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Mwau, Cynthia Mwende, Patrick Weke, Bundi Ntwiga, and Joseph Makoteku Ottieno. "Phase Type Zero Truncated Poisson Lindley Distributions and their application in modeling Secondary Cancer Cases." Afrika Statistika 17, no. 1 (January 1, 2022): 3145–64. http://dx.doi.org/10.16929/as/2022.3145.199.
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L'assurance des maladies chroniques dont le cancer gagne du terrain au Kenya peu à peu. Ce pendant le traitement de ces maladies, pouvant entrainer des changements d'organes humains, tend à coûter plus cher, et en conséquence, à augmenter les primes d'assurance notablement. La modélisation de ces primes ne peut plus se faire avec des distributions ordinaires. Les méthodes utilisant des distributons zero-tronquées sont utilisées en particulier. Dans ce papier, elles sont utilisées en rapport avec des distributions Pareto, Weibul etc. Nous procédons à une comparaison de ces distributions et en proposons deux qui sont les meilleures
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Legal, Renaud. "L'influence de l'offre de soins et du niveau des primes sur la demande d'assurance complémentaire santé en France." Revue économique 60, no. 2 (2009): 441. http://dx.doi.org/10.3917/reco.602.0441.
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Okano, Kana, Jonathan Grainger, and Phillip J. Holcomb. "Rapid modulation of spoken word recognition by visual primes." Journal of Neurolinguistics 37 (February 2016): 58–67. http://dx.doi.org/10.1016/j.jneuroling.2015.09.002.
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Kellenbach, Marion L., and Patricia T. Michie. "Modulation of Event-Related Potentials by Semantic Priming: Effects of Color-Cued Selective Attention." Journal of Cognitive Neuroscience 8, no. 2 (April 1996): 155–73. http://dx.doi.org/10.1162/jocn.1996.8.2.155.
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The processing nature of N400, an event-related brain potential (ERP) component associated with semantic processing, was investigated in a paradigm combining a semantic priming lexical decision task and color-cued selective attention. Semantic priming effects on ERPs and reaction time (RT) were examined when targets and preceding semantically related primes were either both attended or both unattended, and when only either the prime or target was the focus of attention. Priming effects were determined by comparing semantically primed target ERPs (and RTs when appropriate) to their prime (in those conditions where the prime and target had the same attentional status) and/or to an unprimed control target matched to the attentional status of the primed target. Control stimuli were examined for ERP effects of color-cued selective attention unconfounded by priming factors. Experiment 1 required overt responses to words and nonwords in a binary choice task, while Experiment 2 required response only to nonwords. RTs in Experiment 1 indicated facilitatory priming effects to all semantically primed attended targets. In Experiments 1 and 2 ERPs to primes and controls were consistently more negative than the primed target trace in the N400 latency range in conditions with attended primes, suggesting priming effects on N400 are contingent on attentional processing of the prime. Removal of the attention manipulation (Experiment 3) resulted in an N400 component with a well-defined peak not evident in the first two experiments, indicating modulation of N400 by overlapping effects of attention.
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Benthien, Fenja Mareike, and Guido Hesselmann. "Does Location Uncertainty Modulate Unconscious Processing Under Continuous Flash Suppression?" Advances in Cognitive Psychology 17, no. 1 (March 2021): 3–14. http://dx.doi.org/10.5709/acp-0312-3.
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Previous research suggests that selective spatial attention is a determining factor for unconscious processing under continuous flash suppression (CFS), and specifically, that inattention toward stimulus location facilitates its unconscious processing by reducing the depth of CFS (Eo et al., 2016). The aim of our study was to further examine this modulation-by-attention model of CFS using a number priming paradigm. Participants (N = 26) performed a number comparison task on a visible target number (“compare target to five”). Prime-target pairs were either congruent (both smaller or larger than five) or incongruent. Spatial attention toward the primes was varied by manipulating the uncertainty of the primes’ location. Based on the modulation-by-attention model, we hypothesized the following: In trials with uncertain prime location, RTs for congruent prime-target pairs should be faster than for incongruent ones. In trials with certain prime location, RTs for congruent versus incongruent prime-target pairs should not differ. We analyzed our data with sequential Bayes factors (BFs). Our data showed no effect of location uncertainty on unconscious priming under CFS (BF0+ = 5.16). However, even visible primes only weakly influenced RTs. Possible reasons for the absence of robust number priming effects in our study are discussed. Based on exploratory analyses, we conclude that the numerical order of prime and target resulted in a response conflict and interfered with the predicted priming effect.
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Boukarras, Sarah, Vanessa Era, Salvatore Maria Aglioti, and Matteo Candidi. "Modulation of preference for abstract stimuli following competence-based social status primes." Experimental Brain Research 238, no. 1 (December 12, 2019): 193–204. http://dx.doi.org/10.1007/s00221-019-05702-z.
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Wu, Yan, Mengyuan Zhang, Chi Zhang, and Xuehong Tian. "Fairness-related behaviour modulation by friendship is moderated by American primes in Chinese participants." Asian Journal of Social Psychology 18, no. 4 (August 18, 2015): 299–310. http://dx.doi.org/10.1111/ajsp.12111.
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Lavigne, Frédéric, Laurent Dumercy, and Nelly Darmon. "Determinants of Multiple Semantic Priming: A Meta-analysis and Spike Frequency Adaptive Model of a Cortical Network." Journal of Cognitive Neuroscience 23, no. 6 (June 2011): 1447–74. http://dx.doi.org/10.1162/jocn.2010.21504.
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Recall and language comprehension while processing sequences of words involves multiple semantic priming between several related and/or unrelated words. Accounting for multiple and interacting priming effects in terms of underlying neuronal structure and dynamics is a challenge for current models of semantic priming. Further elaboration of current models requires a quantifiable and reliable account of the simplest case of multiple priming resulting from two primes on a target. The meta-analytic approach offers a better understanding of the experimental data from studies on multiple priming regarding the additivity pattern of priming. The meta-analysis points to the effects of prime–target stimuli onset asynchronies on the pattern of underadditivity, overadditivity, or strict additivity of converging activation from multiple primes. The modeling approach is then constrained by results of the meta-analysis. We propose a model of a cortical network embedding spike frequency adaptation, which allows frequency and time-dependent modulation of neural activity. Model results give a comprehensive understanding of the meta-analysis results in terms of dynamics of neuron populations. They also give predictions regarding how stimuli intensities, association strength, and spike frequency adaptation influence multiple priming effects.
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Godard, Marc, Yannick Wamain, and Solène Kalénine. "Do manufactured and natural objects evoke similar motor information? The case of action priming." Quarterly Journal of Experimental Psychology 72, no. 12 (July 17, 2019): 2801–6. http://dx.doi.org/10.1177/1747021819862210.
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There is considerable evidence that visually presented manipulable objects evoke motor information, supporting the existence of affordance effects during object perception. However, most arguments come from stimulus–response compatibility paradigms, raising the issue of the automaticity of affordance effects. Action priming paradigms overcome this issue but show less reliable results, possibly because affordance effects are moderated by additional factors. The present study aimed to assess whether affordance effects highlighted in action priming paradigms could be affected by object category (manufactured or natural). A total of 24 young adults performed a semantic categorisation task on natural and manufactured target objects presented after neutral (non-grasping hand postures) or action (congruent power or precision grips) primes. Results revealed a modulation of action priming effects as a function of object category. Object semantic categorisation was faster after action than neutral primes, but only for manufactured objects. Results suggest that natural and manufactured objects evoke distinct types of affordances and that action priming paradigms favour the evocation of functional affordances during object semantic categorisation. This finding fuels the debate on the nature of the motor information evoked by visual objects.
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Watkins, Kate, and Tomáš Paus. "Modulation of Motor Excitability during Speech Perception: The Role of Broca's Area." Journal of Cognitive Neuroscience 16, no. 6 (July 2004): 978–87. http://dx.doi.org/10.1162/0898929041502616.
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Studies in both human and nonhuman primates indicate that motor and premotor cortical regions participate in auditory and visual perception of actions. Previous studies, using transcranial magnetic stimulation (TMS), showed that perceiving visual and auditory speech increased the excitability of the orofacial motor system during speech perception. Such studies, however, cannot tell us which brain regions mediate this effect. In this study, we used the technique of combining positron emission tomography with TMS to identify the brain regions that modulate the excitability of the motor system during speech perception. Our results show that during auditory speech perception, there is increased excitability of motor system underlying speech production and that this increase is significantly correlated with activity in the posterior part of the left inferior frontal gyrus (Broca's area). We propose that this area “primes” the motor system in response to heard speech even when no speech output is required and, as such, operates at the interface of perception and action.
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Miozzi, Laura, Anna Maria Vaira, Federico Brilli, Valerio Casarin, Mara Berti, Alessandra Ferrandino, Luca Nerva, Gian Paolo Accotto, and Luisa Lanfranco. "Arbuscular Mycorrhizal Symbiosis Primes Tolerance to Cucumber Mosaic Virus in Tomato." Viruses 12, no. 6 (June 22, 2020): 675. http://dx.doi.org/10.3390/v12060675.
