Complexin has a dual synaptic function as checkpoint protein in vesicle priming and as a promoter of vesicle fusion.

The presynaptic SNARE-complex regulator complexin (Cplx) enhances the fusogenicity of primed synaptic vesicles (SVs). Consequently, Cplx deletion impairs action potential-evoked transmitter release. Conversely, though, Cplx loss enhances spontaneous and delayed asynchronous release at certain synapse types. Using electrophysiology and kinetic modeling, we show that such seemingly contradictory transmitter release phenotypes seen upon Cplx deletion can be explained by an additional of Cplx in the control of SV priming, where its ablation facilitates the generation of a "faulty" SV fusion apparatus. Supporting this notion, a sequential two-step priming scheme, featuring reduced vesicle fusogenicity and increased transition rates into the faulty primed state, reproduces all aberrations of transmitter release modes and short-term synaptic plasticity seen upon Cplx loss. Accordingly, we propose a dual presynaptic function for the SNARE-complex interactor Cplx, one as a "checkpoint" protein that guarantees the proper assembly of the fusion machinery during vesicle priming, and one in boosting vesicle fusogenicity.

Minocycline and photodynamic priming significantly improve chemotherapy efficacy in heterotypic spheroids of pancreatic ductal adenocarcinoma.

The prognosis for patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) remains dismal. It is generally accepted that combination cancer therapies offer the most promise, such as Folforinox, despite their associated high toxicity. This study addresses the issue of chemoresistance by introducing a complementary dual priming approach to attenuate the DNA repair mechanism and to improve the efficacy of a type 1 topoisomerase (Top1) inhibitor. The result is a regimen that integrates drug-repurposing and nanotechnology using 3 clinically relevant FDA-approved agents (1) Top1 inhibitor (irinotecan) at subcytotoxic doses (2) benzoporphyrin derivative (BPD) as a photoactive molecule for photodynamic priming (PDP) to improve the delivery of irinotecan within the cancer cell and (3) minocycline priming (MNP) to modulate DNA repair enzyme Tdp1 (tyrosyl-DNA phosphodiesterase) activity. We demonstrate in heterotypic 3D cancer models that incorporate cancer cells and pancreatic cancer-associated fibroblasts that simultaneous targeting of Tdp1 and Top1 were significantly more effective by employing MNP and photoactivatable multi-inhibitor liposomes encapsulating BPD and irinotecan compared to monotherapies or a cocktail of dual or triple-agents. These data are encouraging and warrant further work in appropriate animal models to evolve improved therapeutic regimens.

Therapeutic trends of priming mesenchymal stem cells: A bibliometric analysis.

Mesenchymal stem cells (MSCs) have gained substantial attention in regenerative medicine due to their multilineage differentiation potential and immunomodulatory capabilities. MSCs have demonstrated therapeutic promise in numerous preclinical and clinical studies across a variety of diseases, including neurodegenerative disorders, cardiovascular diseases, and autoimmune conditions. Recently, priming MSCs has emerged as a novel strategy to enhance their therapeutic efficacy by preconditioning them for optimal survival and function in challenging in vivo environments. This study presented a comprehensive bibliometric analysis of research activity in the field of priming mesenchymal stem cells (MSCs) from 2003 to 2023. Utilizing a dataset of 585 documents, we explored research trends, leading authors and countries, productive journals, and frequently used keywords. We also explored priming strategies to augment the therapeutic efficacy of MSCs. Our findings show increasing research productivity with a peak in 2019, identified the United States as the leading contributor, and highlighted WANG JA as the most prolific author. The most published journal was Stem Cell Research & Therapy. Keyword analysis revealed core research areas emerging hotspots, while coword and cited sources visualizations elucidated the conceptual framework and key information sources. Further studies are crucial to advance the translation of primed MSCs from bench to bedside, potentially revolutionizing the landscape of regenerative medicine.

A Robust In Vitro Culture Model and Generation of Memory Monocytes.

Innate monocytes can be trained or reprogrammed to adopt distinct memory states, such as low-grade inflammation and immune exhaustion, bearing fundamental relevance to the pathogenesis of both acute diseases such as sepsis as well as chronic diseases such as atherosclerosis. Therefore, it is critically important to develop a regimen for generating memory monocytes in vitro in order to better define key monocyte memory states with diverse potentials for proliferation, differentiation, and activation, as well as underlying mechanisms. Here, we describe an efficient in vitro system to propagate a large number of highly purified murine memory monocytes through sustaining bone marrow-derived monocytes with macrophage colony-stimulating factor (M-CSF, 10 ng/mL)-containing medium, together with other polarization agents such as lipopolysaccharide (LPS) for a 5-day period. This method can yield high-purity monocytes, capable of exhibiting dynamic memory behaviors upon training with various polarizing agents.

