Peripheral blood mononuclear cell transcriptome profile in a clinical trial with subcutaneous, grass pollen allergoid immunotherapy.

INTRODUCTION: Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment in allergic airway diseases. Underlying immunological mechanisms and candidate biomarkers, which may be translated into predictive/surrogate measures of clinical efficacy, remain an active area of research. The aim of this study was to evaluate Pollinex Quattro (PQ) Grass AIT induced immunomodulatory mechanisms, based on transcriptome profiling of peripheral blood mononuclear cells. METHODS: 119 subjects with grass pollen induced seasonal allergic rhinitis (SAR) were randomized in a 2:2:1:1 ratio to receive a cumulative dose of PQ Grass as a conventional or extended pre-seasonal regimen, placebo, or placebo with MicroCrystalline Tyrosine. Gene expression analysis was an exploratory endpoint evaluated in a subgroup of 30 subjects randomly selected from the four treatment arms. Samples were collected at three time points: screening (baseline), before the start of the grass pollen season and at the end of the season. This study was funded by the manufacturer of PQ. RESULTS: Transcriptome analysis demonstrated that the most significant changes in gene expression, for both treatment regimens, were at the end of the grass pollen season, with the main Th1 candidate molecules (IL-12A, IFNγ) upregulated and Th2 signature cytokines downregulated (IL-4, IL-13, IL-9) (p < .05). Canonical pathways analysis demonstrated Th1, Th2, Th17 and IL-17 as the most significantly enriched pathways based on absolute value of activation z-score (IzI score ≥ 2, p < .05). Upstream regulator analysis showed pronounced inhibition of pro-inflammatory allergic molecules IgE, IL-17A, IL-17F, IL-25 (IL-17E) (IzI score ≥ 2, FDR < 0.05) and activation of pro-tolerogenic molecules IL-12A, IL-27, IL-35 (EBI3) at the end of the grass pollen season. CONCLUSION: Peripheral blood mononuclear cells transcriptome profile showed an inhibition of Th2, Th17 pro-inflammatory allergic responses and immune deviation towards Th1 responses. PQ Grass extended regimen exhibited a superior mechanistic efficacy profile in comparison with PQ conventional regimen.

10-min exposure to a 2.5% hypercapnic environment increases cerebral blood blow but does not impact executive function.

Space travel and exploration are associated with increased ambient CO2 (i.e., a hypercapnic environment). Some work reported that the physiological changes (e.g., increased cerebral blood flow [CBF]) associated with a chronic hypercapnic environment contributes to a "space fog" that adversely impacts cognition and psychomotor performance, whereas other work reported no change or a positive change. Here, we employed the antisaccade task to evaluate whether transient exposure to a hypercapnic environment influences top-down executive function (EF). Antisaccades require a goal-directed eye movement mirror-symmetrical to a target and are an ideal tool for identifying subtle EF changes. Healthy young adults (aged 19-25 years) performed blocks of antisaccade trials prior to (i.e., pre-intervention), during (i.e., concurrent) and after (i.e., post-intervention) 10-min of breathing factional inspired CO2 (FiCO2) of 2.5% (i.e., hypercapnic condition) and during a normocapnic (i.e., control) condition. In both conditions, CBF, ventilatory and cardiorespiratory responses were measured. Results showed that the hypercapnic condition increased CBF, ventilation and end-tidal CO2 and thus demonstrated an expected physiological adaptation to increased FiCO2. Notably, however, null hypothesis and equivalence tests indicated that concurrent and post-intervention antisaccade reaction times were refractory to the hypercapnic environment; that is, transient exposure to a FiCO2 of 2.5% did not produce a real-time or lingering influence on an oculomotor-based measure of EF. Accordingly, results provide a framework that - in part - establishes the FiCO2 percentage and timeline by which high-level EF can be maintained. Future work will explore CBF and EF dynamics during chronic hypercapnic exposure as more direct proxy for the challenges of space flight and exploration.

Influence of antigen density and TLR ligands on preclinical efficacy of a VLP-based vaccine against peanut allergy.