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Tomato plants can establish symbiotic interactions with arbuscular mycorrhizal fungi (AMF) able to promote plant nutrition and prime systemic plant defenses against pathogens attack; the mechanism involved is known as mycorrhiza-induced resistance (MIR). However, studies on the effect of AMF on viral infection, still limited and not conclusive, indicate that AMF colonization may have a detrimental effect on plant defenses against viruses, so that the term “mycorrhiza-induced susceptibility” (MIS) has been proposed for these cases. To expand the case studies to a not yet tested viral family, that is, Bromoviridae, we investigated the effect of the colonization by the AMF Funneliformis mosseae on cucumber mosaic virus (CMV) infection in tomato by phenotypic, physiological, biochemical, and transcriptional analyses. Our results showed that the establishment of a functional AM symbiosis is able to limit symptoms development. Physiological and transcriptomic data highlighted that AMF mitigates the drastic downregulation of photosynthesis-related genes and the reduction of photosynthetic CO2 assimilation rate caused by CMV infection. In parallel, an increase of salicylic acid level and a modulation of reactive oxygen species (ROS)-related genes, toward a limitation of ROS accumulation, was specifically observed in CMV-infected mycorrhizal plants. Overall, our data indicate that the AM symbiosis influences the development of CMV infection in tomato plants and exerts a priming effect able to enhance tolerance to viral infection.
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Roberts, James W., Simon J. Bennett, and Spencer J. Hayes. "Impression or expression? The influence of self-monitoring on the social modulation of motor contagion." Quarterly Journal of Experimental Psychology 71, no. 4 (January 1, 2018): 850–58. http://dx.doi.org/10.1080/17470218.2017.1307430.
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Social primes (pro-social, anti-social) can modulate mimicry behaviour. To date, these social modulation effects have been explained by the primed incentive to affiliate with another (Social Top-Down Response Modulation; STORM) and the primed active-self-concept leading to behaviour that is either consistent or inconsistent with the primed-construct (Active-Self account). This study was designed to explore the explanatory power of each of these accounts and thereby gain a greater understanding of how social modulation unfolds. To do this, we assessed social modulation of motor contagion in individuals high or low in self-monitoring. It was reasoned that high self-monitors would modulate mimicry according to the primed social incentive, whereas low self-monitors would modulate according to the primed active-self-concept. Participants were primed with a pro-social and anti-social cue in the first-person and third-person perspective. Next, they completed an interpersonal observation–execution task featuring the simultaneous observation and execution of arm movements that were either congruent or incongruent to each other. Results showed increased incongruent movement deviation (motor contagion) for the anti-social compared to the pro-social prime in the high self-monitors only. Findings support the STORM account of mimicry by showing observers modulate behaviour based on the social incentive underpinning an interpersonal exchange.
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Fu, Yong, Yan Ding, Taoli Zhou, Xiaolan Fu, and Wenyue Xu. "Plasmodium yoelii blood-stage primes macrophage-mediated innate immune response through modulation of toll-like receptor signalling." Malaria Journal 11, no. 1 (2012): 104. http://dx.doi.org/10.1186/1475-2875-11-104.
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Aizawa, Kei, Lawrence A. Turner, Dorothee Weihrauch, Zeljko J. Bosnjak, and Wai-Meng Kwok. "Protein Kinase C-ε Primes the Cardiac Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel to Modulation by Isoflurane." Anesthesiology 101, no. 2 (August 1, 2004): 381–89. http://dx.doi.org/10.1097/00000542-200408000-00019.
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Background Cardioprotection by volatile anesthetic-induced preconditioning is known to involve intracellular signaling pathways. Recent studies have shown that protein kinase C (PKC) plays an important role in anesthetic-induced preconditioning. In this study, the effects of the activation of specific isozymes of PKC, specifically PKC-epsilon and -delta, on the modulation of the sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channel by isoflurane were investigated. Methods The sarcKATP current was measured in ventricular myocytes isolated from guinea pig hearts using the whole cell configuration of the patch clamp technique. Peptides that induced the translocation of specific PKC isozymes were used to activate PKC-epsilon and PKC-delta. Results Under whole cell conditions, isoflurane alone was unable to elicit the opening of the sarcKATP channel. Pretreatment with the specific PKC-epsilon activator, PP106, primed the sarcKATP channel to open in the presence of isoflurane. The resulting sarcKATP current densities in the presence of 0.88 mm isoflurane were 6.5 +/- 6.0 pA/pF (n = 7) and 40.4 +/- 18.2 pA/pF (n = 7) after pretreatment with 100 and 200 nm PP106, respectively. The PKC-epsilon antagonist PP93 abolished this effect. A scrambled peptide of the PKC-epsilon activator PP105 did not prime the sarcKATP channel. The PKC-delta activator PP114 was significantly less effective in priming the sarcKATP channel. 5-Hydroxydecanoate significantly attenuated the effect of the PKC-epdsilon activator on the sarcKATP channel. In addition, immunohistochemical analysis showed that the PKC-epsilon isoform translocated to both the mitochondria and sarcolemma after anesthetic-induced preconditioning, whereas the PKC-delta isoform translocated to the mitochondria. Conclusion The PKC-epsilon isozyme primed the sarcKATP channel to open in the presence of isoflurane. The PKC-delta isozyme was significantly less effective in modulating the isoflurane effect on this channel.
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Chang, Ruohan, Xiaoting Wang, and Jinfeng Ding. "Semantic Activation in Badminton Action Processing and Its Modulation by Action Duration: An ERP Study." Brain Sciences 12, no. 11 (October 27, 2022): 1458. http://dx.doi.org/10.3390/brainsci12111458.
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Action processing is crucial for sports activities. Using event-related potentials (ERPs), the present study investigated whether semantics were activated in action processing and, if so, whether semantic activation was modulated by action duration. Badminton athletes were recruited to finish a lexical decision task following an action-semantic priming paradigm, in which short (400 ms) or long (1000 ms) action videos served as primes, and semantically congruent or incongruent action words served as targets. The ERP results showed a P300 effect, that is, larger P300 amplitudes were observed for targets primed by semantically incongruent action videos than for targets primed by semantically congruent action videos, only when the action videos were long and not when the action videos were short. Moreover, a late positive component (LPC) was only sensitive to action duration, showing that the targets primed by long action videos elicited larger LPC amplitudes compared to the targets primed by short action videos. These results suggested that semantics could be activated in action processing and that semantic activation was modulated by action duration, supporting a link between the language system and action processing.
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Diaz-Garrido, Natalia, Josefa Badia, and Laura Baldomà. "Modulation of Dendritic Cells by Microbiota Extracellular Vesicles Influences the Cytokine Profile and Exosome Cargo." Nutrients 14, no. 2 (January 14, 2022): 344. http://dx.doi.org/10.3390/nu14020344.
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Gut bacteria release extracellular vesicles (BEVs) as an intercellular communication mechanism that primes the host innate immune system. BEVs from E. coli activate dendritic cells (DCs) and subsequent T-cell responses in a strain-specific manner. The specific immunomodulatory effects were, in part, mediated by differential regulation of miRNAs. This study aimed to deepen understanding of the mechanisms of BEVs to drive specific immune responses by analyzing their impact on DC-secreted cytokines and exosomes. DCs were challenged with BEVs from probiotic and commensal E. coli strains. The ability of DC-secreted factors to activate T-cell responses was assessed by cytokine quantification in indirect DCs/naïve CD4+ T-cells co-cultures on Transwell supports. DC-exosomes were characterized in terms of costimulatory molecules and miRNAs cargo. In the absence of direct cellular contacts, DC-secreted factors triggered secretion of effector cytokines by T-cells with the same trend as direct DC/T-cell co-cultures. The main differences between the strains influenced the production of Th1- and Treg-specific cytokines. Exosomes released by BEV-activated DCs were enriched in surface proteins involved in antigen presentation and T-cell activation, but differed in the content of immune-related miRNA, depending on the origin of the BEVs. These differences were consistent with the derived immune responses.
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Maldonado, Maricela, Rebeccah J. Luu, Michael E. P. Ramos, and Jin Nam. "ROCK inhibitor primes human induced pluripotent stem cells to selectively differentiate towards mesendodermal lineage via epithelial-mesenchymal transition-like modulation." Stem Cell Research 17, no. 2 (September 2016): 222–27. http://dx.doi.org/10.1016/j.scr.2016.07.009.
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Borrero Garcia, Luis, Oliver Reiners, Alba Gonzalez-Junca, Hideho Okada, and Mary Helen Barcellos-Hoff. "RDNA-09. RADIATION PRIMES SB28 GLIOBLASTOMA FOR RESPONSE TO TGFβ AND PD-L1 NEUTRALIZING ANTIBODIES." Neuro-Oncology 21, Supplement_6 (November 2019): vi208. http://dx.doi.org/10.1093/neuonc/noz175.868.
