Memory Responses Research Articles

Staphylococcus aureus lysate induces an IgE response via memory B cells in nasal polyps

Locally increased IgE levels plays a pathologic role in chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to investigate whether Staphylococcus aureus could induce aberrant IgE synthesis in CRSwNP and the potential mechanisms involved. Total IgE, IL-4, IL-5, and IL-13 concentrations in the supernatants of the cultures stimulated with S aureus lysate were assessed by ELISA. S aureus-induced cellular responses were investigated by single-cell RNA sequencing. Flow cytometry and quantitative reverse transcription PCR were used to analyze B-cell subsets and stimulated cell ε-germline transcript expression, respectively. IgE-positive B-cell and germinal center localization were assessed by immunohistochemistry and immunofluorescence. S aureus lysate induced IgE production in the supernatants of nasal polyp (NP) tissues but not in those of healthy nasal mucosa. Moreover, IgE levels increased from days 2 to 4 after stimulation, paralleling the enhanced ε-germline transcript, IL-5, and IL-13 expression. Single-cell RNA sequencing revealed that there were increased IL-5 and IL-13 in group 2 innate lymphoid cells and identified a clonal overlap between unstimulated memory B cells and S aureus-stimulated plasma cells. The enriched IgE within NPs was mainly produced by IgE-negative memory B cells. Cellular evidence indicated that the IgE memory response to S aureus might also exist in the peripheral blood of CRSwNP patients. The S aureus-induced IgE memory response was associated with elevated IgE levels in NPs, asthma, and postoperative CRSwNP recurrence. S aureus induced an IgE response via IgE-negative memory B cells in CRSwNP patients, possibly contributing to CRSwNP development.

Metabolic Syndrome‐Associated Oligodendrocyte Dysfunction and Cognitive Impairment

AbstractBackgroundOne in nine people aged 65 and older in the United States suffer from cognitive decline, including dementias such as Alzheimer’s disease (AD) and AD‐related Dementias (ADRD). A major risk factor for cognitive impairment is midlife metabolic syndrome (MetS). MetS‐associated cognitive impairment progresses in a non‐cell autonomous manner and implicates a breakdown in metabolic support. This breakdown in metabolic support is likely due to disruption of metabolic crosstalk between neurons and glia, especially oligodendrocytes. Our aim was therefore to elucidate midlife MetS effects on oligodendrocytes and subsequent impact on oligodendrocyte metabolism and cognition.MethodTo accomplish this aim, middle‐aged mice (12‐month old) were fed either standard diet (SD, 10% fat) or high‐fat diet (HFD, 60% fat) for 13 weeks, followed by full assessment of metabolic parameters and cognitive function. Oligodendrocytes were then isolated for single cell RNA‐sequencing (scRNA‐seq), and protein expression of monocarboxylate transporters (MCTs).ResultWe observed that, as expected, HFD mice gained more weight and had higher blood glucose and fat mass versus SD controls. Middle‐aged HFD mice also performed worse in puzzle box and social recognition tests, reflecting impaired executive function and impaired short‐ and long‐term memory responses. scRNA‐seq analysis identified multiple oligodendrocyte clusters. One cluster of interest contained genes involved in cognition (Fam171a2, Nrsn1, Dlgap4) and metabolism (Ldhb, Slc25a5, Cox7c, Cox17), which were differentially expressed in HFD versus SD mice. This was coupled with downregulated MCT1 protein expression in HFD mouse oligodendrocytes versus oligodendrocytes from their SD counterparts. In vitro, human oligodendrocytes treated with palmitate to mimic MetS developed insulin resistance and had downregulated MCT1 protein expression.ConclusionCollectively, these results suggest that midlife MetS impairs oligodendrocyte metabolic function, suggesting a novel mechanism underlying MetS‐associated cognitive impairment.

Advances in understanding the mechanism of action of adult vaccines.