BACKGROUND: Virus-like particle (VLP) Peanut is a novel immunotherapeutic vaccine candidate for the treatment of peanut allergy. The active pharmaceutical ingredient represents cucumber mosaic VLPs (CuMVTT -VLPs) that are genetically fused with one of the major peanut allergens, Ara h 2 (CuMVTT -Ara h 2). We previously demonstrated the immunogenicity and the protective capacity of VLP Peanut-based immunization in a murine model for peanut allergy. Moreover, a Phase I clinical trial has been initiated using VLP Peanut material manufactured following a GMP-compliant manufacturing process. Key product characterization studies were undertaken here to understand the role and contribution of critical quality attributes that translate as predictive markers of immunogenicity and protective efficacy for clinical vaccine development. METHOD: The role of prokaryotic RNA encapsulated within VLP Peanut on vaccine immunogenicity was assessed by producing a VLP Peanut batch with a reduced RNA content (VLP Peanut low RNA). Immunogenicity and peanut allergen challenge studies were conducted with VLP Peanut low RNA, as well as with VLP Peanut in WT and TLR 7 KO mice. Furthermore, mass spectrometry and SDS-PAGE based methods were used to determine Ara h 2 antigen density on the surface of VLP Peanut particles. This methodology was subsequently applied to investigate the relationship between Ara h 2 antigen density and immunogenicity of VLP Peanut. RESULTS: A TLR 7 dependent formation of Ara h 2 specific high-avidity IgG antibodies, as well as a TLR 7 dependent change in the dominant IgG subclass, was observed following VLP Peanut vaccination, while total allergen-specific IgG remained relatively unaffected. Consistently, a missing TLR 7 signal caused only a weak decrease in allergen tolerability after vaccination. In contrast, a reduced RNA content for VLP Peanut resulted in diminished total Ara h 2 specific IgG responses, followed by a significant impairment in peanut allergen tolerability. The discrepant effect on allergen tolerance caused by an absent TLR 7 signal versus a reduced RNA content is explained by the observation that VLP Peanut-derived RNA not only stimulates TLR 7 but also TLR 3. Additionally, a strong correlation was observed between the number of Ara h 2 antigens displayed on the surface of VLP Peanut particles and the vaccine's immunogenicity and protective capacity. CONCLUSIONS: Our findings demonstrate that prokaryotic RNA encapsulated within VLP Peanut, including antigen density of Ara h 2 on viral particles, are key contributors to the immunogenicity and protective capacity of the vaccine. Thus, antigenicity and RNA content are two critical quality attributes that need to be determined at the stage of manufacturing, providing robust information regarding the immunogenicity and protective capacity of VLP Peanut in the mouse which has translational relevance to the human setting.

Distinct cortical haemodynamics during squat-stand and continuous aerobic exercise do not influence the magnitude of a postexercise executive function benefit.

A single bout of aerobic exercise benefits executive function (EF). A potential mechanism for this benefit is an exercise-mediated increase in cerebral blood flow (CBF) that elicits vascular endothelial shear-stress improving EF efficiency. Moderate intensity continuous aerobic exercise (MCE) asymptotically increases CBF, whereas continuous body weight squat-stand exercise (SSE) provides a large amplitude oscillatory response. Some work has proposed that an increase in CBF oscillation amplitude provides the optimal shear-stress for improving EF and brain health. We examined whether a large amplitude oscillatory CBF response associated with a single bout of SSE imparts a larger postexercise EF benefit than an MCE cycle ergometer protocol. Exercise changes in middle cerebral artery velocity (MCAv) were measured via transcranial Doppler ultrasound to estimate CBF, and pre- and postexercise EF was assessed via the antisaccade task. MCE produced a steady state increase in MCAv, whereas SSE produced a large amplitude MCAv oscillation. Both conditions produced a postexercise EF benefit that null hypothesis and equivalence tests showed to be comparable in magnitude. Accordingly, we provide a first demonstration that a single bout of SSE benefits EF; however, the condition's oscillatory CBF response does not impart a larger benefit than a time- and intensity-matched MCE protocol.

Acute stress imparts a transient benefit to task-switching that is not modulated following a single bout of exercise.

