that receptor antagonists are well-suited anti-thermoinhibition agents. We further explored interactions between ANT and seed priming, which is used commercially to improve seed germination and reduce thermoinhibition and is achieved by partial hydration and subsequent desiccation of seeds. We show that co-priming with ANT improves germination at elevated temperatures better than priming alone, and thus, the two treatments can be combined to improve germination. Our data demonstrate that ABA antagonists are potentially useful agrochemical leads for mitigating the effects of high temperatures on seed germination and stand establishment that may be of increasing importance due to climate change. More generally, ABA antagonists should be useful in physiological processes where ABA's effects are counterproductive to yield.

Neutrophil prime unique transcriptional responses in intestinal organoids during infection with nontyphoidal Salmonella enterica serovars.

Nontyphoidal strains of Salmonella enterica are a major cause of foodborne illnesses, and infection with these bacteria results in inflammatory gastroenteritis. Polymorphonuclear leukocytes (PMNs), also known as neutrophils, are a dominant immune cell type found at the site of infection in Salmonella-infected individuals, but how they regulate infection outcome is not well understood. Here, we used a co-culture model of primary human PMNs and human intestinal organoids to probe the role of PMNs during infection with two of the most prevalent Salmonella serovars: Salmonella enterica serovar Enteritidis and Typhimurium. Using a transcriptomics approach, we identified a dominant role for PMNs in mounting differential immune responses including production of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. We also identified specific gene sets that were induced by PMNs in response to Enteritidis or Typhimurium infection. By comparing host responses to these serovars, we uncovered differential regulation of host metabolic pathways particularly induction of cholesterol biosynthetic pathways during Typhimurium infection and suppression of RNA metabolism during Enteritidis infection. Together, these findings provide insight into the role of human PMNs in modulating different host responses to pathogens that cause similar disease in humans.IMPORTANCENontyphoidal serovars of Salmonella enterica are known to induce robust recruitment of polymorphonuclear leukocytes (PMNs) in the gut during early stages of infection, but the specific role of PMNs in regulating infection outcome of different serovars is poorly understood. Due to differences in human infection progression compared to small animal models, characterizing the role of PMNs during infection has been challenging. Here, we used a co-culture model of human intestinal organoids with human primary PMNs to study the role of PMNs during infection of human intestinal epithelium. Using a transcriptomics approach, we define PMN-dependent reprogramming of the host response to Salmonella, establishing a clear role in amplifying pro-inflammatory gene expression. Additionally, the host response driven by PMNs differed between two similar nontyphoidal Salmonella serovars. These findings highlight the importance of building more physiological infection models to replicate human infection conditions to study host responses specific to individual pathogens.

Does affective processing require awareness? On the use of the Perceptual Awareness Scale in response priming research.

Masked priming paradigms are frequently used to shine light on the processes of nonconscious cognition. Introducing a new method to this field, Lähteenmäki et al. (2015) claimed that affective priming requires awareness. Specifically, they administered a subjective rating task after the priming task in each trial to directly assess awareness of the prime. Their main result was a lack of priming for subjectively unaware primes. In four experiments, we compared their method with the traditional paradigm, that is, a single-task priming phase followed by a direct test of prime recognition. We used faces with anger versus sadness expressions as primes and targets; emotion categorization was the task. In contrast to Lähteenmäki et al., primes and targets were drawn from different sets, such that priming effects can be unequivocally attributed to the processing of evaluative features. In Experiments 1a, b, we followed their approach of using different prime durations to produce variance in awareness ratings. With a duration of 40 ms, significant priming effects for subjectively unaware primes were found. This duration was also associated with priming effects in the traditional paradigm with near-zero objective prime categorization, suggesting that priming does not require awareness. In Experiment 2a, employing a constant 40-ms duration, we replicated the traditional effect. However, the parallel Experiment 2b with subjective awareness ratings produced a null result at a sharply increased response time level. We conclude that the claim that affective processing requires awareness is not justified. Subjective trial-by-trial visibility ratings can severely alter processing strategies in response priming paradigms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Linking symbioses with intrinsic chemical defences in conifers: Fungal‐mediated resistance against an invasive pathogen