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Abstract SB28 is a new luciferase expressing murine glioblastoma (GBM) cell line whose morphology, growth pattern, mutational burden immune infiltrate more closely resembles human GBM and is unresponsive to immunotherapy (OncoImmunology, 7:12, e1501137). Radiation therapy (RT) has the potential to improve response to combinations by multiple means: cell kill that may activate an immune response, effects on vascular system may improve drug access, induction of DNA damage that can be augmented by targeted or chemotherapy, and modulation of the tumor microenvironment. High transforming growth factor β (TGFβ) activity in most GBM, which increases with radiation, likely opposes effective therapy by endorsing an effective DNA damage response and being immunosuppressive. Here evaluated the response of SB28 to radiation in combination with PD-L1 checkpoint blockade or neutralizing TGFβ. Establishment of intracranial tumors was monitored by bioluminescence. We determined that SB28 endogenously activate TGFβ as evaluated by biomarkers. We used radiolabeled antibodies and PET-CT to demonstrate access to intracranial tumors, indicative of a compromised blood-brain barrier. TGFβ neutralizing antibody, 1D11, had little effect on tumor growth compared to mice receiving IgG control antibody (median survival control: 19 days vs 1D11: 20.5 days). A single dose of radiation of 10 Gy delivered to the tumor site increased median survival to 21 day, which was increased to 31 days in mice treated with 1D11. In a second experiment in which the radiation dose was 6 Gy, 1D11 provided no benefit. In contrast, median survival of mice treated with PD-L1 neutralizing antibodies 3 days after being irradiated with 6 Gy demonstrated increased median survival (Control: 18 day; anti-PD-L1 20.5; RT: 25 days; RT + anti- PD-L1: 28 days). Double treatment resulted in 1/7 long term survival and loss of bioluminescence indicative of tumor elimination. Thus, radiation can prime SB28 GBM for response to biological agents.
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Savotchenko, Alina, Arthur Romanov, Dmytro Isaev, Oleksandr Maximyuk, Vadym Sydorenko, Gregory L. Holmes, and Elena Isaeva. "Neuraminidase Inhibition Primes Short-Term Depression and Suppresses Long-Term Potentiation of Synaptic Transmission in the Rat Hippocampus." Neural Plasticity 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/908190.
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Neuraminidase (NEU) is a key enzyme that cleaves negatively charged sialic acid residues from membrane proteins and lipids. Clinical and basic science studies have shown that an imbalance in NEU metabolism or changes in NEU activity due to various pathological conditions parallel with behavior and cognitive impairment. It has been suggested that the decreases of NEU activity could cause serious neurological consequences. However, there is a lack of direct evidences that modulation of endogenous NEU activity can impair neuronal function. Using combined rat entorhinal cortex/hippocampal slices and a specific inhibitor of NEU, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NADNA), we examined the effect of downregulation of NEU activity on different forms of synaptic plasticity in the hippocampal CA3-to-CA1 network. We show that NEU inhibition results in a significant decrease in long-term potentiation (LTP) and an increase in short-term depression. Synaptic depotentiation restores LTP in NADNA-pretreated slices to the control level. These data suggest that short-term NEU inhibition produces the LTP-like effect on neuronal network, which results in damping of further LTP induction. Our findings demonstrate that downregulation of NEU activity could have a major impact on synaptic plasticity and provide a new insight into the cellular mechanism underlying behavioral and cognitive impairment associated with abnormal metabolism of NEU.
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Platta, Harald W., Mykhaylo O. Debelyy, Fouzi El Magraoui, and Ralf Erdmann. "The AAA peroxins Pex1p and Pex6p function as dislocases for the ubiquitinated peroxisomal import receptor Pex5p." Biochemical Society Transactions 36, no. 1 (January 22, 2008): 99–104. http://dx.doi.org/10.1042/bst0360099.
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The discovery of the peroxisomal ATPase Pex1p triggered the beginning of the research on AAA (ATPase associated with various cellular activities) proteins and the genetic dissection of peroxisome biogenesis. Peroxisomes are virtually ubiquitous organelles, which are connected to diverse cellular functions. The highly diverse and adaptive character of peroxisomes is accomplished by modulation of their enzyme content, which is mediated by dynamically operating protein-import machineries. The import of matrix proteins into the peroxisomal lumen has been described as the ATP-consuming step, but the corresponding reaction, as well as the ATPase responsible, had been obscure for nearly 15 years. Recent work using yeast and human fibroblast cells has identified the peroxisomal AAA proteins Pex1p and Pex6p as mechano-enzymes and core components of a complex which dislocates the cycling import receptor Pex5p from the peroxisomal membrane back to the cytosol. This AAA-mediated process is regulated by the ubiquitination status of the receptor. Pex4p [Ubc10p (ubiquitin-conjugating enzyme 10)]-catalysed mono-ubiquitination of Pex5p primes the receptor for recycling, thereby enabling further rounds of matrix protein import, whereas Ubc4p-catalysed polyubiquitination targets Pex5p to proteasomal degradation.
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Manske, Jill, Lucas Brand, Amanda Kastelic, and Angelene Westin. "Substance P modulation of anti-tumor responses: enhanced tumor resistance by adoptive transfer of SP-treated T cells and increased NK cell activity (50.5)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S91. http://dx.doi.org/10.4049/jimmunol.178.supp.50.5.
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Abstract Substance P (SP) is a neuropeptide that has been shown to have immunoregulatory properties including effects on mediators involved in anti-tumor immunity. In previous studies we have shown that treatment of mice with SP provides protection against tumor growth. This protection requires both T cells and NK cells, and adoptive transfer of cells from SP-treated animals can transfer tumor protection. These studies suggest a model in which SP treatment prior to tumor challenge primes immune mediators to prevent or delay tumor establishment. In this study we examined the role of NK cells and T cells in tumor protection. The cytotoxic activity of NK cells against Yac-1 targets was examined by labeling cells with annexin-V and measuring apoptotic cell death by flow cytometry. NK cells from mice treated with SP had significantly higher cytotoxic activity compared to NK cells from controls. To examine whether SP-primed T cells could increase tumor resistance, purified T cells from SP-treated donor mice were adoptively transferred into animals prior to tumor challenge. Mice adoptively transferred with T cells from SP-treated donors developed significantly fewer tumors than did controls. These results suggest that SP mediates anti-tumor immunity in part by increasing NK cytotoxic activity. Since SP-primed T cells can transfer tumor protection, these cells may play a role in this increase in NK activity.
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Wu, Chenggang, Juan Zhang, and Zhen Yuan. "Exploring Affective Priming Effect of Emotion-Label Words and Emotion-Laden Words: An Event-Related Potential Study." Brain Sciences 11, no. 5 (April 27, 2021): 553. http://dx.doi.org/10.3390/brainsci11050553.
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In order to explore the affective priming effect of emotion-label words and emotion-laden words, the current study used unmasked (Experiment 1) and masked (Experiment 2) priming paradigm by including emotion-label words (e.g., sadness, anger) and emotion-laden words (e.g., death, gift) as primes and examined how the two kinds of words acted upon the processing of the target words (all emotion-laden words). Participants were instructed to decide the valence of target words, and their electroencephalogram was recorded at the same time. The behavioral and event-related potential (ERP) results showed that positive words produced a priming effect whereas negative words inhibited target word processing (Experiment 1). In Experiment 2, the inhibition effect of negative emotion-label words on emotion word recognition was found in both behavioral and ERP results, suggesting that modulation of emotion word type on emotion word processing could be observed even in the masked priming paradigm. The two experiments further supported the necessity of defining emotion words under an emotion word type perspective. The implications of the findings are proffered. Specifically, a clear understanding of emotion-label words and emotion-laden words can improve the effectiveness of emotional communications in clinical settings. Theoretically, the emotion word type perspective awaits further explorations and is still at its infancy.
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Alfayez, Eman, Lorenzo Veschini, Monica Dettin, Annj Zamuner, Massimiliano Gaetani, Anna P. Carreca, Stevo Najman, Shahram Ghanaati, Trevor Coward, and Lucy Di Silvio. "DAR 16-II Primes Endothelial Cells for Angiogenesis Improving Bone Ingrowth in 3D-Printed BCP Scaffolds and Regeneration of Critically Sized Bone Defects." Biomolecules 12, no. 11 (November 2, 2022): 1619. http://dx.doi.org/10.3390/biom12111619.
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Bone is a highly vascularized tissue and relies on the angiogenesis and response of cells in the immediate environmental niche at the defect site for regeneration. Hence, the ability to control angiogenesis and cellular responses during osteogenesis has important implications in tissue-engineered strategies. Self-assembling ionic-complementary peptides have received much interest as they mimic the natural extracellular matrix. Three-dimensional (3D)-printed biphasic calcium phosphate (BCP) scaffolds coated with self-assembling DAR 16-II peptide provide a support template with the ability to recruit and enhance the adhesion of cells. In vitro studies demonstrated prompt the adhesion of both human umbilical vein endothelial cells (HUVEC) and human mesenchymal stem cells (hMSC), favoring endothelial cell activation toward an angiogenic phenotype. The SEM-EDS and protein micro bicinchoninic acid (BCA) assays demonstrated the efficacy of the coating. Whole proteomic analysis of DAR 16-II-treated HUVECs demonstrated the upregulation of proteins involved in cell adhesion (HABP2), migration (AMOTL1), cytoskeletal re-arrangement (SHC1, TMOD2), immuno-modulation (AMBP, MIF), and morphogenesis (COL4A1). In vivo studies using DAR-16-II-coated scaffolds provided an architectural template, promoting cell colonization, osteogenesis, and angiogenesis. In conclusion, DAR 16-II acts as a proactive angiogenic factor when adsorbed onto BCP scaffolds and provides a simple and effective functionalization step to facilitate the translation of tailored 3D-printed BCP scaffolds for clinical applications.