Introduction: Cognitive flexibility represents a core component of executive function that promotes the ability to efficiently alternate-or "switch"-between different tasks. Literature suggests that acute stress negatively impacts cognitive flexibility, whereas a single bout of aerobic exercise supports a postexercise improvement in cognitive flexibility. Here, we examined whether a single bout of aerobic exercise attenuates a stress-induced decrement in task-switching. Materials and Methods: Forty participants (age range = 19-30) completed the Trier Social Stress Test (TSST) and were randomized into separate Exercise or Rest groups entailing 20-min sessions of heavy intensity exercise (80% of heart rate maximum via cycle ergometer) or rest, respectively. Stress induction was confirmed via state anxiety and heart rate. Task-switching was assessed prior to the TSST (i.e., pre-TSST), following the TSST (i.e., post-TSST), and following Exercise and Rest interventions (i.e., post-intervention) via pro- (i.e., saccade to veridical target location) and antisaccades (i.e., saccade mirror-symmetrical to target location) arranged in an AABB task-switching paradigm. The underlying principle of the AABB paradigm suggests that when prosaccades are preceded by antisaccades (i.e., task-switch trials), the reaction times are longer compared to their task-repeat counterparts (i.e., unidirectional prosaccade switch-cost). Results: As expected, the pre-TSST assessment yielded a prosaccade switch cost. Notably, post-TSST physiological measures indicated a reliable stress response and at this assessment a null prosaccade switch-cost was observed. In turn, post-intervention assessments revealed a switch-cost independent of Exercise and Rest groups. Conclusion: Accordingly, the immediate effects of acute stress supported improved task-switching in young adults; however, these benefits were not modulated by a single bout of aerobic exercise.

Look into my eyes: What can eye-based measures tell us about the relationship between physical activity and cognitive performance?

BACKGROUND: There is a growing interest to understand the neurobiological mechanisms that drive the positive associations of physical activity and fitness with measures of cognitive performance. To better understand those mechanisms, several studies have employed eye-based measures (e.g., eye movement measures such as saccades, pupillary measures such as pupil dilation, and vascular measures such as retinal vessel diameter) deemed to be proxies for specific neurobiological mechanisms. However, there is currently no systematic review providing a comprehensive overview of these studies in the field of exercise-cognition science. Thus, this review aimed to address that gap in the literature. METHODS: To identify eligible studies, we searched 5 electronic databases on October 23, 2022. Two researchers independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX scale, for interventional studies) and the critical appraisal tool from the Joanna Briggs Institute (for cross-sectional studies). RESULTS: Our systematic review (n = 35 studies) offers the following main findings: (a) there is insufficient evidence available to draw solid conclusions concerning gaze-fixation-based measures; (b) the evidence that pupillometric measures, which are a proxy for the noradrenergic system, can explain the positive effect of acute exercise and cardiorespiratory fitness on cognitive performance is mixed; (c) physical training- or fitness-related changes of the cerebrovascular system (operationalized via changes in retinal vasculature) are, in general, positively associated with cognitive performance improvements; (d) acute and chronic physical exercises show a positive effect based on an oculomotor-based measure of executive function (operationalized via antisaccade tasks); and (e) the positive association between cardiorespiratory fitness and cognitive performance is partly mediated by the dopaminergic system (operationalized via spontaneous eye-blink rate). CONCLUSION: This systematic review offers confirmation that eye-based measures can provide valuable insight into the neurobiological mechanisms that may drive positive associations between physical activity and fitness and measures of cognitive performance. However, due to the limited number of studies utilizing specific methods for obtaining eye-based measures (e.g., pupillometry, retinal vessel analysis, spontaneous eye blink rate) or investigating a possible dose-response relationship, further research is necessary before more nuanced conclusions can be drawn. Given that eye-based measures are economical and non-invasive, we hope this review will foster the future application of eye-based measures in the field of exercise-cognition science.

A single bout of passive exercise mitigates a mental fatigue-induced inhibitory control deficit.