Abstract Invasive pathogens threaten the sustainability of forest ecosystems globally. Trees possess intrinsic pathogen defence mechanisms, including major gene resistance (MGR) and quantitative disease resistance (QDR). Plant‐symbiotic fungi can enhance tree defences, generating far‐reaching ecosystem impacts. However, the specific contributions of various fungal guilds to this symbiont‐mediated resistance remain unclear. In this study, we inoculated six Pinus monticola seedling families exhibiting resistance (MGR or QDR) or high susceptibility to the introduced invasive pathogen Cronartium ribicola, the causative agent of white pine blister rust (WPBR), with endophytic and ectomycorrhizal fungi, either alone or in combination (symbiont treatments), in an open‐air greenhouse study. Over a period of 25 months, we monitored the growth, foliar terpene defences, and disease progression in trees before and after C. ribicola infection and in trees inoculated with the symbionts but never inoculated with C. ribicola. We observed enhanced inducible host defences and evidence of defensive priming in response to symbiont treatments. In WPBR‐free control treatments, differences in pine defences coincided with an increased seedling growth rate. For WPBR‐infected seedlings, symbiont treatments reduced disease symptoms in seedlings with QDR and to a lesser extent in susceptible families, but not in those with MGR. Furthermore, disease symptoms correlated with variations in terpene composition. Synthesis and applications: Interactions with fungal symbionts should be considered when breeding native trees for resistance against invasive pathogens. Our study underscores the capacity of endophytic and ectomycorrhizal fungi to enhance tree growth and defence while also reducing disease symptoms. We also show that fungi can induce long‐lasting changes in conifer foliar terpenes, suggesting potential applications in tree protection from invasive pathogens.

Supplemental Material for Does Affective Processing Require Awareness? On the Use of the Perceptual Awareness Scale in Response Priming Research

Supplemental Material for Does Affective Processing Require Awareness? On the Use of the Perceptual Awareness Scale in Response Priming Research

Multi-site Ultrasound-guided Fine Needle Aspiration to Study Cells and Soluble Factors From Human Lymph Nodes.

Lymph nodes (LNs) are specialized secondary lymphoid tissues essential to the priming and maintenance of adaptive immune responses, including the B cell germinal center response; thus, they are central to immunity. However, the anatomically restricted and time-resolved nature of immune priming means that sampling disease-relevant human LNs requires specialized techniques. This article describes the application of ultrasound-guided fine-needle aspiration (FNA) to sample LNs, using cervical LNs of the head and neck as an exemplar. This minimally invasive technique allows collection of both immune cells and cell-free material that are relevant to both neuroimmune diseases and basic lymphatic functions. Downstream use of cellular material can include multiplexed flow cytometry, single-cell transcriptome sequencing (RNA-seq), and B cell cultures. The cell-free supernatant can be used for proteomics or other similar 'omics approaches. This unit describes collection of samples by FNA as well as processing and storage of samples for downstream assays. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Sampling of human cervical lymph nodes by ultrasound-guided fine-needle aspiration Alternate Protocol: Sampling of human lymph nodes by ultrasound-guided fine-needle aspiration with negative pressure Basic Protocol 2: Processing and storage of human lymph node samples.

β-aminobutyric acid does not induce defenses or increase Norway spruce resistance to the bluestain fungus Grosmannia penicillata.

Priming of Norway spruce (Picea abies) inducible defenses is a promising way to protect young trees from herbivores and pathogens. Methyl jasmonate (MeJA) application is known to induce and potentially prime Norway spruce defenses but may also reduce plant growth. Therefore, we tested β-aminobutyric acid (BABA) as an alternative priming chemical to enhance spruce resistance, using 2-year-old Norway spruce plants. We compared inducible defense responses, i.e. traumatic resin duct formation and accumulation of defensive metabolites, in bark and xylem tissues of BABA- or MeJA-treated plants before and after wounding. We also evaluated the effect of these chemical treatments on Norway spruce resistance to the pathogenic bluestain fungus Grosmania penicilliata. BABA did not induce defense responses or pathogen resistance, it even reduced concentrations of total terpenes in the treated plants. In contrast, MeJA induced traumatic resin duct formation, accumulation of flavonoids, pathogen resistance, and did not affect plant growth. For the first time, flavan-3-ols (catechins) were shown to have a primed response to MeJA treatment in Norway spruce. Our results indicated that BABA is not a suitable alternative priming chemical to MeJA in Norway spruce.