The occurrence of herpes zoster (HZ) correlates with declining memory T cells that had responded to earlier infection with varicella-zoster virus (VZV). There are especially lower T cell responses to the single immunodominant VZV protein glycoprotein E (gE) in people over 50 years of age, although antibody responses to VZV persist. Therefore, a live attenuated zoster vaccine (ZVL) aimed at restoring T cell responses was developed. Surprisingly, a recombinant zoster vaccine (RZV) consisting of gE combined with the AS01B adjuvant system proved superior in efficacy and durability. In this issue of the JCI, Laing, Ford, and colleagues showed that both vaccines stimulated preimmunization naive CD4+ T cells, not just memory CD4+ T cells, to gE, and recruited these naive responses into the overall memory response. However, compared with ZVL, RZV stimulated this response to a much greater degree. These results will help guide development of more effective and durable vaccines for older individuals.

Abstract B131: NXC03, an AI-designed, affinity-attenuated IL-21 mutein with half-life extension enhances antitumor immunity

Abstract Background:IL-21 is a pleotropic cytokine with actions including functional programming of CD8+ T cells towards a central memory phenotype with enhanced activation, expansion and survival. Indeed, recombinant IL-21 exhibited antitumor activity in preclinical and clinical studies, but its clinical development has been hindered due to short serum half-life and high dose-limiting toxicities such as hepatotoxicity and neutropenia. We hypothesized that an IL-21 mutein with weaker binding to IL-21 receptor (IL-21R) and increased stability and half-life may achieve an optimal therapeutic index for development. Here we describe the discovery and preclinical profile of such an AI-designed IL-21-Fc fusion mutein, NXC03. Methods:We computationally evaluated ~400,000 combinatorial mutations of IL-21 to look for those with desired affinity and stability profile via multiple techniques, including direct coupling analysis and physical energy functions. Following iterative in silico and in vitro screening, we selected NXC03-9804 out of the top-20 hits and fashioned it as an IgG4 Fc fusion protein (NXC03). We measured the affinity of NXC03 to human IL-21R by biolayer interferometry and its melting temperature (Tm) by label-free nano differential scanning fluorimetry. We determined the bioactivity of NXC03 by assessing human primary T-cell proliferation and STAT3 phosphorylation (pSTAT3) in huT78 cells. We evaluated the antitumor efficacy of NXC03 alone or in combination with a murine PD-1 mAb (aPD1) in MC38 and anti-PD-1 resistant B16-F10 syngeneic tumor models in hIL21R knock-in mice. We also studied the safety profiles and pharmacokinetics of NXC03 following subcutaneous (SC) administrations in monkeys. Results:NXC03 differs from wildtype (WT) IL-21 by 4 amino acid residues and displays a unique fast-on fast-off binding kinetics to IL-21R with a 1000-fold larger KD than that of WT IL-21. It has a Tm of 62.0 °C, notably higher than that of WT IL-21 (48.5 °C). Despite a ~10-fold reduction in potency in inducing pSTAT3 in huT78 cells, NXC03 was comparable to WT IL-21 in enriching CCR7+CD45RO-CD8+ stem memory T cells (TSCM) in PBMC culture. In both MC38 and B16-F10 mouse models, NXC03 monotherapy demonstrated strong, dose-dependent antitumor activity and was more potent than WT IL-21. Combination treatment of NXC03 with aPD1 further increased efficacy compared to either alone. Fusion of NXC03 and aPD1 had similar effect. Moreover, NXC03 treatment produced lasting memory response that protected against tumor rechallenge following drug cessation. NXC03 exhibited a half-life in monkeys (14.1 h, IV; 55.5h, SC) much greater than that of WT IL-21 (0.8 h, IV). NXC03 was well tolerated with no neutropenia or hepatotoxicity observed in monkeys. Conclusion:NXC03, an AI-designed attenuated IL-21 mutein, exhibits strong antitumor activity and holds promise as an immunostimulatory agent for combination with checkpoint inhibitors. Given its excellent drug developability profile, NXC03 is being fast-tracked for development towards clinical testing. Citation Format: Puwei Yuan, Junli Liu, Fei Zhang, Ying Lei, Yanan Zhu, Songsong Gao, Fan Liu, Taylor B Guo. NXC03, an AI-designed, affinity-attenuated IL-21 mutein with half-life extension enhances antitumor immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B131.