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Iqbal, Jameel, and Mone Zaidi. "CD38 is required for priming by TNF-α: a mechanism for extracellular coordination of cell fate." American Journal of Physiology-Renal Physiology 292, no. 4 (April 2007): F1283—F1290. http://dx.doi.org/10.1152/ajprenal.00381.2006.
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Cytokines are protein messengers that act to modulate the differentiation or activation of their target cells. Bone marrow macrophages can become activated tissue macrophages, dendritic cells, or osteoclasts depending on to which cytokines they are exposed. However, one cytokine can often induce divergent outcomes, suggesting that other signals are needed to establish the specificity of the result. We hypothesize that these signals may derive from the local environment and serve to prime cells to respond toward a specific outcome. Here, it is shown that the cytokine TNF-α is capable of affecting the fate of macrophages by upregulating the NADase CD38. CD38 upregulation primes macrophages, such that signals induced by inflammatory stimuli are augmented, while those leading to osteoclast formation are inhibited. We show that TNF-α-induced CD38 expression negatively affects the expression of osteoclast markers, while it enhances inflammatory gene expression by decreasing ERK1/2 phosphorylation and increasing NF-κB activation. Furthermore, it is shown that CD38 may reduce osteoclastogenesis and increase inflammatory gene induction by decreasing cellular histone deacetylase activity. These results provide a demonstration of how a cytokine can prime cells to differentiate toward a certain lineage or acquire enhanced activation characteristics. Since CD38 is an ectoenzyme, we suggest that the modulation of extracellular NAD+metabolism likely serves as a unique mechanism to coordinate the fate of cells within a local environment.
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Krisna Dewi, Desak Ayu, I. Nengah Sudipa, and Ni Wayan Sukarini. "THE TRANSLATION OF STATE VERBS IN GONE WITH THE WIND INTO LALU BERSAMA ANGIN : NATURAL SEMANTIC METALANGUAGE APPROACH." KULTURISTIK: Jurnal Bahasa dan Budaya 3, no. 1 (January 18, 2019): 54. http://dx.doi.org/10.22225/kulturistik.3.1.940.
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This writing aims to reveal what translation techniques are applied in translating state verbs and. to analyze how meanings are retained from source language text to target language text in the novel. It is also highlights the correlation between translation and semantic primes studies. The data focuses on the translation of state verbs taken from the novel Gone with the Wind into Lalu Bersama Angin written by Margareth Mitchell by applying the Natural Semantic Metalanguage approach. This study used a qualitative method means the data are collected by observation and note taking process. There are two main theories applied in this study they are the theory of the Natural Semantic Metalanguage (NSM) and the theory of translation techniques. NSM is used for a term of reference to break the concept or word down by using a small collection of semantic primes in order to make the differences clear among the meanings of state verbs in the form of paraphrases. The theory of translation techniques by Molina and Albir (2002) is applied in order to discuss the techniques of translation used in state verb lexicon. The result found literal translation is dominating the translation technique that indicates the direct transfer SL text word per word. There is also found translation by applying transposition involved the changes in word class. Another techniques found are modulation technique which change the point of view and discursive creation which deal with establishing a temporary equivalence that is totally unpredictable out of context and the last translation technique found: particularization technique. The findings of the meaning retained from SL text into TL text are based on the subtype of state verb and explicated comprehensively using NSM approach. The categorization of state verb including type of cognition (e.g believing), type of know (e.g remember), type of feel (e.g loved), type of see (e.g stared), type of want (e.g anxious to get). There is also found several phenomena caused by the translation process. The change of intensity of state verb is the one from a higher intensity of meaning to a lower in accordance with the context such as from SL text stared into TL text menatap. The change of type of state verb also found; from type of feel into the type of want such as anxious into menginginkan.
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Berger, Alexander, Simon Sanwald, Christian Montag, and Markus Kiefer. "The Influence of the BDNF Val66Met Polymorphism on Mechanisms of Semantic Priming: Analyses with Drift-Diffusion Models of Masked and Unmasked Priming." Advances in Cognitive Psychology 17, no. 1 (March 2021): 70–87. http://dx.doi.org/10.5709/acp-0318-z.
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Automatic and strategic processes in semantic priming can be investigated with masked and unmasked priming tasks. Unmasked priming is thought to enable strategic processes due to the conscious processing of primes, while masked priming exclusively depends on automatic processes due to the invisibility of the prime. Besides task properties, interindividual differences may alter priming effects. In a recent study, masked and unmasked priming based on mean response time (RT) and error rate (ER) differed as a function of the BDNF Val66Met polymorphism (Sanwald et al., 2020). The BDNF Val66Met polymorphism is related to the integrity of several cognitive executive functions and might thus influence the magnitude of priming. In the present study, we reanalyzed this data with drift-diffusion models. Drift-diffusion models conjointly analyze single trial RT and ER data and serve as a framework to elucidate cognitive processes underlying priming. Masked and unmasked priming effects were observed for the drift rates ν, presumably reflecting semantic preactivation. Priming effects on nondecision time t0 were especially pronounced in unmasked priming, suggesting additional conscious processes to be involved in the t0 modulation. Priming effects on the decision thresholds a may reflect a speed-accuracy tradeoff. Considering the BDNF Val66Met polymorphism, we found lowered drift rates and decision thresholds for Met allele carriers, possibly reflecting a superficial processing style in Met allele carriers. The present study shows that differences in cognitive tasks between genetic groups can be elucidated using drift-diffusion modeling.
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Ong, C. P. "A Scientific Perspective of the Three Harmony Principle of Taijiquan." Journal of Integrative Medicine 11, no. 1 (June 27, 2022): 12. http://dx.doi.org/10.30564/jim.v11i1.4654.
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The Three Harmony Principle helps to regulate whole-body motion in harmony by balancing and aligning the movements of the body segments. Taijiquan uses the fangsong-relaxtion modality to resolve the switching back and forth of the active muscle forces and the passive tensional forces of tendons, ligaments and fascial tissues. Fangsong induces the modulation of the muscles to resettle in a better state of balance, thus is necessarily a manipulation of the fascial tissues enveloping the muscles, organs and structures. In so doing, fangsong-relaxation cultivates the cognition and sensation of the fascial tensional network, which traditional Taiji theory refers to as Qi. Taijiquan harnesses Qi in the discipline of body motion to balance and align the momenta of the body segments in force transmission. This gives rise to maximal force potential in balance—the force of neijin (internal strength)—in response of application. Crucially, the settling into balance by fangsong functions as a neutral countermovement in the stretch-shorten cycle that primes the muscle-tendon unit in an ever-ready state of action, which endows neijin with the liveliness of response. Secondly, the fangsong manipulation of the fascial tissues serves as a fascial massage and release that provides relief to chronic pain syndrome caused by tenseness of muscles and fascia, a therapy that accrues with the many health benefits of Taijiquan. Lastly, but not least, the attentiveness required in the fangsong process develops into the meditation component of the practice which brings tranquility and the insight of mindfulness. Taijiquan thus bestows the triple gems of neijin, health well-being, and equanimity.
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Gentsch, Antje, and Simone Schütz-Bosbach. "I Did It: Unconscious Expectation of Sensory Consequences Modulates the Experience of Self-agency and Its Functional Signature." Journal of Cognitive Neuroscience 23, no. 12 (December 2011): 3817–28. http://dx.doi.org/10.1162/jocn_a_00012.
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The ability to recognize oneself in voluntary action is called the sense of agency and refers to the experience of causing one's own actions and their sensory consequences. This form of self-awareness is important not only for motor control but also for social interactions and the ascription of causal responsibility. Here, we examined the sense of agency at early and prereflective stages of action perception using ERPs. Subjects performed a visual forced-choice response task in which action effects were either caused by the subject or by the computer. In addition, to modulate the conscious experience of agency, action effects were subliminally primed by the presentation of congruent, incongruent, or neutral effect stimuli before the action. First, we observed sensorimotor attenuation in the visual ERP selectively for self-generated action effects. That is, the N1 component, a negative deflection around 100 msec after a visual stimulus, was smaller in amplitude for visual effects caused by the subject as compared with effects caused by the computer. Second, congruent effect priming enhanced the explicit judgment of agency and further reduced the N1 amplitude for self-generated effects, although effect primes were not consciously processed. Taken together, these results provide evidence of a top–down modulation of sensory processing of action effects by prior effect information and support the neurophysiological mechanism of sensorimotor attenuation as underlying self-registration in action. Our findings suggest that both efferent information and prior thoughts about the action consequence provide important cues for a prereflective form of the experience of being an agent.
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Low, Justin, Vidya Chandramohan, Michelle Bowie, Michael Brown, Matthew Waitkus, Aaron Briley, Kevin Stevenson, et al. "BSCI-20 STING EPIGENETIC SILENCING IN GLIOMAS CAN BE RESCUED BY METHYLTRANSFERASE INHIBITION: IMPLICATIONS FOR NOVEL THERAPEUTIC APPROACHES." Neuro-Oncology Advances 4, Supplement_1 (August 1, 2022): i5. http://dx.doi.org/10.1093/noajnl/vdac078.018.