G-Quadruplex Structures as Epigenetic Regulatory Elements in Priming of Defense Genes upon Short-Term Trichoderma atroviride Inoculation in Maize.

Symbiosis establishment between Trichoderma atroviride and plant roots triggers the priming of defense responses, among other effects. Currently, there is no clear evidence regarding the molecular mechanisms that allow the plant to remain alert to future stimulus, either by pathogen attack or any other abiotic stress. Epigenetic modifications have emerged as a strategy to explain the increased defense response of plants in a priming state conferred by Trichoderma. Recently, various non-canonical structures of nucleic acids, especially G-quadruplex structures (G-quadruplexes or G4s), have been identified as potential targets during the establishment or maintenance of plant signals. In the present study, we developed a screening test for the identification of putative G4-forming sequences (PQSs) in previously identified Z. mays priming genes. Bioinformatic analysis revealed the presence of PQSs in the promoter region of five essential genes playing a critical role in priming in maize. Biophysical and spectroscopy studies showed the formation of G4s by these PQSs in vitro, and ChIP assays demonstrate their formation in vivo. Therefore, G4 formation could play a role as an epigenetic regulatory mechanism involved in the long-lasting primed state in maize plants.

Transcriptomics reveals the regulation of the immune system of the mushroom-forming fungus Schizophyllum commune during interaction with four competitors

Mushroom-forming fungi frequently encounter competitors during their lifecycle, but their defense mechanisms remain largely unexplored. We studied the response of the mushroom-forming fungus Schizophyllum commune during interaction with the fungal competitors Trichoderma harzianum, Trichoderma aggressivum and Purpureocillium lilacinum and the bacterial competitor Serratia quinivorans. Transcriptomics revealed 632 up-regulated genes in the direct interaction zone, which were enriched in small secreted proteins and transporters. A set of 26 genes were up-regulated during all interactions, indicating a core transcriptomic defense response. In the non-interacting edge of the mycelium of S. commune, there were 154 up-regulated genes, suggesting that there is a systemic response due to a signal that reaches unaffected areas. The GATA zinc finger transcription factor gene gat1 was up-regulated during interaction and a Δgat1 strain displayed increased colonization by T. harzianum. Previously linked to mushroom development, this transcription factor apparently has a dual role. Moreover, 138 genes were up-regulated during both interaction and mushroom development, indicating priming of the defense response during development to prepare the fruiting body for future interactions. Overall, we unveiled a defensive response of S. commune during interaction with fungal and bacterial competitors and identified a regulator of this response.

Unconscious Processing Contaminates Objective Measures of Conscious Perception: Evidence From the Liminal Prime Paradigm.

Assessing unconscious processing requires a valid measure of conscious perception. However, the two measures most commonly used, subjective reports and forced-choice discrimination, do not always converge: observers can discriminate stimuli rated as invisible better than chance. A debated issue is whether this phenomenon indicates that subjective reports of unawareness are contaminated by conscious perception, or that forced-choice discrimination performance is contaminated by unconscious processing. To address this question, we took advantage of a previously reported dissociation using masked response priming: for primes rated as invisible on a multi-point scale, response priming occurs only for fast trials, whereas for consciously perceived primes, response priming occurs across response times. Here, we replicated this dissociation, confirming that invisibility-reports were not contaminated by conscious perception. Crucially, we measured prime-discrimination performance within the same experiment and found above-chance performance for unseen primes. Together, these findings suggest that forced-choice discrimination performance is contaminated by unconscious processing.

The assessment of attentional bias to cleanliness stimuli in different versions of the dot-probe task: Evidence for a motivational account.