Abstract A054: Anti-CTLA-4 generates memory T-cell with greater expansion and functionality than anti-PD-1

Abstract Blocking either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death-1 (PD-1) pathway results in distinct T-cell differentiation. We investigated the effects of anti-CTLA-4 and anti-PD-1 on memory T-cell formation in mice. Anti-CTLA-4 generates a more potent memory response than anti-PD-1. Memory T-cells generated by anti-CTLA-4 expand at a greater frequency, have greater cytokine production, and exhibit higher antitumor activity than those generated by anti-PD-1. These memory cells also more frequently differentiate into KLRG1+ effector CD8 T-cells during re-challenge. Additionally, anti-CTLA-4 generates more TCF-1+ memory-like T-cells, while anti-PD-1 results in more TOX+ terminally differentiated T-cells. Together, we provide insights into the long-term effects of these immunotherapies on the immune system. Citation Format: Stephen Mok, Huey Liu, Nana-Ama A.S. Anang, James J Mancuso, Didem Ağaç Çobanoğlu, James P Allison. Anti-CTLA-4 generates memory T-cell with greater expansion and functionality than anti-PD-1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A054.

Dynamic physiological and transcriptomic changes reveal memory effects of salt stress in maize

BackgroundPre-exposing plants to abiotic stresses can induce stress memory, which is crucial for adapting to subsequent stress exposure. Although numerous genes involved in salt stress response have been identified, the understanding of memory responses to salt stress remains limited.ResultsIn this study, we conducted physiological and transcriptional assays on maize plants subjected to recurrent salt stress to characterize salt stress memory. During the second exposure to salt stress, the plants exhibited enhanced salt resistance, as evidenced by increased proline content and higher POD and SOD activity, along with decreased MDA content, indicative of physiological memory behavior. Transcriptional analysis revealed fewer differentially expressed genes and variations in response processes during the second exposure compared to the first, indicative of transcriptional memory behavior. A total of 2,213 salt stress memory genes (SMGs) were identified and categorized into four response patterns. The most prominent group of SMGs consisted of genes with elevated expression during the first exposure to salt stress but reduced expression after recurrent exposure to salt stress, or vice versa ([+ / −] or [− / +]), indicating that a revised response is a crucial process in plant stress memory. Furthermore, nine transcription factors (TFs) (WRKY40, WRKY46, WRKY53, WRKY18, WRKY33, WRKY70, MYB15, KNAT7, and WRKY54) were identified as crucial factors related to salt stress memory. These TFs regulate over 53% of SMGs, underscoring their potential significance in salt stress memory.ConclusionsOur study demonstrates that maize can develop salt stress memory, and the genes identified here will aid in the genetic improvement of maize and other crops.

Call and response: Ethnomusicological methods to awaken specific memories with targeted songs encoded in neuronal populations of a dementia patient

AbstractThis study collaborates with a fellow expert ethnomusicologist Sean Williams to trigger specific contextual memories associated with songs of her mother Julian Williams, born in 1932, and currently struggling with the early stages of dementia. The goal was to ascertain the success rate of a one‐to‐one correspondence type: The use of targeted, known songs of the dementia patient as a means to trigger the patient’s contextual memories.By adopting a methodology in Ethnomusicology involving the autobiography of one’s music history and their corresponding memories of the patient Julian Williams, I set up the experiment for Sean Williams to conduct. Dividing the study into discrete music time periods (infancy, childhood, teenager, young adult, older adult), I asked Sean Williams to choose specific songs with specific memories to the patient to be sung. The memory responses of the patient on video were then recorded.Each of those songs had deep levels of recognition by the Alzheimer’s patient, as evidenced in her singing with some memories (lyrics and contextual environment) stronger than than others. The fact that there is some autobiographical recall, despite a weakened sense of time and space after the onset of Alzheimer’s, suggests there may be use for this technique in dementia care. Of note, is the fun‐filled disposition of the participants during the recording of the singing. That speaks to a higher quality of life one could expect by using music as a memory‐recall and time‐ travel companion.This single case study needs to be broadened into a larger‐scale experiment involving many participants from different cultures to ascertain the use of individualized targeted songs to awaken specific memories of the dementia patients. In the area of dementia care, this approach also makes it possible for families to participate actively since the songs will probably be known to them as well.