A Comprehensive Examination of Prediction-Based Error as a Mechanism for Syntactic Development: Evidence From Syntactic Priming.

Prediction-based accounts of language acquisition have the potential to explain several different effects in child language acquisition and adult language processing. However, evidence regarding the developmental predictions of such accounts is mixed. Here, we consider several predictions of these accounts in two large-scale developmental studies of syntactic priming of the English dative alternation. Study 1 was a cross-sectional study (N = 140) of children aged 3-9 years, in which we found strong evidence of abstract priming and the lexical boost, but little evidence that either effect was moderated by age. We found weak evidence for a prime surprisal effect; however, exploratory analyses revealed a protracted developmental trajectory for verb-structure biases, providing an explanation as for why prime surprisal effects are more elusive in developmental populations. In a longitudinal study (N = 102) of children in tightly controlled age bands at 42, 48, and 54 months, we found priming effects emerged on trials with verb overlap early but did not observe clear evidence of priming on trials without verb overlap until 54 months. There was no evidence of a prime surprisal effect at any time point and none of the effects were moderated by age. The results relating to the emergence of the abstract priming and lexical boost effects are consistent with prediction-based models, while the absence of age-related effects appears to reflect the structure-specific challenges the dative presents to English-acquiring children. Overall, our complex pattern of findings demonstrates the value of developmental data sets in testing psycholinguistic theory.

Thermo-priming triggers species-specific physiological and transcriptome responses in Mediterranean seagrasses.

Heat-priming improves plants' tolerance to a recurring heat stress event. The underlying molecular mechanisms of heat-priming are largely unknown in seagrasses. Here, ad hoc mesocosm experiments were conducted with two Mediterranean seagrass species, Posidonia oceanica and Cymodocea nodosa. Plants were first exposed to heat-priming, followed by a heat-triggering event. A comprehensive assessment of plant stress response across different levels of biological organization was performed at the end of the triggering event. Morphological and physiological results showed an improved response of heat-primed P. oceanica plants while in C. nodosa both heat- and non-primed plants enhanced their growth rates at the end of the triggering event. As resulting from whole transcriptome sequencing, molecular functions related to several cellular compartments and processes were involved in the response to warming of non-primed plants, while the response of heat-primed plants involved a limited group of processes. Our results suggest that seagrasses acquire a primed state during the priming event, that eventually gives plants the ability to induce a more energy-effective response when the thermal stress event recurs. Different species may differ in their ability to perform an improved heat stress response after priming. This study provides pioneer molecular insights into the emerging topic of seagrass stress priming and may benefit future studies in the field.

Symbiotic symphony: Understanding host-microbiota dialogues in a spatial context.

Modern precision sequencing techniques have established humans as a holobiont that live in symbiosis with the microbiome. Microbes play an active role throughout the life of a human ranging from metabolism and immunity to disease tolerance. Hence, it is of utmost significance to study the eukaryotic host in conjunction with the microbial antigens to obtain a complete picture of the host-microbiome crosstalk. Previous attempts at profiling host-microbiome interactions have been either superficial or been attempted to catalogue eukaryotic transcriptomic profile and microbial communities in isolation. Additionally, the nature of such immune-microbial interactions is not random but spatially organised. Hence, for a holistic clinical understanding of the interplay between hosts and microbiota, it's imperative to concurrently analyze both microbial and host genetic information, ensuring the preservation of their spatial integrity. Capturing these interactions as a snapshot in time at their site of action has the potential to transform our understanding of how microbes impact human health. In examining early-life microbial impacts, the limited presence of communities compels analysis within reduced biomass frameworks. However, with the advent of spatial transcriptomics we can address this challenge and expand our horizons of understanding these interactions in detail. In the long run, simultaneous spatial profiling of host-microbiome dialogues can have enormous clinical implications especially in gaining mechanistic insights into the disease prognosis of localised infections and inflammation. This review addresses the lacunae in host-microbiome research and highlights the importance of profiling them together to map their interactions while preserving their spatial context.

Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors.

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, and tolerance regulate similar "signature" inflammatory genes such as TNF, IL6, and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating JAK-STAT signaling and interferon-stimulated genes, also play a key role in regulating training, priming, and tolerance via chromatin-mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-γ-mediated priming, affects regulation of AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a "training-priming continuum" model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.

Stress priming transcranial direct current stimulation (tDCS) enhances updating of emotional content in working memory.