Vogt et al. (2011) investigated the role of goal-relevance in attention. Specifically, they induced the emotional state of disgust and showed an attentional bias (AB) to goal-related stimuli (i.e., cleanliness pictures) using the dot-probe task. In two experiments, we tested (a) an alternative interpretation and (b) the role of an important methodological feature of the dot-probe task. As the effect can be interpreted alternatively as affective counter-regulation (i.e., cleanliness-related pictures attracted attention because they are positive in the negative disgust state), we added positive stimuli to test whether the AB in the disgust state extends to these stimuli. In Experiment 1, we used the location dot-probe task. That is, participants had to categorise the location of the target. It can be argued that this task confounds attentional processes with response priming processes. In Experiment 2, we used a discrimination dot-probe task, that is, participants had to categorise a target feature that varied orthogonally to location, thus eliminating the confound. In Experiment 1, we did not replicate the effect of emotional state on AB for cleanliness stimuli, whereas in Experiment 2, we did. Mean AB scores for positive stimuli were not affected by emotional state. Two conclusions were drawn: First, the result of Experiment 2 supports the motivational account of Vogt and colleagues. Second, the results support the use of the discrimination task for both theoretical reasons (i.e., effects can be more clearly interpreted as based on attentional processes) and empirical reasons (i.e., the location task did not replicate the expected pattern).

Effect of Anti-PEG Antibody on Immune Response of mRNA-Loaded Lipid Nanoparticles.

Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines have been approved for use to combat coronavirus disease 2019 (COVID-19). The mRNA-LNPs contain PEG-conjugated lipids. Clinical studies have reported that mRNA-LNPs induce the production of anti-PEG antibodies, but the anti-PEG antibodies do not affect the production of neutralizing antibodies. However, the detailed influence of anti-PEG antibodies on mRNA-LNP vaccines remains unclear. Therefore, in this study, we prepared ovalbumin (OVA) as a model antigen-encoding mRNA-loaded LNP (mRNA-OVA-LNP), and we determined whether anti-PEG antibodies could affect the antigen-specific immune response of mRNA-OVA-LNP vaccination in mice pretreated with PEG-modified liposomes to induce the production of anti-PEG antibodies. After intramuscular (i.m.) injection of the mRNA-LNP, the anti-PEG antibodies did not change the expression of protein or induction of cytokine and cellular immune response but did slightly increase the induction of antigen-specific antibodies. Furthermore, repeated mRNA-LNP i.m. injection induced the production of anti-PEG IgM and anti-PEG IgG. Our results suggest that mRNA-LNP induces the production of anti-PEG antibodies, but the priming of the antigen-specific immune response of mRNA-LNP vaccination is not notably affected by anti-PEG antibodies.

Immunological responses to brain metastasis stereotactic radiosurgery in patient-matched longitudinal blood and tumour samples

BackgroundStereotactic radiosurgery (SRS) is highly effective as focal treatment for brain metastases (BrMs), but whether it can promote anti-tumour immune responses that synergise with immunotherapy remains unclear. We investigated this by examining blood samples from a clinical trial for HER2-amplified breast cancer (HER2-BC) BrMs, matched with longitudinal HER2-BC BrM samples resected from the same location in the same patient. MethodsBlood samples from 10 patients taken pre- and 7–14 days post-SRS were analysed by mass and flow cytometry. One patient received pre-operative SRS for a BrM that recurred 7 months after resection, followed by planned re-resection 8 days post-SRS. Pre- and post-SRS tumours from this patient were analysed by bulk RNAseq, multiplex immunohistochemistry (mIHC), and TCR sequencing. ResultsMonocytes, central memory CD8+ T and regulatory T cells were enriched in blood post-SRS, together with increased MHC-II expression on monocytes, conventional DCs, and monocytic MDSCs. In tumour, SRS upregulated antigen presentation, T cell proliferation and T cell co-stimulation signatures, alongside an influx of tumour-associated macrophages (TAMs) and CD4+ T cells. Specifically, TAMs and CD4+ T cells, but not CD8+ T cells, demonstrated spatial co-localisation post-SRS. These TAMs were lowly PD-L1 expressing, but CD4+ T cells showed increased PD-1 expression. A sizeable proportion of T cell clonotypes were retained post-SRS, and four clones demonstrated significant, non-stochastic expansion. ConclusionSystemic and local immunological changes in this homogenous patient cohort suggest that SRS may facilitate MHC-II-restricted T cell priming responses involving the monocyte-macrophage lineage and CD4+ T cells, which should be further explored.