Reconfigurable Physical Reservoir Enabled by Polarization of Ferroelectric Polymer P(VDF–TrFE) and Interface Charge‐Trapping/Detrapping in Dual‐Gate IGZO Transistor

AbstractNeuromorphic computers promise to enhance computing efficiency by eliminating conventional von Neumann architecture bottlenecks. Bio‐inspired artificial neural networks, such as feedforward neural networks and reservoir computing (RC), face challenges due to the unique memristor requirements. In this study, a dual‐gate ferroelectric polymer P(VDF–TrFE)‐coupled thin film transistor (DG–TFT) with an IGZO channel is presented. It yields complementary short‐ and long‐term memory functionalities are derived from the charge‐trapping/detrapping process at the IGZO‐SiO2 dielectric interface and ferroelectric polarization. These memory functionalities can be switched using different gated modes to meet the requirements of the reservoir and readout layers in RC. The bottom‐gated mode (BG‐mode) exhibits short‐term memory effects and nonlinear dynamics, whereas the top‐gated mode (TG‐mode) displays improved long‐term memory characteristics. To evaluate the long‐term memory properties, Python is used for pattern recognition. For the nonlinear dynamics and short‐term memory response of the BG‐mode, the DG–TFT is employed as a reservoir layer to handle various temporal tasks. Notably, the polarization level of the ferroelectric layer is coupled to improve the richness of the reservoir states, providing a reconfigurable RC system with an expanded capacity to effectively process and accommodate diverse signals. This holds potential for next‐generation hybrid intelligent applications.

Metabolic Reprograming of Exhausted Intratumoral CD8+ T-Cell Underlies Anti-Tumor Activity of Sumoylation Inhibitors in Large B Cell Lymphoma

Immune checkpoint inhibitors (ICI) targeting PD1 have revolutionized our approach to solid tumors and Hodgkin lymphoma, but they have not been effective in treating Large B Cell Lymphoma (LBCL). In prior work, we used single cell spatial profiling of human tumors to show that exhausted CD8 tumor and TREG populations were associated with PD1 resistance in LBCL (Colombo et al. Blood Adv 2022). Here we show, using a syngeneic model of LBCL, that PD1 resistance is associated with lower CD8+ T-cell basal metabolic rate (BMR) in tumor infiltrating lymphocytes (TIL), and that treatment with the covalent SUMOylation inhibitor (SB-4826) increases the metabolic rate of TIL by metabolic reprograming. Single cell metabolic profiling of human LBCL is on-going and will be presented as well. In summary these studies demonstrate that metabolic dysfunction of T cells in LBCL underlie resistance to PD1 checkpoint inhibitors and that this can be overcome by treatment with SUMOlyation inhibitors. Direct measurement of intra-tumoral metabolic state is difficult to perform on clinical samples, however large tumor size is hypothesized to be a surrogate for increased metabolic derangement. As tumors expand and become more metabolically active themselves, infiltrating immune cells experience decreased O2 tension as well as nutrient deprivation, ultimately leading to decreased anti-tumor immune responses. In support of this idea, it has been observed that high metabolic tumor volume at baseline predicts survival in LBCL patients, independent of their initial response to therapy. We have shown that mice with established (>125mm 3) A20 tumors are resistant to anti-PD1 therapy. However, A20 bearing mice treated ~5 days post implantation are responsive to anti-PD1 therapy. To understand these findings, we examined sensitive (small) and resistant (large) A20 tumors by flow cytometry analysis and found that resistant tumors had lower relative numbers of T cells, lower absolute numbers of CD8+ T cells, increased absolute numbers of TREG and a strikingly decreased CD8/TREG ratio. Additionally, the resistant tumors had increased absolute numbers of pre-exhausted and exhausted CD8+ T cells as well as decreased BMR. Small ubiquitin-like modifiers (SUMO) proteins regulate a variety of cellular processes in tumor and immune cells and inhibitors of SUMOylation have shown anti-tumor activity in a variety of preclinical tumor models with potential synergy with checkpoint inhibitors targeting PD-1 (Cannon et al. Cancer Res, 2023). We demonstrate that a dose of 100mg/kg of SB-4826 led to a complete response in all mice treated (Fig. 1A) and we also show that this effect is dependent on CD8+ T-cells and elicits a long term memory response, with 0 of 15 mice in remission developing tumor upon rechallenge. A low dose (25mg/kg) of SB-4826 failed to elicit a response in any of the mice treated while anti-PD1 therapy elicited a response in 1/6 mice (Fig. 1A). Combination of 25mg/kg SB-4826 with anti-PD1 therapy demonstrated synergism with a response in 3/6 mice (Fig. 1A). We also demonstrate that global SUMOylation levels are higher in PD1+ TIM3+ CD8+ TILs compared to PD1- TIM3- CD8+ T-cells, suggesting that SUMOylation may be acting as a negative regulator of T-cell function. Using SCENITH (Arguello et al. Cell Metabolism 2020) for single cell metabolic studies, we demonstrate that SB-4826 increases the BMR (Fig. 1B), mitochondrial dependency and proliferative capacity of tumor infiltrating PD1+ TIM3+ CD8+ T-cells (TILs). While both SB-4826 and PD1 inhibition led to increased CD8+ TIL numbers, SB-4826 led to increased BMR in CD8+ TILs while PD1 inhibition did not affect CD8+ TILs BMR. Additionally, PD1 inhibition significantly decreased CD8+ TILs mitochondrial dependency for metabolism, while SB-4826 increased mitochondrial dependency (Fig. 1B). Additionally, we recapitulate these metabolic enhancements in an in vitro system of T-cell activation, further confirming a T-cell intrinsic effect following SB-4826. Mechanistically, we found that SB-4826 led to increased HIF-1a levels in both CD4+ and CD8+ cells following TCR activation, likely through stabilization of HIF-1a due to decreased SUMOylation-dependent turnover (Cheng J et al. Cell 2007). We hypothesize that metabolic reprograming of CD8 T-cells through increased HIF-1a is the basis for synergy between SUMOylation inhibition and immune checkpoint inhibitors in LBCL.