Transcranial direct current stimulation (tDCS) targeting the prefrontal cortex has emerged as a valuable tool in psychiatric research. Understanding the impact of affective states, such as stress at the time of stimulation, on the efficacy of prefrontal tDCS is crucial for advancing tDCS interventions. Stress-primed tDCS, wherein stress is used as a priming agent, has the potential to modulate neural plasticity and enhance cognitive functions, particularly in emotional working memory. However, prior research using stress-primed tDCS focused solely on non-emotional working memory performance, yielding mixed results. In this sham-controlled study, we addressed this gap by investigating the effects of stress-primed bifrontal tDCS (active versus sham) on both non-emotional and emotional working memory performance. The study was conducted in 146 healthy individuals who were randomly assigned to four experimental groups. The Trier Social Stress Test (TSST) or a control variant of the test was used to induce a stress versus control state. The results showed that stress priming significantly enhanced the effects of tDCS on the updating of emotional content in working memory, as evidenced by improved accuracy. Notably, no significant effects of stress priming were found for non-emotional working memory performance. These findings highlight the importance of an individual's prior affective state in shaping their response to tDCS, especially in the context of emotional working memory.

Corrigendum: Mesenchymal stromal cell derived extracellular vesicles as a therapeutic tool: immune regulation, MSC priming, and applications to SLE.

[This corrects the article DOI: 10.3389/fimmu.2024.1355845.].

Multi-scale analysis of heat stress acclimation in Arabidopsis seedlings highlights the primordial contribution of energy-transducing organelles.

Much progress has been made in understanding the molecular mechanisms of plant adaptation to heat stress. However, the great diversity of models and stress conditions, and the fact that analyses are often limited to a small number of approaches, complicate the picture. We took advantage of a liquid culture system in which Arabidopsis seedlings are arrested in their development, thus avoiding interference with development and drought stress responses, to investigate through an integrative approach seedlings' global response to heat stress and acclimation. Seedlings perfectly tolerate a noxious heat shock (43°C) when subjected to a heat priming treatment at a lower temperature (38°C) the day before, displaying a thermotolerance comparable to that previously observed for Arabidopsis. A major effect of the pre-treatment was to partially protect energy metabolism under heat shock and favor its subsequent rapid recovery, which was correlated with the survival of seedlings. Rapid recovery of actin cytoskeleton and mitochondrial dynamics were another landmark of heat shock tolerance. The omics confirmed the role of the ubiquitous heat shock response actors but also revealed specific or overlapping responses to priming, heat shock, and their combination. Since only a few components or functions of chloroplast and mitochondria were highlighted in these analyses, the preservation and rapid recovery of their bioenergetic roles upon acute heat stress do not require extensive remodeling of the organelles. Protection of these organelles is rather integrated into the overall heat shock response, thus allowing them to provide the energy required to elaborate other cellular responses toward acclimation.

Prime-induced illusion of control: The influence of unconscious priming on self-initiated actions and the role of regression to the mean.

To what degree human cognition is influenced by subliminal stimuli is a controversial empirical question. One striking example was reported by Linser and Goschke (2007): participants overestimated how much control they had over objectively uncontrollable stimuli when masked congruent primes were presented immediately before the action. Critically, however, unawareness of the masked primes was established by post hoc data selection. In our preregistered study we sought to explore these findings while adjusting prime visibility based on individual thresholds, so that each participant underwent both visible and non-visible conditions. In experiment 1, N = 39 participants engaged in a control judgement task: following the presentation of a semantic prime, they freely selected between two keys, which triggered the appearance of a colored circle. The color of the circles, however, was independent of the key-press. Subsequently, participants assessed their perceived control over the circle's color, based on their key-presses, via a rating scale that ranged from 0 % (no control) to 100 % (complete control). Contrary to Linser and Goschke (2007)'s findings, this experiment demonstrated that predictive information influenced the experience of agency only when primes were consciously processed. In experiment 2, utilizing symbolic (arrow) primes, N = 35 participants had to rate their feeling of control over the effect-stimulus' identity during a two-choice identification paradigm (i.e., they were instructed to press a key corresponding to a target stimulus; with a contingency between target and effect stimulus of 75 %/25 %). The results revealed no significant influence of subliminal priming on agency perceptions. In summary, this study implies that unconscious stimuli may not exert a substantial influence on the conscious experience of agency, underscoring the need for careful consideration of methodological aspects and experimental design's impact on observed phenomena.

Shedding Light on Chemoresistance: The Perspective of Photodynamic Therapy in Cancer Management.