Immune checkpoint blockade lowers the threshold of naïve T-cell priming to drug-associated antigens in a dose-dependent fashion.

A growing body of clinical and experimental evidence indicates that immune checkpoint blockade enhances patient susceptibility to hypersensitivity reactions to co-administered medications. In this study, we utilized an in vitro T-cell priming assay to demonstrate one of the mechanistic hypotheses on how this occurs; through lowering of the threshold in patients to elicit aberrant T-cell responses. We outline the dependency of de novo T-cell priming responses to drug-associated antigens on dose at initial exposure. Findings support the aforementioned hypothesis and offer an experimental representation of fundamental parameters at play in hypersensitivity reactions to low molecular weight compounds.

Guess what? Only correct choices forge immediate stimulus–response bindings in guessing scenarios

A central mechanism of human action control is the prompt binding between actions and the stimuli provoking them. Perceiving the same stimuli again retrieves any bound responses, facilitating their execution. An open question is whether such binding and retrieval only emerges when stimulus–response rules are known upon taking action or also when agents are forced to guess and receive feedback about whether they were successful or not afterward. In two experiments, we tested the hypothesis that knowing rules before responding would boost binding between stimuli and responses during action-taking relative to guessing situations. Second, we assessed whether the content of the feedback matters for binding in that agents might use feedback to build correct stimulus–response bindings even for wrong guesses. We used a sequential prime-probe design to induce stimulus–response binding for prime responses that were either rule-based or guesses, and to measure retrieval of these bindings in response times and errors in the probe. Results indicate that binding and retrieval emerge for successful but not for wrong guesses. Binding effects for correct guesses were consistently small in effect size, suggesting that pre-established stimulus–response bindings from instructed rules might indeed boost binding when taking action.

The Vacuolar H+-ATPase subunit C is involved in oligogalacturonide (OG) internalization and OG-triggered immunity

In plants, the perception of cell wall fragments initiates signal transduction cascades that activate the immune response. Previous research on early protein dynamics induced by oligogalacturonides (OGs), pectin fragments acting as damage-associated molecular patterns (DAMPs), revealed significant phosphorylation changes in several proteins. Among them, the subunit C of the vacuolar H+-ATPase, known as DE-ETIOLATED 3 (DET3), was selected to elucidate its role in the OG-triggered immune response. The Arabidopsis det3 knockdown mutant exhibited defects in H2O2 accumulation, mitogen-activated protein kinases (MAPKs) activation, and induction of defense marker genes in response to OG treatment. Interestingly, the det3 mutant showed a higher basal resistance to the fungal pathogen Botrytis cinerea that, in turn, was completely reversed by the pre-treatment with OGs. Our results suggest a compromised ability of the det3 mutant to maintain a primed state over time, leading to a weaker defense response when the plant is later exposed to the fungal pathogen. Using fluorescently labelled OGs, we demonstrated that endocytosis of OGs was less efficient in the det3 mutant, implicating DET3 in the internalization process of OGs. This impairment aligns with the observed defect in the priming response in the det3 mutant, underscoring that proper internalization and signaling of OGs are crucial for initiating and maintaining a primed state in plant defense responses.

Characterization of the SARS-CoV-2 antibody landscape in Norway in the late summer of 2022: high seroprevalence in all age groups with patterns of primary Omicron infection in children and hybrid immunity in adults