A SARS-CoV-2 NSP7 homolog of a Treg epitope suppresses CD4+ and CD8+ T cell memory responses.

Pathogens escape host defenses by T-cell epitope mutation or deletion (immune escape) and by simulating the appearance of human T cell epitopes (immune camouflage). We identified a highly conserved, human-like T cell epitope in non-structural protein 7 (NSP7) of SARS-CoV-2, RNA-dependent RNA polymerase (RdRp) hetero-tetramer complex. Remarkably, this T cell epitope has significant homology to a T regulatory cell epitope (Tregitope) previously identified in the Fc region of human immunoglobulin G (IgG) (Tregitope 289). We hypothesized that the SARS-CoV-2 NSP7 epitope (NSP7-289) may induce suppressive responses by engaging and activating pre-existing regulatory T cells. We therefore compared NSP7-289 and IgG Tregitopes (289 and 289z, a shorter version of 289 that isolates the shared NSP7 epitope) in vitro. Tregitope peptides 289, 289z and NSP7-289 bound to multiple HLA-DRB1 alleles in vitro and suppressed CD4+ and CD8+ T cell memory responses. Identification and in vitro validation of SARS-CoV-2 NSP7-289 provides further evidence of immune camouflage and suggests that pathogens can use human-like epitopes to evade immune response and potentially enhance host tolerance. Further exploration of the role of cross-conserved Tregs in human immune responses to pathogens such as SARS-CoV-2 is warranted.

Does habitual moderate alcohol consumption enhance working memory performance?

The present study aimed to establish whether habitual alcohol consumption benefits verbal and spatial working memory performance after addressing the main criticisms that have been raised against the finding that alcohol benefits cognition. An adult lifespan sample of 1,652 healthy adults between 21 and 80 years of age participated in the study. Participants were classified as lifetime nondrinkers or drinkers, and several demographic and biological variables were controlled. Alcohol consumption was assessed through a lifestyle questionnaire created for the study. Working memory was measured through a 2-back computerized task. Discrimination and speed in verbal and spatial working memory among drinkers were superior to those among nondrinkers. Total alcohol intake across life and the amount of alcohol intake per week predicted higher verbal and spatial working memory discrimination. Beer drinkers showed more accurate and faster responses in verbal and spatial working memory than nondrinkers, wine drinkers and spirit drinkers. The optimal amount of alcohol intake to benefit working memory for women and men was 100 g per week, which is equivalent to one drink per day. After consuming 350 g of alcohol per week, equivalent to 25 drinks per week, the effects of alcohol on working memory become more negative than the effects of alcohol abstinence. While alcohol consumption is considered a risk factor for several diseases, we found that moderate alcohol intake benefits working memory performance throughout the adult lifespan to a greater extent than whole-life abstinence.