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Abstract The stimulator of interferon genes (STING) is a key component of the innate immune response to pathogenic cytosolic DNA, resulting in IRF3- and NFκB-dependent transcription of type I interferons (IFN) and pro-inflammatory cytokines. STING activation primes endogenous antitumor immunity and is disrupted in a variety of cancers. Here we investigate STING signalling in glioblastoma (GBM) patient samples. STING agonist treatment of ex vivo gliomas leads to inconsistent induction of type I IFN responses that are restricted to tumor associated myeloid cells. Indeed, single-cell transcriptome and multiplex immunofluorescence analyses demonstrate that STING expression is suppressed in neoplastic cells but not tumor-associated immune cells or stroma. Methylation analyses reveal a STING promoter region that is highly methylated in bulk tumor samples from glioma and other neuroectoderm-derived cancers, but not in most extracranial cancers. Methylation in this region strongly correlates inversely with STING RNA expression. STING epigenetic silencing is also present in normal fetal and adult brains. We demonstrate that STING expression in glioma cell lines may be rescued by decitabine, a DNA methyltransferase inhibitor (DNMTi) that is commonly used to treat hematologic malignancies. However, transduction of a STING-expressing vector into these glioma cell lines is insufficient to reconstitute STING signalling, suggesting that additional decitabine-stimulated mechanisms are necessary for STING pathway rescue. Collectively, our results suggest that epigenetic silencing of STING occurs early in brain development and may provide an immunosuppressive context for the genesis of brain tumors. Furthermore, our work raises the potential of epigenetic modulation to reconstitute STING signalling as a therapeutic strategy for glioblastoma and potentially other STING-silenced, immunologically-cold cancers.
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Carbone, Carmine, Geny Piro, Antonio Agostini, Pietro Delfino, Francesco De Sanctis, Vincenzo Nasca, Francesco Spallotta, et al. "Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer." Journal for ImmunoTherapy of Cancer 9, no. 9 (September 2021): e002876. http://dx.doi.org/10.1136/jitc-2021-002876.
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BackgroundComplex tumor and immune microenvironment render pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint inhibitors (ICIs). Therefore, a strategy to convert the immune hostile into an immunopermissive tumor is required. Recent studies showed that intratumoral injection of Toll-like receptor 9 agonist IMO-2125 primes the adaptive immune response. Phase I and II trials with intratumoral IMO-2125 demonstrated its safety and antitumoral activity.MethodsWe generated an array of preclinical models by orthotopically engrafting PDAC-derived cell lines in syngeneic mice and categorized them as high, low and no immunogenic potential, based on the ability of tumor to evoke T lymphocyte or NK cell response. To test the antitumor efficacy of IMO-2125 on locally treated and distant sites, we engrafted cancer cells on both flanks of syngeneic mice and treated them with intratumoral IMO-2125 or vehicle, alone or in combination with anti-PD1 ICI. Tumor tissues and systemic immunity were analyzed by transcriptomic, cytofluorimetric and immunohistochemistry analysis.ResultsWe demonstrated that intratumoral IMO-2125 as single agent triggers immune system response to kill local and distant tumors in a selected high immunogenic subtype affecting tumor growth and mice survival. Remarkably, intratumoral IMO-2125 in combination with systemic anti-PD1 causes a potent antitumor effect on primary injected and distant sites also in pancreatic cancer models with low immunogenic potential, preceded by a transition toward an immunopermissive microenvironment, with increase in tumor-infiltrating dendritic and T cells in tumor and lymph nodes.ConclusionWe demonstrated a potent antitumor activity of IMO-2125 and anti-PD1 combination in immunotherapy-resistant PDAC models through the modulation of immune microenvironment, providing the rationale to translate this strategy into a clinical setting.
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Espinosa-Garcia, Claudia, Fahim Atif, Seema Yousuf, Iqbal Sayeed, Gretchen N. Neigh, and Donald G. Stein. "Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury." International Journal of Molecular Sciences 21, no. 11 (May 26, 2020): 3740. http://dx.doi.org/10.3390/ijms21113740.
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NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.
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McColl, S. R., E. Krump, P. H. Naccache, P. E. Poubelle, P. Braquet, M. Braquet, and P. Borgeat. "Granulocyte-macrophage colony-stimulating factor increases the synthesis of leukotriene B4 by human neutrophils in response to platelet-activating factor. Enhancement of both arachidonic acid availability and 5-lipoxygenase activation." Journal of Immunology 146, no. 4 (February 15, 1991): 1204–11. http://dx.doi.org/10.4049/jimmunol.146.4.1204.
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Abstract Granulocyte-macrophage CSF (GM-CSF) primes human neutrophils for increased functional responsiveness to a variety of inflammatory agonists. In the present report, we have investigated the effect of human GM-CSF on the ability of platelet-activating factor (PAF) to induce the synthesis of 5-lipoxygenase products in human neutrophils. Human neutrophils stimulated with PAF in the range of 10(-5) to 10(-7) M for 15 min released small quantities of leukotriene B4 and its omega-oxidation products, 20-OH- and 20-COOH-leukotriene B4 in amounts that were detectable by enzyme immunoassay. Preincubation of normal peripheral blood neutrophils with human rGM-CSF enhanced the synthesis of the 5-lipoxygenase products in a time- and dose-dependent manner. Treatment with GM-CSF enabled their detection in response to lower concentrations of PAF (greater than or equal to 10(-9) M). The PAF receptor antagonist BN52021 inhibited the synthesis of 5-lipoxygenase products by GM-CSF-treated neutrophils in response to PAF. In addition to its effect on PAF-induced leukotriene synthesis, GM-CSF also augmented intracellular calcium mobilization by PAF. This observation prompted us to examine the effect of GM-CSF on two calcium-dependent events that are essential for leukotriene synthesis, arachidonic acid liberation, and 5-lipoxygenase activation. GM-CSF by itself, did not directly activate either of these two processes, however, it consistently and markedly enhanced the ability of PAF to do so. These results indicate that preincubation of peripheral blood neutrophils with GM-CSF enhances the ability of PAF to stimulate leukotriene synthesis by increasing both arachidonic acid availability and 5-lipoxygenase activation in response to PAF. These observations provide additional evidence of an important role for GM-CSF in the modulation of inflammatory responses to endogenous agonists through enhancement of the production of potent cellular inflammatory mediators such as leukotrienes.
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Reiner, N. E., W. Ng, C. B. Wilson, W. R. McMaster, and S. K. Burchett. "Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1." Journal of Clinical Investigation 85, no. 6 (June 1, 1990): 1914–24. http://dx.doi.org/10.1172/jci114654.
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Kim, Chihwa, Wu Wan, Rui Liu, Magdalena Kucia, Janina Ratajczak, and Mariusz Z. Ratajczak. "An Unexpected Role for the Complement C5b-C9 Membrane Attack Complex (MAC) In Trafficking of Hematopoietic Stem/Progenitor Cells - a Novel Unexpected Link Between Innate Immunity and Hematopoiesis." Blood 116, no. 21 (November 19, 2010): 555. http://dx.doi.org/10.1182/blood.v116.21.555.555.
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Abstract Abstract 555 We previously reported that complement cascade (CC) is activated in bone marrow (BM) during mobilization of hematopoietic stem/progenitor cells (HSPCs; Blood 2003;101:3784; Blood 2004;103:2071; and Blood 2005;105:40) and that C5 cleavage fragments direct egress of HSPCs from BM into peripheral blood (PB) (Leukemia 2009;23:2052 and Leukemia 2010;24:976). Accordingly, C5 cleavage fragments (C5a and desArgC5a) stimulate myeloid cells in BM to secrete proteolytic enzymes and chemoattract granulocytes into peripheral blood (PB). Therefore, granulocytes form a first wave of cells that permeabilize the BM-PB endothelial barrier and prime it for subsequent egress of HSPCs. We have also observed that activation of the distal part of the complement cascade (CC), which leads to formation of C5b-C9 (also known as the membrane attack complex [MAC]), is crucial for egress/mobilization of HSPCs. It is known that proteins that form MAC can be inserted into cell membranes, resulting in cell lysis, or may remain in biological fluids as soluble MAC (sMAC) and in this “non-lytic” form may interact with target cells. We have already reported that sMAC releases bioactive lipid - sphingosine-1 phosphate (S1P) from erythrocytes, which is a major chemoattractant in mobilized peripheral blood (mPB) for HSPCs (Leukemia 2010;24:976). Since the level of sMAC increases in PB during mobilization as well as following conditioning for transplantation, we became interested in whether this protein complex affects the biology of normal HSPCs. First, we observed that, while sMAC does not affect proliferation and viability of clonogenic progenitors, it activates phosphorylation of MAPKp42/44 and AKT in both human CD34+ and murine SKL cells. Furthermore, sMAC primes and enhances chemotactic responsiveness of HSPCs to S1P and SDF-1 gradients and increases adhesiveness of these cells to BM stroma and endothelium. This effect is probably lipid raft mediated, because exposure of cells to methylo-b-cyclodextrin before chemotaxis abrogates this phenomenon. We also found that HSPCs, as well as PB mononuclear cells exposed to sMAC, secrete increased levels of PGE2 and metalloproteinases, which indicates that an increase in sMAC level in PB after conditioning for transplantation may enhance the homing properties of HSPCs. Thus, our results in toto provide novel evidence that sMAC is an underappreciated and potent regulator of HSPC trafficking and plays an important role, both direct and indirect (via released from cells S1P), in mobilization and homing of HSPCs after transplantation. In support of this notion, we found that mice displaying defects in CC activation and sMAC generation display a defect in homing of HSPCs. Thus, our data provide yet more evidence that innate immunity and the complement cascade regulate trafficking of HSPCs by (1) releasing active C3 and C5 cleavage fragments that increase the level of bioactive lipids chemoattractants in PB and BM and by (2) modulating the migratory properties of HSPCs with sMAC. We propose modulation of CC as a novel strategy for controlling both mobilization and homing of HSPCs. Disclosures: No relevant conflicts of interest to declare.