BackgroundAccording to Norwegian registries, 91% of individuals ≥ 16 years had received ≥ 1 dose of COVID-19 vaccine by mid-July 2022, whereas less than 2% of children < 12 years were vaccinated. Confirmed COVID-19 was reported for 27% of the population, but relaxation of testing lead to substantial underreporting. We have characterized the humoral immunity to SARS-CoV-2 in Norway in the late summer of 2022 by estimating the seroprevalence and identifying antibody profiles based on reactivity to Wuhan or Omicron-like viruses in a nationwide cross-sectional collection of residual sera, and validated our findings using cohort sera.Methods1,914 anonymized convenience sera and 243 NorFlu-cohort sera previously collected from the Oslo-area with reported infection and vaccination status were analyzed for antibodies against spike, the receptor-binding domain (RBD) of the ancestral Wuhan strain and Omicron BA.2 RBD, and nucleocapsid (N). Samples were also tested for antibodies inhibiting RBD-ACE2 interaction. Neutralization assays were performed on subsets of residual sera against B.1, BA.2, XBB.1.5 and BQ.1.1.ResultsThe national seroprevalence estimate from vaccination and/or infection was 99.1% (95% CrI 97.0-100.0%) based on Wuhan (spike_W and RBD_W) and RBD_BA2 antibodies. Sera from children < 12 years had 2.2 times higher levels of antibodies against RBD_BA2 than RBD_W and their seroprevalence estimate showed a 14.4 percentage points increase when also including anti-RBD_BA2 antibodies compared to Wuhan-antibodies alone. 50.3% (95% CI 45.0-55.5%) of residual sera from children and 38.1% (95% CI 36.0-40.4%) of all residual sera were positive for anti-N-antibodies. By combining measurements of binding- and ACE2-RBD-interaction-inhibiting antibodies, reactivity profiles indicative of infection and vaccination history were identified and validated using cohort sera. Residual sera with a profile indicative of hybrid immunity were able to neutralize newer Omicron variants XBB.1.5 and BQ.1.1.ConclusionsBy late summer of 2022, most of the Norwegian population had antibodies to SARS-CoV-2, and almost all children had been infected. Antibody profiles indicated that children mostly had experienced a primary Omicron infection, while hybrid immunity was common among adults. The finding that sera displaying hybrid immunity could neutralize newer Omicron variants indicates that Wuhan-like priming of the immune response did not have a harmful imprinting effect and that infections induce cross-reacting antibodies against future variants.

Persistent tailoring of MSC activation through genetic priming

Mesenchymal stem/stromal cells (MSCs) are an attractive platform for cell therapy due to their safety profile and unique ability to secrete broad arrays of immunomodulatory and regenerative molecules. Yet, MSCs are well known to require preconditioning or priming to boost their therapeutic efficacy. Current priming methods offer limited control over MSC activation, yield transient effects, and often induce the expression of pro-inflammatory effectors that can potentiate immunogenicity. Here, we describe a genetic priming method that can both selectively and sustainably boost MSC potency via the controlled expression of the inflammatory-stimulus-responsive transcription factor interferon response factor 1 (IRF1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFN-γ). This includes the upregulation of anti-inflammatory effector molecules and the potentiation of MSC capacities to suppress Tcell activation. However, we show that IRF1-mediated genetic priming is much more persistent than biochemical priming and can circumvent IFN-γ-dependent expression of immunogenic MHC class II molecules. Together, the ability to sustainably activate and selectively tailor MSC priming responses creates the possibility of programming MSC activation more comprehensively for therapeutic applications.

Timbral brightness perception investigated through multimodal interference

Brightness is among the most studied aspects of timbre perception. Psychoacoustically, sounds described as “bright” versus “dark” typically exhibit a high versus low frequency emphasis in the spectrum. However, relatively little is known about the neurocognitive mechanisms that facilitate these metaphors we listen with. Do they originate in universal magnitude representations common to more than one sensory modality? Triangulating three different interaction paradigms, we investigated using speeded classification whether intramodal, crossmodal, and amodal interference occurs when timbral brightness, as modeled by the centroid of the spectral envelope, and pitch height/visual brightness/numerical value processing are semantically congruent and incongruent. In four online experiments varying in priming strategy, onset timing, and response deadline, 189 total participants were presented with a baseline stimulus (a pitch, gray square, or numeral) then asked to quickly identify a target stimulus that is higher/lower, brighter/darker, or greater/less than the baseline after being primed with a bright or dark synthetic harmonic tone. Results suggest that timbral brightness modulates the perception of pitch and possibly visual brightness, but not numerical value. Semantically incongruent pitch height-timbral brightness shifts produced significantly slower reaction time (RT) and higher error compared to congruent pairs. In the visual task, incongruent pairings of gray squares and tones elicited slower RTs than congruent pairings (in two experiments). No interference was observed in the number comparison task. These findings shed light on the embodied and multimodal nature of experiencing timbre.