Antitumor Effect by Either FLASH or Conventional Dose Rate Irradiation Involves Equivalent Immune Responses

Purpose: The capability of ultra-high dose rate FLASH radiotherapy (FLASH) to generate the FLASH effect has opened the possibility to enhance the therapeutic index of radiotherapy. The contribution of the immune response has frequently been hypothesized to account for a certain fraction of the anti-tumor efficacy and tumor kill of FLASH but has yet to be rigorously evaluated. Methods: To investigate the immune response as a potentially important mechanism of the anti-tumor effect of FLASH, various murine tumor models were grafted either subcutaneously or orthotopically into immunocompetent mice, or in moderately and severely immunocompromised mice. Mice were locally irradiated with single dose (20 Gy) or hypo-fractionated regimens (3 × 8 Gy; 2 × 6 Gy), using FLASH (≥ 2000 Gy/s) and Conventional dose rates (0.1 Gy/s, CONV), with/without anti-CTLA-4. Tumor growth was monitored over time, and immune profiling performed. Results: 20 Gy FLASH and CONV were isoeffective in delaying tumor growth in immunocompetent and moderately immunodeficient hosts, and increased tumor doubling time to >14 days vs. >7 days in control animals. Similar observations were obtained with hypo-fractionated scheme, regardless the microenvironment (subcutaneous flank vs. ortho lungs). Interestingly, in profoundly immunocompromised mice, 20 Gy FLASH retained anti-tumor activity and significantly increased tumor doubling time to >14 days vs. >8 days in control animals, suggesting a possible anti-tumor mechanism independent of the immune response. Analysis of the tumor microenvironment showed similar immune profiles after both irradiation modalities with significant decrease of lymphoid cells by ∼40 % and a corresponding increase of myeloid cells. In addition, FLASH and CONV did not increase TGF-β1 levels in tumors as compared to unirradiated control animals. Furthermore, when a complete and long-lasting anti-tumor response was obtained (> 140 days), both modalities of irradiation were able to generate a long-term immunological memory response. Conclusions: The present results clearly document that the tumor responses across multiple immunocompetent and immunodeficient mouse models are largely dose rate independent, and simultaneously contradict a major role of the immune response in the anti-tumor efficacy of FLASH. Therefore, our study indicates that FLASH is as potent as CONV in modulating anti-tumor immune response and can be used as an immunomodulatory agent.

Fronto-parietal theta high-definition transcranial alternating current stimulation may modulate working memory under postural control conditions in young healthy adults.

This study aimed to investigate the immediate effects of fronto-parietal θ HD-tACS on a dual task of working memory-postural control. In this within-subject cross-over pilot study, we assessed the effects of 20 min of 6 Hz-tACS targeting both the left dorsolateral prefrontal cortex (lDLPFC) and posterior parietal cortex (PPC) in 20 healthy adults (age: 21.6 ± 1.3 years). During each session, single- and dual-task behavioral tests (working memory single-task, static tandem standing, and a dual-task of working memory-postural control) and closed-eye resting-state EEG were assessed before and immediately after stimulation. Within the tACS group, we found a 5.3% significant decrease in working memory response time under the dual-task following tACS (t = -3.157, p = 0.005, Cohen's d = 0.742); phase synchronization analysis revealed a significant increase in the phase locking value (PLV) of θ band between F3 and P3 after tACS (p = 0.010, Cohen's d = 0.637). Correlation analyses revealed a significant correlation between increased rs-EEG θ power in the F3 and P3 channels and faster reaction time (r = -0.515, p = 0.02; r = -0.483, p = 0.031, respectively) in the dual-task working memory task after tACS. However, no differences were observed on either upright postural control performance or rs-EEG results (p-values <0.05). Fronto-parietal θ HD-tACS has the potential of being a neuromodulatory tool for improving working memory performance in dual-task situations, but its effect on the modulation of concurrently performed postural control tasks requires further investigation.

Bestatin, A Pluripotent Immunomodulatory Small Molecule, Drives Robust and Long-Lasting Immune Responses as an Adjuvant in Viral Vaccines.