Sustained cognitive effort associated with the psychomotor vigilance task (PVT) increases objective and subjective measures of mental fatigue and elicits a post-PVT inhibitory control deficit. In contrast, passive exercise wherein an individual's limbs are moved via an external force (i.e., mechanically driven cycle ergometer flywheel) provides a postexercise inhibitory control benefit linked to an exercise-based increase in cerebral blood flow. Here, we examined whether passive exercise performed concurrently with the PVT 'blunts' an inhibitory control deficit. On separate days, participants (N = 27) completed a 20 min PVT protocol (control condition) and same duration PVT protocol paired with passive cycle ergometry (passive exercise condition). Prior to (i.e., baseline), immediately after and 30 min after each condition inhibitory control was assessed via the antisaccade task. Antisaccades require a goal-directed eye movement (i.e., saccade) mirror-symmetrical to a target and provide an ideal tool for evaluating task-based changes in inhibitory control. PVT results showed that vigilance (as assessed via reaction time: RT) during control and passive exercise conditions decreased from the first to last 5 min of the protocol and increased subjective ratings of mental fatigue. As well, in the control condition, immediate (but not 30-min) post-intervention antisaccade RTs were longer than their baseline counterparts-a result evincing a transient mental fatigue-based inhibitory control deficit. For the passive exercise condition, immediate and 30-min post-intervention antisaccade RTs were shorter than their baseline counterparts and this result was linked to decreased subjective ratings of mental fatigue. Thus, passive exercise ameliorated the selective inhibitory control deficit associated with PVT-induced mental fatigue and thus provides a potential framework to reduce executive dysfunction in vigilance-demanding occupations.

The next generation virus-like particle platform for the treatment of peanut allergy.

BACKGROUND: Allergy to peanut is one of the leading causes of anaphylactic reactions among food allergic patients. Immunization against peanut allergy with a safe and protective vaccine holds a promise to induce durable protection against anaphylaxis caused by exposure to peanut. A novel vaccine candidate (VLP Peanut), based on virus-like particles (VLPs), is described here for the treatment of peanut allergy. METHODS AND RESULTS: VLP Peanut consists of two proteins: a capsid subunit derived from Cucumber mosaic virus engineered with a universal T-cell epitope (CuMVTT ) and a CuMVTT subunit fused with peanut allergen Ara h 2 (CuMVTT -Ara h 2), forming mosaic VLPs. Immunizations with VLP Peanut in both naïve and peanut-sensitized mice resulted in a significant anti-Ara h 2 IgG response. Local and systemic protection induced by VLP Peanut were established in mouse models for peanut allergy following prophylactic, therapeutic, and passive immunizations. Inhibition of FcγRIIb function resulted in a loss of protection, confirming the crucial role of the receptor in conferring cross protection against peanut allergens other than Ara h 2. CONCLUSION: VLP Peanut can be delivered to peanut-sensitized mice without triggering allergic reactions, while remaining highly immunogenic and offering protection against all peanut allergens. In addition, vaccination ablates allergic symptoms upon allergen challenge. Moreover, the prophylactic immunization setting conferred the protection against subsequent peanut-induced anaphylaxis, showing the potential for preventive vaccination. This highlights the effectiveness of VLP Peanut as a prospective break-through immunotherapy vaccine candidate toward peanut allergy. VLP Peanut has now entered clinical development with the study PROTECT.

Cerebral blood flow and immediate and sustained executive function benefits following single bouts of passive and active exercise.

Passive exercise occurs when an individual's limbs are moved via an external force and is a modality that increases cerebral blood flow (CBF) and provides an immediate postexercise executive function (EF) benefit. To our knowledge, no work has examined for how long passive exercise benefits EF. Here, healthy young adults (N = 22; 7 female) used a cycle ergometer to complete three 20-min conditions: passive exercise (via mechanically driven flywheel), a traditional light intensity (37 W) "active" exercise condition (i.e., via volitional pedalling) and a non-exercise control condition. An estimate of CBF was obtained via transcranial Doppler ultrasound measurement of middle cerebral artery blood velocity (MCAv) and antisaccades (i.e., saccade mirror-symmetrical to a target) were completed prior to and immediately, 30- and 60-min following each condition to assess EF. Passive and active exercise increased MCAv; however, the increase was larger in the latter condition. In terms of antisaccades, passive and active exercise provided an immediate postexercise reaction time benefit. At the 30-min assessment, the benefit was observed for active but not passive exercise and neither produced a benefit at the 60-min assessment. Thus, passive exercise provided an evanescent EF "boost" and is a finding that may reflect a smaller cortical hemodynamic response.