The persistent failure of standard chemotherapy underscores the urgent need for innovative and targeted approaches in cancer treatment. Photodynamic therapy (PDT) has emerged as a promising photochemistry-based approach to address chemoresistance in cancer regimens. PDT not only induces cell death but also primes surviving cells, enhancing their susceptibility to subsequent therapies. This review explores the principles of PDT and discusses the concept of photodynamic priming (PDP), which augments the effectiveness of treatments like chemotherapy. Furthermore, the integration of nanotechnology for precise drug delivery at the right time and location and PDT optimization are examined. Ultimately, this study highlights the potential and limitations of PDT and PDP in cancer treatment paradigms, offering insights into future clinical applications.

The Role of Attention in Category Representation.

Numerous studies have found that selective attention affects category learning. However, previous research did not distinguish between the contribution of focusing and filtering components of selective attention. This study addresses this issue by examining how components of selective attention affect category representation. Participants first learned a rule-plus-similarity category structure, and then were presented with category priming followed by categorization and recognition tests. Additionally, to evaluate the involvement of focusing and filtering, we fit models with different attentional mechanisms to the data. In Experiment 1, participants received rule-based category training, with specific emphasis on a single deterministic feature (D feature). Experiment 2 added a recognition test to examine participants' memory for features. Both experiments indicated that participants categorized items based solely on the D feature, showed greater memory for the D feature, were primed exclusively by the D feature without interference from probabilistic features (P features), and were better fit by models with focusing and at least one type of filtering mechanism. The results indicated that selective attention distorted category representation by highlighting the D feature and attenuating P features. To examine whether the distorted representation was specific to rule-based training, Experiment 3 introduced training, emphasizing all features. Under such training, participants were no longer primed by the D feature, they remembered all features well, and they were better fit by the model assuming only focusing but no filtering process. The results coupled with modeling provide novel evidence that while both focusing and filtering contribute to category representation, filtering can also result in representational distortion.

Carbon Nanomaterials for Plant Priming through Mechanostimulation: Emphasizing the Role of Shape.

The use of nanomaterials to improve plant immunity for sustainable agriculture is gaining increasing attention; yet, the mechanisms involved remain unclear. In contrast to metal-based counterparts, carbon-based nanomaterials do not release components. Determining how these carbon-based nanomaterials strengthen the resistance of plants to diseases is essential as well as whether shape influences this process. Our study compared single-walled carbon nanotubes (SWNTs) and graphene oxide (GO) infiltration against the phytopathogen Pseudomonas syringae pv tomato DC3000. Compared with plants treated with GO, plants primed with SWNTs showed a 29% improvement in the pathogen resistance. Upon nanopriming, the plant displayed wound signaling with transcriptional regulation similar to that observed under brushing-induced mechanostimulation. Compared with GO, SWNTs penetrated more greatly into the leaf and improved transport, resulting in a heightened wound response; this effect resulted from the tubular structure of SWNTs, which differed from the planar form of GO. The shape effect was further demonstrated by wrapping SWNTs with bovine serum albumin, which masked the sharp edges of SWNTs and resulted in a significant decrease in the overall plant wound response. Finally, we clarified how the local wound response led to systemic immunity through increased calcium ion signaling in distant plant areas, which increased the antimicrobial efficacy. In summary, our systematic investigation established connections among carbon nanomaterial priming, mechanostimulation, and wound response, revealing recognition patterns in plant immunity. These findings promise to advance nanotechnology in sustainable agriculture by strengthening plant defenses, enhancing resilience, and reducing reliance on traditional chemicals.

Redox regulation by priming agents towards a sustainable agriculture.

Plant are sessile organisms that are often subjected to a multitude of environmental stresses, with the occurrence of these events being further intensified by global climate change. Crop species therefore require specific adaptations to tolerate climatic variability for sustainable food production. Plant stress results in excess accumulation of reactive oxygen species (ROS) leading to oxidative stress, and loss of cellular redox balance in the plant cells. Moreover, enhancement of cellular oxidation as well as oxidative signals have recently been recognized as crucial players in plant growth regulation under stress conditions. Multiple roles of redox regulation in crop production have been well documented, and major emphasis has focused on key redox-regulated proteins and non-protein molecules, such as NAD(P)H, thioredoxins, glutathione, glutaredoxins, peroxiredoxins, ascorbate, and reduced ferredoxin. These have been widely implicated in the regulation of (epi)genetic factors modulating growth and vigor of crop plants, particularly within an agricultural context. In this regard, priming with the employment of chemical and biological agents has emerged as a fascinating approach to improve plant tolerance against various abiotic and biotic stressors. Priming in plants is a physiological process, where prior exposure to specific stressors induces a state of heightened alertness, enabling a more rapid and effective defense response upon subsequent encounters with similar challenges. Priming is reported to play an important role in the regulation of cellular redox homeostasis, maximizing crop productivity under stress conditions and thus achieving yield security. By taking this into consideration, the present review is an up-to-date critical evaluation of promising plant priming technologies and their role in the regulation of redox components towards enhanced plant adaptations to extreme unfavorable environmental conditions. The challenges and opportunities of plant priming are addressed, with the aim to encourage future research in this field towards effective application in crop stress management including horticultural species.