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Li, Baorong, Yingmiao Liu, Cong Zhang, Yan Kou, Lili Zou, Hui Liang, Li Hou, et al. "Neutrophil Extracellular Traps Enhance Procoagulant Activity in Patients with Oral Squamous Cell Carcinoma." Blood 132, Supplement 1 (November 29, 2018): 2399. http://dx.doi.org/10.1182/blood-2018-99-115737.
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Abstract Background: Cancer patients are considered to be prothrombotic with major disturbances in hemostasis that are associated with an increased risk of venous thromboembolism, especially in patients with advanced cancer. Recently reports show that the high levels of circulating microparticles (MPs) have procoagulant activity (PCA) in oral squamous cell carcinoma (OSCC). However, this study did not address the question of what specific mechanism might underlie the PCA in OSCC. Neutrophil extracellular traps (NETs) are activated neutrophil-derived web-like structures, which have emerged as important mediators in cancer progression, metastasis and cancer-associated thrombosis. Additionally, the cytokines and neutrophils were known to become aggregated in cancers and are usually present in high numbers in OSCC patients and are associated with poor outcomes. The exact molecular mechanisms responsible for modulation of neutrophils procoagulant functions in OSCC are, however, poorly understood. Thus, we hypothesized that cytokines might activate neutrophils to release NETs, thereby predisposing OSCC patients to a hypercoagulative state. Moreover, we evaluated NETs interaction with human umbilical vein endothelial cells (HUVECs) and their association with pathological lesions in this disease. Methods: OSCC patients (n = 58) were divided into four stages according to the 2009 guidelines of the American Joint Committee on Cancer staging classification, and compared to healthy controls (n = 25). Cell-free DNA (cf-DNA) was quantified using the Quant-iT PicoGreen dsDNA Assay Kit. ELISA was used to detect MPO-DNA complexes, TAT (thrombin-antithrombin) complexes, neutrophil elastase, nucleosomes, and cytokines. PCA of NETs was evaluated using coagulation time and purified coagulation complex and fibrin production assays. Phosphatidylserine (PS) exposure, fibrin strands, and FVa/Xa binding on cells were observed using confocal microscopy. Results:Plasma levels of NET markers in patients with stage III/IV OSCC were significantly higher than those in stage I/II patients or controls (all p<0.05), and positively correlated with thrombin-antithrombin (TAT) complex and fibrinogen levels. Interestingly, neutrophils from OSCC patients with stage III/IV were more prone to release NETs compared to those from stage I/II patients and controls. Additionally, we found that plasma from patients with stage III/IV OSCC was able to prime neutrophils to generate higher amounts of NETs than from stage I/II patients and controls. Depleting IL-8, IL-6 and TNF-a reduced plasma-enhance NETs release. In addition, NETs released by stage III/IV OSCC neutrophils significantly increased the potency of control plasma to generate thrombin and fibrin, greatly shortened the coagulation time (all p<0.05). These effects were attenuated by DNase I. Finally, isolated NETs induced ECs to lose normal morphology and retract from their cell-cell junctions, converting them to a pro-coagulant phenotype. DNase I attenuated this cytotoxicity. Conclusion s :These results suggest that OSCC creates a systemic inflammation environment that primes neutrophils to release procoagulant NETs in patients with stage III/IV OSCC. The NETs formation correlated positively with the parameters of disease severity. The information that results from these investigations may serve as a rational basis for the design of future drug intervention trials that target coagulation reactions, mechanisms and/or interactions relevant to OSCC. Disclosures No relevant conflicts of interest to declare.
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Fernandez, Matthew Emilio, Yasir Alshehry, Laura Graham, Jennifer E. Koblinski, Harry D. Bear, Doug H. Sweet, and Sandro R. da Rocha. "Abstract 6521: Macrophage-targeting immunotherapy enhances chemotherapy response in primary and metastatic triple-negative breast cancer models." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6521. http://dx.doi.org/10.1158/1538-7445.am2024-6521.
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Abstract Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks targeted treatment options. While immune checkpoint blockade leads to significant benefits in the treatment of TNBC when in combination with chemotherapy, recurrence, metastasis, and chemoresistance still remain major challenges. The purpose of this study was to assess the ability of a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri) to shift the phenotype of the tumor microenvironment (TME) in murine models of TNBC, and the potential benefit of such in enhancing standard of care chemotherapy. We focused on targeting tumor-associated macrophages (TAMs) as they are the most abundant immune infiltrate in the TNBC TME and are associated with worsening overall survival (OS) and metastasis free survival (MFS). Targeting TAMs, specifically M2-like TAMs, has been shown to inhibit tumor progression and improve OS in the clinic. We selected pexidartinib (PLX) as the CSF-1Ri of choice, given its translational potential (FDA approved) and gemcitabine (GEM) as chemotherapy, given its ability to target myeloid derived suppressor cells and M2-like TAMs. For primary TNBC we employed 4T1 mammary carcinoma cells transfected with luciferase reporter gene in BALB/c mice as an immunocompetent model. Mice were injected with 100,000 cells in the 4th mammary fat pad, and tumors established over the course of fifteen days. Mice were then exposed to daily administrations of PLX (8 mg/kg), and weekly administrations of GEM (60 mg/kg). Tumor volumes were recorded every other day. The TME was analyzed with flow cytometry (FC), immunohistochemistry (IHC), and multiplex immunofluorescence (mIF). For the metastatic model, mice were inoculated with 100,000 4T1-luc cells in the flank. On day six, mice were exposed to treatments as outlined above. Mice underwent survival surgery to remove the primary tumor on day thirteen and were then treated with adjuvant therapy. Metastasis and OS were tracked. FC analysis indicated only combination therapy (11.8% ± 2.1) significantly decreased total TAMs compared to vehicle (22% ± 2) in the primary tumor. Combination therapy also showed the greatest depletion of M2-like TAMs (2.2% ± 0.6), with a significant decrease compared to both vehicle (15.6% ± 0.4) and GEM (6.6% ± 0.9). This TME modulation was confirmed using IHC and mIF. After four cycles of treatment, combination therapy (232.9 mm3 ± 130.8) had a significant effect on tumor burden compared to GEM alone (369.7 mm3 ± 165.8), indicating a correlation between tumor phenotype and therapeutic benefit. Furthermore, combination therapy led to the greatest prolongation of MFS and OS in the resection model, indicating that combination therapy has efficacy in the neoadjuvant and adjuvant setting. In conclusion, targeting TAMs in TNBC primes the tumor for combination with chemotherapy in TNBC. Citation Format: Matthew Emilio Fernandez, Yasir Alshehry, Laura Graham, Jennifer E. Koblinski, Harry D. Bear, Doug H. Sweet, Sandro R. da Rocha. Macrophage-targeting immunotherapy enhances chemotherapy response in primary and metastatic triple-negative breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6521.
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"Hausse des primes d'assurance-maladie: seuil de tolérance atteint!" Schweizerische Ärztezeitung 86, no. 41 (October 12, 2005): 2309. http://dx.doi.org/10.4414/saez.2005.11510.
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"Hausse des primes d'assurance-maladie: seuil de tolérance atteint!" Bulletin des Médecins Suisses 86, no. 41 (October 12, 2005): 2309. http://dx.doi.org/10.4414/bms.2005.11510.
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"Assurance groupe — Réduction des primes payables par la compagnie et les employés à la suite de l'adoption de la loi de l'assurance hospitalisation du Québec." Jurisprudence du travail 17, no. 3 (January 28, 2014): 333–34. http://dx.doi.org/10.7202/1021579ar.
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Sommaire Sans pour cela que soient en rien diminués ou modifiés les bénéfices et avantages énumérés au plan d'assurance-groupe inclus dans la convention collective liant les parties, la Compagnie a le droit de diminuer sa contribution à ce plan, lorsque, par l'adoption de la Loi de l'assurance hospitalisation, l'Etat a assumé une partie des frais hospitaliers prévus par la convention collective existante. Hafner Fabrics of Canada Ltd., Granby, vs l'Union des Employés de Hafner Fabrics de Granby, Que.; M. le Juge André Montpetit, président; Me Jean-H. Gagné, C.R., arbitre patronal; Me Jean Marquis, arbitre syndical, dissident; Ministère du Travail, Province de Québec, Bulletin d'information No 1646, 1962, 18 avril 1962.