Ex Vivo Immunomodulatory Effects of Lactobacillus-, Lacticaseibacillus-, and Bifidobacterium-Containing Synbiotics on Human Peripheral Blood Mononuclear Cells and Monocyte-Derived Dendritic Cells in the Context of Grass Pollen Allergy.

Sensing of the intestinal microbiota by the host immune system is important to induce protective immune responses. Hence, modification of the gut microbiota might be able to prevent or treat allergies, mediated by proinflammatory Th2 immune responses. The aim was to investigate the ex vivo immunomodulatory effects of the synbiotics Pollagen® and Kallergen®, containing the probiotic bacterial strains Lactobacillus, Lacticaseibacillus and Bifidobacterium, in the context of grass pollen allergy. Peripheral blood mononuclear cells (PBMCs) from grass pollen-allergic patients and healthy controls were stimulated with grass pollen extract (GPE) and synbiotics and Gata3 expression and cytokine secretion analyzed. Monocyte-derived dendritic cells (MoDCs) cells were matured in the presence of GPE and synbiotics, co-cultured with autologous naïve T cells and maturation markers and cytokine secretion analyzed. GPE stimulation of PBMCs from grass pollen-allergic patients resulted in a significant higher production of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13 compared to healthy controls. Gata3+CD4+ T cell induction was independent of the allergic status. The synbiotics promoted IL-10 and IFN-γ secretion and downregulated the GPE-induced Th2-like phenotype. Co-culturing naïve T cells with MoDCs, matured in the presence of GPE and synbiotics, shifted the GPE-induced Th2 cytokine release towards Th1-Th17-promoting conditions in allergic subjects. The investigated synbiotics are effective in downregulating the GPE-induced Th2 immune response in PBMCs from grass pollen-allergic patients as well as in autologous MoDC-T cell stimulation assays. In addition to increased IL-10 release, the data indicates a shift from a Th2- to a more Th1- and Th17-like phenotype.

In situ delivery of nanoparticles formulated with micron-sized crystals protects from murine melanoma.

INTRODUCTION: Intratumoral injections of novel therapeutics can activate tumor antigen-specific T cells for locoregional tumor control and may even induce durable systemic protection (against distant metastases) via recirculating T cells. Here we explored the possibility of a universal immunotherapy that promotes T-cell responses in situ and beyond, upon intratumoral injection of nanoparticles formulated with micron-sized crystals. METHODS: Cucumber mosaic virus-like particles containing a tetanus toxin peptide (CuMVTT) were formulated with microcrystalline tyrosine (MCT) adjuvant and injected directly in B16F10 melanoma tumors. To further enhance immunogenicity, we loaded the nanoparticles with a TLR7/8 ligand and incorporated a universal tetanus toxin T-helper cell peptide. We assessed therapeutic efficacy and induction of local and systemic immune responses, including RNA sequencing, providing broad insight into the tumor microenvironment and correlates of protection. RESULTS: MCT crystals were successfully decorated with CuMVTT nanoparticles. This 'immune-enhancer' formed immunogenic depots in injected tumors, enhanced polyfunctional CD8+ and CD4+ T cells, and inhibited B16F10 tumor growth locally and systemically. Local inflammation and immune responses were associated with upregulation of genes involved in complement activation and collagen formation. CONCLUSIONS: Our new immune-enhancer turned immunologically cold tumors into hot ones and inhibited local and distant tumor growth. This type of immunotherapy does not require the identification of (patient-individual) relevant tumor antigens. It is well tolerated, non-infectious, and affordable, and can readily be upscaled for future clinical testing and broad application in melanoma and likely other solid tumors.

Passive exercise increases cerebral blood flow velocity and supports a postexercise executive function benefit.