An inactivated whole-virus vaccine is currently used to prevent foot-and-mouth disease (FMD). Although this vaccine is effective, it offers short-term immunity that requires regular booster immunizations and has several side effects, including local reactions at the vaccination site. To address these limitations, herein, we evaluated the efficacy of bestatin as a novel small molecule adjuvant for inactivated FMD vaccines. Our findings showed that the FMD vaccine formulated with bestatin enhanced early, intermediate-, and particularly long-term immunity in experimental animals (mice) and target animals (pigs). Furthermore, cytokines (interferon (IFN)α, IFNβ, IFNγ, and interleukin (IL)-29), retinoic acid-inducible gene (RIG)-I, and T-cell and B-cell core receptors (cluster of differentiation (CD)28, CD19, CD21, and CD81) markedly increased in the group that received the FMD vaccine adjuvanted with bestatin in pigs compared with the control. These results indicate the significant potential of bestatin to improve the efficacy of inactivated FMD vaccines in terms of immunomodulatory function for the simultaneous induction of potent cellular and humoral immune response and a long-lasting memory response.

The State-of-the-Art of the Humoral Memory Response to Snakebites: Insights from the Yanomami Population.

Snakebite envenomation (SBE)-induced immunity refers to individuals who have been previously bitten by a snake and developed a protective immune response against subsequent envenomations. The notion stems from observations of individuals, including in the indigenous population, who present only mild signs and symptoms after surviving multiple SBEs. Indeed, these observations have engendered scientific interest and prompted inquiries into the potential development of a protective immunity from exposure to snake toxins. This review explores the evidence of a protective immune response developing following SBE. Studies suggest that natural exposure to snake toxins can trigger protection from the severity of SBEs, mediated by specific antibodies. However, the evaluation of the immune memory response in SBE patients remains challenging. Further research is needed to elucidate the immune response dynamics and identify potential targets for therapeutic interventions. Furthermore, the estimation of the effect of previous exposures on SBE epidemiology in hyperendemic areas, such as in the indigenous villages of the Amazon region (e.g., the Yanomami population) is a matter of debate.

Ozone as Redox Bioregulator in Preventive Medicine: The Molecular and Pharmacological Basis of the Low-Dose Ozone Concept-A Review.

The best form of prevention against human infection through bacteria, viruses, and other parasites is ozone disinfection of wastewater and drinking water as a highly effective, well-known method. Various preclinical studies showed promising results, which are being revisited and reconsidered in times of pandemics and led to interesting results in recent clinical trials and reports, as presented by the example of protective measures against COVID-19 in particularly vulnerable clinical personnel. The application of ozone in the form of the low-dose concept induces its regulation by interference of ozone or its peroxides into the redox equilibrium of the biological system, which finally results in the restoration of the glutathione equilibrium. The antioxidant system is activated, the immune system is modulated, and thus the defense mechanisms are improved. In patients with rheumatoid arthritis, repeated ozone treatments have led to new findings in "immunomodulation" through ozone. The more effective immune response is discussed as the response of innate immune memory and opens interesting aspects for complementary treatment of autoimmune diseases.

Interferon-γ couples CD8+ T cell avidity and differentiation during infection

Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.

Broadly Reactive SARS-CoV-2-Specific T-Cell Response and Participation of Memory B and T Cells in Patients with Omicron COVID-19 Infection.

January 2022 onward, India witnessed a sudden increase in Omicron COVID-19 infections, having a mild course that prompted us to identify the key host factors/immune molecules modulating disease course/outcomes. The current study evaluated the percentages of lymphocyte subsets by flowcytometry, SARS-CoV-2 specific T-cell immune response by ELISPOT, estimation of plasma cytokine/chemokine levels on a Bio-plex Multiplex Immunoassay System and anti-SARS-CoV-2 IgG levels by enzyme-linked immunosorbent assay in 19 mild Omicron infected patients, 45 mild SARS-CoV-2 (2020) patients and 36 uninfected controls from India. Natural killer cells, B and memory B cells were high in vaccinated and total Omicron-infected patients groups compared to the mild SARS-CoV-2 (2020) patient group, while CD8+ T cells were high in total Omicron-infected patients group compared to the uninfected control group (p < 0.05 each). Omicron-infected patients had T-cell response against SARS-CoV-2 whole virus, S1 proteins (wild type and delta variant) in 10 out of 17 (59%), 10 out of 17 (59%), and 8 out of 17 (47%), respectively. The current study of Omicron-infected patients elucidates broadly reactive antibody, T-cell response, and participation of memory B and T cells induced by vaccination/natural infection. The limited effect of Omicron's mutations on T-cell response is suggestive of protection from severity. Pro-inflammatory IL-6, IFN-γ, chemokines CCL-2, CCL-3, CCL-4, CCL-5, and IL-8 as potential biomarkers of Omicron infection may have future diagnostic importance. The cellular immune response data in Omicron-infected patients with parental Omicron lineage could serve as a starting point to define the readouts of protective immunity against circulating Omicron subvariants.