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Cypryk, Wojciech, Liliana Czernek, Katarzyna Horodecka, Jędrzej Chrzanowski, Marcin Stańczak, Katariina Nurmi, Marcelina Bilicka, et al. "Lipopolysaccharide Primes Human Macrophages for Noncanonical Inflammasome-Induced Extracellular Vesicle Secretion." Journal of Immunology, December 14, 2022. http://dx.doi.org/10.4049/jimmunol.2200444.
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Abstract Human macrophages secrete extracellular vesicles (EVs) loaded with numerous immunoregulatory proteins. Vesicle-mediated protein secretion in macrophages is regulated by poorly characterized mechanisms; however, it is now known that inflammatory conditions significantly alter both the quantities and protein composition of secreted vesicles. In this study, we employed high-throughput quantitative proteomics to characterize the modulation of EV-mediated protein secretion during noncanonical caspase-4/5 inflammasome activation via LPS transfection. We show that human macrophages activate robust caspase-4–dependent EV secretion upon transfection of LPS, and this process is also partially dependent on NLRP3 and caspase-5. A similar effect occurs with delivery of the LPS with Escherichia coli–derived outer membrane vesicles. Moreover, sensitization of the macrophages through TLR4 by LPS priming prior to LPS transfection dramatically augments the EV-mediated protein secretion. Our data demonstrate that this process differs significantly from canonical inflammasome activator ATP-induced vesiculation, and it is dependent on the autocrine IFN signal associated with TLR4 activation. LPS priming preceding the noncanonical inflammasome activation significantly enhances vesicle-mediated secretion of inflammasome components caspase-1, ASC, and lytic cell death effectors GSDMD, MLKL, and NINJ1, suggesting that inflammatory EV transfer may exert paracrine effects in recipient cells. Moreover, using bioinformatics methods, we identify 15-deoxy-Δ12,14-PGJ2 and parthenolide as inhibitors of caspase-4–mediated inflammation and vesicle secretion, indicating new therapeutic potential of these anti-inflammatory drugs.
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Lyu, Yuanyuan, Francesca Zidda, Stefan T. Radev, Hongcai Liu, Xiaoli Guo, Shanbao Tong, Herta Flor, and Jamila Andoh. "Gamma Band Oscillations Reflect Sensory and Affective Dimensions of Pain." Frontiers in Neurology 12 (January 10, 2022). http://dx.doi.org/10.3389/fneur.2021.695187.
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Pain is a multidimensional process, which can be modulated by emotions; however, the mechanisms underlying this modulation are unknown. We used pictures with different emotional valence (negative, positive, and neutral) as primes and applied electrical painful stimuli as targets to healthy participants. We assessed pain intensity and unpleasantness ratings and recorded electroencephalograms (EEGs). We found that pain unpleasantness and not pain intensity ratings were modulated by emotion, with increased ratings for negative and decreased ratings for positive pictures. We also found two consecutive gamma band oscillations (GBOs) related to pain processing from time frequency analyses of the EEG signals. The early GBO had a cortical distribution contralateral to the painful stimulus and its amplitude was positively correlated with intensity and unpleasantness ratings, but not with prime valence. The late GBO had a centroparietal distribution and its amplitude was larger for negative compared to neutral and positive pictures. The emotional modulation effect (negative vs. positive) of the late GBO amplitude was positively correlated with pain unpleasantness. The early GBO might reflect the overall pain perception, possibly involving the thalamocortical circuit, while the late GBO might be related to the affective dimension of pain and top-down-related processes.
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Gupte, Tejas M., Michael Ritt, Matthew Dysthe, Rabia U. Malik, and Sivaraj Sivaramakrishnan. "Minute-scale persistence of a GPCR conformation state triggered by non-cognate G protein interactions primes signaling." Nature Communications 10, no. 1 (October 23, 2019). http://dx.doi.org/10.1038/s41467-019-12755-9.
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Abstract Despite the crowded nature of the cellular milieu, ligand–GPCR–G protein interactions are traditionally viewed as spatially and temporally isolated events. In contrast, recent reports suggest the spatial and temporal coupling of receptor–effector interactions, with the potential to diversify downstream responses. In this study, we combine protein engineering of GPCR–G protein interactions with affinity sequestration and photo-manipulation of the crucial Gα C terminus, to demonstrate the temporal coupling of cognate and non-cognate G protein interactions through priming of the GPCR conformation. We find that interactions of the Gαs and Gαq C termini with the β2-adrenergic receptor (β2-AR), targeted at the G-protein-binding site, enhance Gs activation and cyclic AMP levels. β2-AR–Gα C termini interactions alter receptor conformation, which persists for ~90 s following Gα C terminus dissociation. Non-cognate G-protein expression levels impact cognate signaling in cells. Our study demonstrates temporal allostery in GPCRs, with implications for the modulation of downstream responses through the canonical G-protein-binding interface.
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de Gaetano, Monica, Kawthar Alghamdi, Simone Marcone, and Orina Belton. "Abstract 204: Conjugated Linoleic Acid Induces an Atheroprotective Macrophage MΦ2 Phenotype and Limits Foam Cell Formation." Arteriosclerosis, Thrombosis, and Vascular Biology 35, suppl_1 (May 2015). http://dx.doi.org/10.1161/atvb.35.suppl_1.204.
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Background: Atherosclerosis, the underlying cause of heart attack and stroke, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Although most of the mechanisms that contribute to the progression of atherosclerosis have been identified, there is limited information on those governing regression. Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds. We have previously shown that a specific CLA blend (80:20 cis-9,trans-11:trans-10,cis-12-CLA) induces regression of pre-established atherosclerosis in vivo, via modulation of monocyte/macrophage function. However, the exact mechanisms through which CLA mediates this effect remain to be elucidated. Methods: Here, we address if CLA primes monocytes towards an anti-inflammatory MΦ2 macrophage and examine the effect of individual CLA isomers and the atheroprotective blend on monocyte-macrophage differentiation cytokine generation, foam cell formation and cholesterol metabolism in human peripheral blood monocyte (HPBMC)-derived macrophages. Results: cis-9,trans-11-CLA and the atheroprotective 80:20 CLA blend regulates expression of pro-inflammatory mediators and modulates the inflammatory cytokine profile of macrophages and foam cells. In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MΦ2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression. Furthermore, this altered macrophage phenotype impacts on foam cell formation, inhibiting ox-LDL accumulation and promoting cholesterol efflux via both PPARγ and LXRα dependent pathways. Conclusion: The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.
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Yang, Wei, Jianwei Cao, Sichen Di, Wenjin Chen, Hui Cheng, Hongze Ren, Yujie Xie, et al. "Immunogenic Material Vaccine for Cancer Immunotherapy by Structure‐dependent Immune Cell Trafficking and Modulation." Advanced Materials, April 17, 2024. http://dx.doi.org/10.1002/adma.202402580.
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AbstractInherently immunogenic materials offer enormous prospects in enhancing vaccine efficacy. However, the understanding and improving material adjuvanticity remain elusive. Herein we report how the structural presentation of immunopotentiators in a material governs the dynamic dialogue between innate and adaptive immunity for enhanced cancer vaccination. We precisely manipulate the immunopotentiator manganese into six differing structures that resemble the architectures of two types of pathogens (spherical viruses or rod‐like bacteria). The results reveal that innate immune cells accurately sense and respond to the architectures, of which two outperformed material candidates (151 nm hollow spheres and hollow micro‐rods with an aspect ratio of 4.5) show higher competence in creating local pro‐inflammatory environment with promoted innate immune cell influx and stimulatory effects on multiple subsets of dendritic cells (DCs). In combination with viral peptides, model proteins or cell lysate antigens, mature CD103+ (CD8+) DCs and CD11b+ DCs induced by the outperformed micro‐rod material remarkably primes antigen‐specific CD8+ and CD4+ cytolytic T cells, respectively. The micro‐rod stimulates DCs with enriched gene signatures associated with plasmacytoid DC, potentially contributing to enhanced type‐I interferon (IFN) mediated cellular immunity. In prophylactic and therapeutic regimens, the micro‐rod adjuvanted vaccines display optimal aptitude in tumor suppression universally in four aggressive malignant murine tumor models, by promoting the infiltration of heterogeneous cytolytic effector cells while decreasing suppressive immunoregulatory populations in tumors. This study demonstrates that a rationally selected architecture of immunogenic materials potentially advances the clinical reality of cancer vaccination .This article is protected by copyright. All rights reserved
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Costello, Brendan, Sendy Caffarra, Noemi Fariña, Jon Andoni Duñabeitia, and Manuel Carreiras. "Reading without phonology: ERP evidence from skilled deaf readers of Spanish." Scientific Reports 11, no. 1 (March 4, 2021). http://dx.doi.org/10.1038/s41598-021-84490-5.
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AbstractReading typically involves phonological mediation, especially for transparent orthographies with a regular letter to sound correspondence. In this study we ask whether phonological coding is a necessary part of the reading process by examining prelingually deaf individuals who are skilled readers of Spanish. We conducted two EEG experiments exploiting the pseudohomophone effect, in which nonwords that sound like words elicit phonological encoding during reading. The first, a semantic categorization task with masked priming, resulted in modulation of the N250 by pseudohomophone primes in hearing but not in deaf readers. The second, a lexical decision task, confirmed the pattern: hearing readers had increased errors and an attenuated N400 response for pseudohomophones compared to control pseudowords, whereas deaf readers did not treat pseudohomophones any differently from pseudowords, either behaviourally or in the ERP response. These results offer converging evidence that skilled deaf readers do not rely on phonological coding during visual word recognition. Furthermore, the finding demonstrates that reading can take place in the absence of phonological activation, and we speculate about the alternative mechanisms that allow these deaf individuals to read competently.