Executive function entails high-level cognitive control supporting activities of daily living. Literature has shown that a single-bout of exercise involving volitional muscle activation (i.e., active exercise) improves executive function and that an increase in cerebral blood flow (CBF) may contribute to this benefit. It is, however, unknown whether non-volitional exercise (i.e., passive exercise) wherein an individual's limbs are moved via an external force elicits a similar executive function benefit. This is a salient question given that proprioceptive and feedforward drive from passive exercise increases CBF independent of the metabolic demands of active exercise. Here, in a procedural validation participants (n = 2) used a cycle ergometer to complete separate 20-min active and passive (via mechanically driven flywheel) exercise conditions and a non-exercise control condition. Electromyography showed that passive exercise did not increase agonist muscle activation or increase ventilation or gas exchange variables (i.e., V̇O2 and V̇CO2 ). In a main experiment participants (n = 28) completed the same exercise and control conditions and transcranial Doppler ultrasound showed that active and passive exercise (but not the control condition) increased CBF through the middle cerebral artery (ps <.001); albeit the magnitude was less during passive exercise. Notably, antisaccade reaction times prior to and immediately after each condition showed that active (p < .001) and passive (p = .034) exercise improved an oculomotor-based measure of executive function, whereas no benefit was observed in the control condition (p = .85). Accordingly, results evince that passive exercise 'boosts' an oculomotor-based measure of executive function and supports convergent evidence that increased CBF mediates this benefit.

The unidirectional prosaccade switch-cost: no evidence for the passive dissipation of an oculomotor task-set inertia.

Cognitive flexibility is a core component of executive function and supports the ability to 'switch' between different tasks. Our group has examined the cost associated with switching between a prosaccade (i.e., a standard task requiring a saccade to veridical target location) and an antisaccade (i.e., a non-standard task requiring a saccade mirror-symmetrical to veridical target) in predictable (i.e., AABB) and unpredictable (e.g., AABAB…) switching paradigms. Results have shown that reaction times (RTs) for a prosaccade preceded by an antisaccade (i.e., task-switch trial) are longer than when preceded by its same task-type (i.e., task-repeat trial), whereas RTs for antisaccade task-switch and task-repeat trials do not differ. The asymmetrical switch-cost has been attributed to an antisaccade task-set inertia that proactively delays a subsequent prosaccade (i.e., the unidirectional prosaccade switch-cost). A salient question arising from previous work is whether the antisaccade task-set inertia passively dissipates or persistently influences prosaccade RTs. Accordingly, participants completed separate AABB (i.e., A = prosaccade, B = antisaccade) task-switching conditions wherein the preparation interval for each trial was 'short' (1000-2000 ms; i.e., the timeframe used in previous work), 'medium' (3000-4000 ms) and 'long' (5000-6000 ms). Results demonstrated a reliable prosaccade switch-cost for each condition (ps < 0.02) and two one-sided test statistics indicated that switch cost magnitudes were within an equivalence boundary (ps < 0.05). Hence, null and equivalence tests demonstrate that an antisaccade task-set inertia does not passively dissipate and represents a temporally persistent feature of oculomotor control.

Allergen Content of Therapeutic Preparations for Allergen-Specific Immunotherapy of European Paper Wasp Venom Allergy.

Allergy to Polistes dominula (European paper wasp) venom is of particular relevance in Southern Europe, potentially becoming a threat in other regions in the near future, and can be effectively cured by venom immunotherapy (VIT). As allergen content in extracts may vary and have an impact on diagnostic and therapeutic approaches, the aim was to compare five therapeutic preparations for VIT of P. dominula venom allergy available in Spain. Products from five different suppliers were analyzed by SDS-PAGE and LC-MS/MS and compared with a reference venom sample. Three products with P. dominula venom and one product with a venom mixture of American Polistes species showed a comparable band pattern in SDS-PAGE as the reference sample and the bands of the major allergens phospholipase A1 and antigen 5 were assignable. The other product, which consists of a mixture of American Polistes species, exhibited the typical band pattern in one, but not in another sample from a second batch. All annotated P. dominula allergens were detected at comparable levels in LC-MS/MS analysis of products containing P. dominula venom. Due to a lack of genomic information on the American Polistes species, the remaining products were not analyzed by this method. The major Polistes allergens were present in comparable amounts in the majority, but not in all investigated samples of venom preparations for VIT of P. dominula venom allergy.

Evaluating the efficacy of an iPad® app in determining a single bout of exercise benefit to executive function.