A new multi-epitope vaccine candidate based on S and M proteins is effective in inducing humoral and cellular immune responses against SARS-CoV-2 variants: an in silico design approach

Available COVID-19 vaccines are primarily based on SARS-CoV-2 spike protein (S). Due to the emergence of new SARS-CoV-2 variants, other virus proteins with more conservancy, such as Membrane (M) protein, are desired for vaccine development. The reverse vaccinology approach was employed to design a multi-epitope SARS-CoV-2 vaccine candidate based on S and M proteins. Cytotoxic T-lymphocyte (CTL), helper T-lymphocyte (HTL), linear B-lymphocyte (LBL) and conformational B-lymphocyte (CBL) of S and M proteins were predicted and screened to choose the best epitopes. A multi-epitope vaccine candidate was constructed using selected CTL, HTL and LBL epitopes. The efficiency of the construct in binding to some immune receptors and an RBD-potent neutralizing monoclonal antibody (bebtelovimab) was predicted, and its immunogenicity was simulated. Finally, in silico cloning of the constructed gene was performed. The potency of our construct as a SARS-CoV-2 vaccine was validated using several bioinformatics tools. The simulation results showed that the construct can induce both cellular and humoral immune responses by producing appropriate cytokines, and it can even create an excellent immune memory response. Furthermore, the designed construct interacts with innate immune receptors such as TLR2 and TLR4 and the terminal variable domain of bebtelovimab with high affinity. We developed a multi-epitope construct based on the S and M proteins of the SARS-CoV-2 virus with high immunogenicity potential using the most up-to-date immunoinformatics and computational biology approaches. The actual efficiency of this multi-epitope vaccine should be further evaluated via in vitro and in vivo studies. Communicated by Ramaswamy H. Sarma

Fluoroethylnormemantine (FENM) shows synergistic protection in combination with a sigma-1 receptor agonist in a mouse model of Alzheimer's disease

Fluoroethylnormemantine (FENM) is a Memantine derivative with anti-amnesic and neuroprotective activities showed in the Aβ25-35 pharmacological mouse model of Alzheimer's disease (AD). As AD is a complex multi-factorial neurodegenerative pathology, combination therapies relying on drugs acting through different pathways, have been suggested to more adequately address neuroprotection. As several agonists of the sigma-1 receptor (S1R), an intracellular chaperone, are presently in phase 2 or 3 clinical trials in neurodegenetrative diseases including AD, we examined the potentialities of S1R drug-based combinations with FENM, or Memantine. Aβ25-35-treated mice were treated with S1R agonists (PRE-084, Igmesine, Cutamesine) and/or FENM, or Memantine, during 7 days after intracerebroventricular administration of oligomerized Aβ25-35. Mice were then tested for spatial short-term memory on day 8 and non-spatial long-term memory on days 9–10, using the spontaneous alternation or passive avoidance tests, respectively. The FENM or Memantine combination with Donepezil, that non-selectively inhibits acetylcholinesterase and activates S1R, was also tested. The efficacy of combinations using maximal non-active or minimal active doses of S1R agonist or FENM was analyzed using calculations of the combination index, based on simple isobologram representation. Data showed that most of the FENM-based combinations led to synergistic protection against Aβ25-35-induced learning deficits, for both long- and short-term memory responses, with a higher efficiency on the latter. Memantine led to synergistic combination in short-term memory but poorly in long-term memory responses, with either PRE-084 or Donepezil. These study showed that drug combinations based on FENM and S1R agonists may lead to highly effective and synergistic protection in AD, particularly on short-term memory.