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Pham, Vincent V., Michael Gao, Jennifer L. Meagher, Janet L. Smith, and Victoria M. D’Souza. "A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA." Communications Biology 5, no. 1 (August 15, 2022). http://dx.doi.org/10.1038/s42003-022-03734-w.
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AbstractProductive transcriptional elongation of many cellular and viral mRNAs requires transcriptional factors to extract pTEFb from the 7SK snRNP by modulating the association between HEXIM and 7SK snRNA. In HIV-1, Tat binds to 7SK by displacing HEXIM. However, without the structure of the 7SK-HEXIM complex, the constraints that must be overcome for displacement remain unknown. Furthermore, while structure details of the TatNL4-3-7SK complex have been elucidated, it is unclear how subtypes with more HEXIM-like Tat sequences accomplish displacement. Here we report the structures of HEXIM, TatG, and TatFin arginine rich motifs in complex with the apical stemloop-1 of 7SK. While most interactions between 7SK with HEXIM and Tat are similar, critical differences exist that guide function. First, the conformational plasticity of 7SK enables the formation of three different base pair configurations at a critical remodeling site, which allows for the modulation required for HEXIM binding and its subsequent displacement by Tat. Furthermore, the specific sequence variations observed in various Tat subtypes all converge on remodeling 7SK at this region. Second, we show that HEXIM primes its own displacement by causing specific local destabilization upon binding — a feature that is then exploited by Tat to bind 7SK more efficiently.
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Biermann, Mitch, Wenxuan Cai, Di Lang, Jack Hermsen, Luke Profio, Annie Shao, Tianxiao Han, et al. "Abstract 17323: Polyinosinic-Polycytidylic Acid Primes Cardiac Progenitors From Human Induced Pluripotent Stem Cells for Enhanced Cell Therapy and Cardiomyocyte Maturation." Circulation 138, Suppl_1 (November 6, 2018). http://dx.doi.org/10.1161/circ.138.suppl_1.17323.
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Cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) hold promise for disease modeling, drug discovery, and therapy, but the challenge remains to create mature cardiomyocytes like those found in the adult heart. While groups have increased the maturity of hiPS-CMs in extended culture with electrical, metabolic, and mechanical stimulation, we hypothesized that epigenetic modulation during the formation of cardiac progenitors (hiPS-CPCs) could enhance their capacity to form mature CMs. We found that priming with the innate immune agonist polyinosinic-polycytidylic acid (pIC) decreased cardiac lineage-HDAC expression during the formation of hiPS-CPCs in defined small molecule monolayer differentiation. While both untreated and primed day 5 hiPS-CPCs contained equivalent >80% purity of KDR+PDGRFα+ CPC populations, gene expression studies using RNAseq demonstrated that pIC priming enhanced the early cardiogenic and Notch signaling programs. When both groups were differentiated in basal media, primed hiPS-CPCs gave rise to more mature cardiomyocytes based on larger cell size, increased optical action potential upstroke velocity, greater oxidative metabolism, enhanced sarcomere maturation, and upregulated transcriptional markers of CM maturation including cTnI, cardiac actin, and αMHC. These maturation effects of pIC treatment were blocked by the Notch inhibitor DAPT. Most impressively, primed hiPS-CPCs improved survival as well as myocardial systolic/diastolic function in a mouse model of myocardial infarction (Figure). Conclusion: pIC-primed hiPS-CPCs with the capacity to give rise to hiPS-CMs of enhanced maturation hold promise for improved disease modeling, drug screening and cell therapy.
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Albayay, Javier, Umberto Castiello, and Valentina Parma. "The Effect of Odour Valence and Odour Detection Threshold on the Withholding and Cancellation of Reach-to-Press Responses." Chemosensory Perception, September 27, 2021. http://dx.doi.org/10.1007/s12078-021-09292-5.
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Abstract Introduction Withholding uninitiated actions and cancelling ongoing ones are two main components of response inhibition, a key element of the executive control. Inhibitory performance is sensitive to emotional contexts elicited by subliminal and supraliminal visual material. However, whether stimuli from other sensory modalities, such as odours, would equally modulate response inhibition remains unclear. Here, we aimed to assess the effect of task-irrelevant odours as a function of their valence and threshold on both action withholding and action cancellation of reach-to-press movements. Method Thirty-two healthy participants performed a Go/No-Go task that included the presentation of pleasant (orange) and unpleasant (trimethyloxazole) odour primes at supra- and sub-threshold levels; clean air was included as a control condition. The reach-to-press responses were composed of an initial release phase and a subsequent reaching phase. Results Only the supra-threshold pleasant (vs. control) odour impaired action withholding. Moreover, the pleasant (vs. control) odour—presented at both sub- and supra-threshold levels—elicited more accurate Go responses, whereas the sub- and supra-threshold pleasant and unpleasant (vs. control) odours triggered faster responses in the release phase. Additionally, only the supra-threshold pleasant (vs. unpleasant) odour impaired action cancellation in the reaching phase. Furthermore, reaching responses were slower following the supra-threshold unpleasant (vs. control) odour. Conclusions Our findings extend the sparse literature on the impact of odour stimuli on goal-directed behaviour, highlighting the role of both odour valence and threshold in the modulation of response inhibition. Implications Determining the mechanisms by which odour stimuli modulate response inhibition lays the foundations for research on odour-triggered disinhibition.
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Sampson, Oliver L., Cecilia Jay, Emily Adland, Anna Csala, Nicholas Lim, Stella M. Ebbrecht, Lorna C. Gilligan, et al. "Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents." Frontiers in Immunology 15 (February 28, 2024). http://dx.doi.org/10.3389/fimmu.2024.1329805.
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mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity.
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Michaels, Tara, and Danzil Joseph. "Investigating molecular interactions between SARS-CoV-2 spike protein variants and glucose metabolic dysregulation in beta-cells." Physiology 39, S1 (May 2024). http://dx.doi.org/10.1152/physiol.2024.39.s1.2231.
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The severity of COVID-19 disease onset is strongly linked to co-morbidities such as diabetes, with hyperglycemia an independent risk factor for mortality. Additionally, hyperglycemia alters intracellular mechanisms to induce oxidative stress and subsequently dysregulate glucose metabolic pathways such as the hexosamine biosynthetic pathway (HBP) and the formation of advanced glycation end-products (AGEs). The emergence of new-onset hyperglycemia following SARS-CoV-2 infection is a cause for concern. One possible explanation is the direct infection of the pancreas leading to damage of β-cells. Binding of SARS-CoV-2 spike (S)-protein to its primary receptor, ACE2, can be enhanced via glycosylation and/or glycation of the receptor, rendering it more susceptible to S-protein interactions. The interplay between hyperglycemia and SARS-CoV-2 infection, however, remains to be fully elucidated. The primary objective of this study is therefore to investigate the effects of hyperglycemia and SARS-CoV-2 binding on pancreatic β-cells. More specifically, we aim to determine the role(s) of AGE production and HBP-mediated O-GlcNAcylation in modulation of SARS-CoV-2 entry and accessory proteins, S-protein binding, and downstream molecular effects in cultured INS-1 β-cells under hyperglycemic conditions. We hypothesize that hyperglycemia primes host cells for SARS-CoV-2 S-protein variants via glycation (AGE) and O-GlcNAcylation (HBP) pathways to promote binding to INS-1 β-cells. INS-1 cells were exposed to 1) high glucose, glucosamine (increases HBP), and methylglyoxal (AGE precursor) and 2) recombinant S-protein (Wild type, β and δ-variants) in separate experiments. Metabolic activity (WST-1 assays) and Western blot analyses were performed to assess markers of mitochondrial oxidative phosphorylation, the AGE (RAGE) and HBP (OGT and O-GlcNAc), SARS-CoV-2 entry (ACE2, DPP4, Basigin, EEA1, VCP) and accessory proteins (TMPRSS2, ADAM10, ADAM17, Cathepsin B, CD13). Glucose-stimulated insulin response was determined using an insulin ELISA. Metabolic activity was increased by high glucose (p<0.0001), glucosamine (p<0.0001) and methylglyoxal (p<0.05) versus controls. Recombinant S-protein variants increased metabolic activity in a time, concentration and variant-dependent manner. Here, the lower (10 ng/ml) concentration showed a >4-fold increase for the β- and δ-variants (p<0.0001 versus control, respectively), while the wild type had a similar response with higher concentrations (100 and 1000 ng/ml). The endosomal protein EEA1 was significantly increased (p<0.05 versus control) in response to AGE modulation. We conclude that hyperglycemia and modulation of the HBP and AGE pathways exert differential β-cell metabolic effects and AGE induction may prime endosomal entry mechanisms for SARS-CoV-2 spike protein. The spike variants significantly stimulate metabolic activity, modulating β-cell function in an acute manner. This project is funded by the National Research Foundation (NRF) of South Africa and the South African Medical Research Council (SAMRC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.