We examined the efficacy and feasibility of an iPad® app used at-home in identifying a postexercise benefit to executive function. The iPad® app required simple reaching movements mirror-symmetrical to an exogenously presented target (i.e., antipointing) and is a task that lab-based behavioral and neuroimaging work has shown to provide a valid measure of the response inhibition component of executive function. Fifty English-speaking individuals (18 female, age range 18-26 years of age) completed the iPad® app before and immediately after a 20-min session of heavy-intensity aerobic exercise, and on a separate day completed the app prior to and following a 20-min non-exercise control condition. Results showed antipointing reaction times (RTs) in the exercise condition decreased by an average of 18 ms postexercise (p < 0.001) with an observed large effect size (dz = 0.90), whereas control condition pre- and post-assessment RTs did not reliably differ (p = 0.12, dz = 0.22) and were within an equivalence boundary (p < 0.005). Further, pre-assessment exercise and control condition antipointing RTs were within an equivalence boundary (p < 0.05). Accordingly, a simple iPad® app provides the requisite resolution to detect subtle executive function benefits derived from a single bout of exercise.

A Single Bout of Exercise Provides a Persistent Benefit to Cognitive Flexibility.

Purpose: A single bout of exercise enhances activity within the cortical networks that support executive function. It is, however, unclear whether exercise improves each core component of executive function and for how long a putative benefit might persist. Method: In Experiment 1, participants completed 20-min of aerobic exercise (via cycle ergometer) and cognitive flexibility-a core component of executive function-was examined pre-exercise, and at immediate, 30- and 60-min post-exercise assessments. Experiment 2 entailed a non-exercise control (i.e., participants sat on the ergometer without exercising) involving the same timeline of cognitive flexibility assessment. Cognitive flexibility was measured via stimulus-driven (SD) and minimally delayed (MD) saccades arranged in an AABB paradigm. SD and MD saccades require a response at target onset and after target offset, respectively, with the latter requiring executive control. Work has shown that reaction times for a SD saccade preceded by a MD saccade are longer than when a SD saccade is preceded by its same task-type, whereas the converse switch does not influence performance (i.e., the unidirectional switch-cost). Results: Experiment 1 showed a unidirectional switch-cost at each assessment; however, the switch-cost magnitude was decreased at immediate and 30-min assessments compared to the pre- and 60-min assessments. In contrast, Experiment 2 did not elicit a change in switch-cost magnitude across the different assessments. Discussion/Conclusion: Thus, a single-bout of exercise benefitted the cognitive flexibility component of executive function in the immediate and 30-min post-exercise assessments.

Distinct visual resolution supports aperture shaping in natural and pantomime-grasping.

Pantomime-grasping is a "simulated" motor response wherein an individual grasps to an area dissociated from a physical target. The task has been used in the apraxia literature as a proxy for natural grasping (i.e., physically grasping a target); however, it is important to recognize that the task's decoupled spatial relations between stimulus and response renders the top-down processing of target features (e.g., size) that accumulating evidence has shown to be mediated by visual information functionally distinct from natural grasping. Here, we examined whether the visual information supporting pantomime-grasps exhibits a visual resolution power commensurate with natural grasps. Participants were presented with a target and nontarget that differed in size below the perceptual threshold (i.e., 0.5 mm or ∼1.3%) and were asked to make a perceptual judgment about the target (i.e., "smaller" or "larger" than the nontarget) before and after completing natural and pantomime-grasps. Results showed that perceptual judgments "before" and "after" natural and pantomime-grasps did not reliably distinguish between target and nontarget. Natural grasp peak grip apertures (PGAs) scaled to target size and were comparable for "before" and "after" perceptual judgment trials-a result indicating that haptic feedback from physically grasping the target did not "boost" perceptual accuracy. Most notably, pantomime-grasp PGAs were insensitive to target size; that is, responses elicited a visual resolution power less than natural grasps. These results provide convergent evidence that pantomime-grasps are mediated by the same visual information as obligatory perceptions and do not provide a proxy for natural grasps. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Immunological effects of adjuvanted low-dose allergoid allergen-specific immunotherapy in experimental murine house dust mite allergy.