Fear-related associations in children of parents with an anxiety disorder.

BACKGROUND AND OBJECTIVES: Children of parents with an anxiety disorder are at elevated risk for developing an anxiety disorder themselves. According to cognitive theories, a possible risk factor is the development of schema-related associations. This study is the first to investigate whether children of anxious parents display fear-related associations and whether these associations relate to parental anxiety. METHODS: 44 children of parents with panic disorder, 27 children of parents with social anxiety disorder, and 84 children of parents without an anxiety disorder filled out the SCARED-71, and the children performed an Affective Priming Task. RESULTS: We found partial evidence for disorder-specificity: When the primes were related to their parent's disorder and the targets were negative, the children of parents with panic disorder and children of parents with social anxiety disorder showed the lowest error rates related to their parents' disorder, but they did not have faster responses. We did not find any evidence for the expected specificity in the relationship between the parents' or the children's self-reported anxiety and the children's fear-related associations, as measured with the APT. LIMITATIONS: Reliability of the Affective Priming Task was moderate, and power was low for finding small interaction effects. CONCLUSIONS: Whereas clearly more research is needed, our results suggest that negative associations may qualify as a possible vulnerability factor for children of parents with an anxiety disorder.

The priming of stimulus-elicited involuntary mental imagery.

Percepts, urges, and even high-level cognitions often enter the conscious field involuntarily. The Reflexive Imagery Task (RIT) was designed to investigate experimentally the nature of such entry into consciousness. In the most basic version of the task, participants are instructed not to subvocalize the names of visual objects. Involuntary subvocalizations arise on the majority of the trials. Can these effects be influenced by priming? In our experiment, participants were exposed to an auditory prime 300 ms before being presented with the RIT stimuli. For example, participants heard the word "FOOD" before seeing two RIT stimuli (e.g., line drawings of BANANA and CAT, with the former being the target of the prime). The short span between prime and target allowed us to assess whether the RIT effect is strategic or automatic. Before each trial, participants were instructed to disregard what they hear, and not to think of the name of any of the objects. On an average of 83% of the trials, the participants thought (involuntarily) of the name of the object associated with the prime. This is the first study to use a priming technique within the context of the RIT. The theoretical implications of these involuntary effects are discussed.

Threat priming diminishes the gaze cueing effect.

Gaze cueing effect (GCE) refers to attention orienting towards the gazed-at location, characterised by faster responses to gazed-at than non-gazed-at stimuli. A previous study investigated the effects of affective priming on GCE and reported that threatening primes enhanced GCE. However, it remains unknown whether the threat or heightened arousal potentiated GCE. We investigated how highly arousing threatening and positive primes, compared to low arousing neutral primes modulate GCE. After a brief exposure to an affective prime (pictures of threat or erotica) or a neutral prime, participants detected an asterisk validly or invalidly cued by the gaze direction of a neutral face. The results showed that the threatening primes diminished the magnitude of GCE. The highly arousing positive primes did not have an effect on GCE. Further analyses showed that, as compared to neutral priming, the reaction times after threatening primes were shortened on invalid trials. This finding was interpreted to suggest that the threatening primes enhanced goal-directed target detection and attenuated attention orienting by irrelevant gaze cues via improving executive control. In sum, the present findings indicate that threat priming modulates GCE, not because of heightened arousal but because of the threat.

Plant-Based Biostimulants for Seeds in the Context of Circular Economy and Sustainability.

Plant-based biostimulants (PBs), agents rich in bioactive compounds, are emerging as key players able to sustainably improve plant growth and crop productivity to address food security. PBs are generally applied as foliar spray or soil irrigation, while more recently, the application as seed priming treatments is being envisaged as a highly sustainable method to also improve seed quality and germination. Therefore, this review proposes to explore the use of PBs for the seeds industry, specifically discussing about the relevance of product market values, sustainable methods for their production, why and how PBs are used for seed priming, and pinpointing specific strengths and challenges. The collected research studies indicate that PBs applied to seeds result in improved germination, seedling growth, and stress tolerance, although the molecular mechanisms at work are still largely overlooked. The high variability of bioactive molecules and used sources point towards a huge reservoir of nature-based solutions in support of sustainable agriculture practices.