BACKGROUND: Native allergen extracts or chemically modified allergoids are routinely used to induce allergen tolerance in allergen-specific immunotherapy (AIT), although mechanistic side-by-side studies are rare. It is paramount to balance optimal dose and allergenicity to achieve efficacy warranting safety. AIT safety and efficacy could be addressed by allergen dose reduction and/or use of allergoids and immunostimulatory adjuvants, respectively. In this study, immunological effects of experimental house dust mite (HDM) AIT were investigated applying high-dose HDM extract and low-dose HDM allergoids with and without the adjuvants microcrystalline tyrosine (MCT) and monophosphoryl lipid A (MPL) in a murine model of HDM allergy. METHODS: Cellular, humoral, and clinical effects of the different AIT strategies were assessed applying a new experimental AIT model of murine allergic asthma based on physiological, adjuvant-free intranasal sensitization followed by subcutaneous AIT. RESULTS: While low-dose allergoid and high-dose extract AIT demonstrated comparable potency to suppress allergic airway inflammation and Th2-type cytokine secretion of lung-resident lymphocytes and draining lymph node cells, low-dose allergoid AIT was less effective in inducing a potentially protective IgG1 response. Combining low-dose allergoid AIT with MCT or MCT and dose-adjusted MPL promoted Th1-inducing mechanisms and robust B-cell activation counterbalancing the allergic Th2 immune response. CONCLUSION: Low allergen doses induce cellular and humoral mechanisms counteracting Th2-driven inflammation by using allergoids and dose-adjusted adjuvants. In light of safety and efficacy improvement, future therapeutic approaches may use low-dose allergoid strategies to drive cellular tolerance and adjuvants to modulate humoral responses.

Dogmas, challenges, and promises in phase III allergen immunotherapy studies.

The concept of treatment of an allergy with the offending allergen was introduced more than a century ago. Allergen immunotherapy (AIT) is the only disease modifying treatment of allergic diseases caused by inhalational allergens and insect venoms. Despite this, only few AIT products have reached licensure in the US or an official marketing authorization status in European countries. Moreover, most of these AIT products are provided on an individual patient basis as named patient products (NPP) in Europe, while individualized preparations of (mixed) allergenic extract vials for subcutaneous administration (compounding) is common practice in the US. AIT products are generally considered safe and well tolerated, but the major practical clinical development challenge is to define the optimal dose and prove the efficacy and safety of these products using state-of-the art Phase II and pivotal Phase III studies. In planning Phase II-III AIT studies, a thorough understanding of the study challenges is essential (e.g. variability and non-validated status of subjective primary endpoints, limitations of pollen season definitions) and dogmas of these products (e.g., for sublingual immunotherapy (SLIT) trials double-blinding conditions cannot be maintained, resulting in stronger placebo responses in the active treatment group and inflated treatment effects in Phase III). There is future promise for more objective biomarker endpoints (e.g. basophil activation (CD63 and CD203c), subsets of regulatory dendritic, T and B cells, IL-10-producing group 2 innate lymphoid cells; alone or in combination) to overcome several of these dogmas and challenges; innovation in AIT clinical trials can only progress with integral biomarker research to complement the traditional endpoints in Phase II-III clinical development. The aim of this paper is to provide an overview of these dogmas, challenges and recommendations based on published data, to facilitate the design of Phase III studies and improve the evidence basis of safe and effective AIT products.

'Delaying' a saccade: Preparatory phase cortical hemodynamics evince the neural cost of response inhibition.

Minimally delayed (MD) saccades require inhibition of a prepotent response until a target is extinguished, and unlike the more extensively studied antisaccade task, do not require the additional cognitive component of vector inversion (i.e., 180° target spatial transposition). Here, participants completed separate blocks of MD and prepotent stimulus-driven saccades (i.e., respond at target onset) while cortical hemodynamics were measured via functional transcranial Doppler ultrasound. MD saccades produced longer and more variable reaction times (RT). In turn, MD and stimulus-driven saccade preparatory phase cortical hemodynamics increased and decreased, respectively, relative to baseline and the two conditions differed from one another throughout the preparatory phase. The longer RTs and increased cortical hemodynamics of MD saccades is taken to evince response complexity and the increased neural activity to accommodate response inhibition. To our knowledge, such findings provide the first work to examine the neural foundations of MD saccades.