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A single bout of aerobic exercise improves executive function; however, the mechanism(s) underlying this improvement remains unclear. Here, we employed a 20-min bout of aerobic exercise, and at pre- and immediate post-exercise sessions examined executive function via pro- (i.e., saccade to veridical target location) and anti-saccade (i.e., saccade mirror symmetrical to a target) performance and pupillometry metrics. Notably, tonic and phasic pupillometry responses in oculomotor control provided a framework to determine the degree that arousal and/or executive resource recruitment influence behavior. Results demonstrated a pre- to post-exercise decrease in pro- and anti-saccade reaction times (p = 0.01) concurrent with a decrease and increase in tonic baseline pupil size and task-evoked pupil dilations, respectively (ps < 0.03). Such results demonstrate that an exercise-induced improvement in saccade performance is related to an executive-mediated “shift” in physiological and/or psychological arousal, supported by the locus coeruleus norepinephrine system to optimize task engagement.

•Aluminium has neurotoxic properties and can form focal accumulations in the body.•Threshold values for foodstuffs established by authorities are regularly exceeded.•Positive benefit–risk assessment of aluminium in essential vaccines is unchanged.•Many more injections with higher proportions of aluminium are applied in SCIT.•Long-term safety and guidance of aluminium in immunotherapy needs further addressing. We are living in an “aluminium age” with increasing bioavailability of the metal for approximately 125 years, contributing significantly to the aluminium body burden of humans. Over the course of life, aluminium accumulates and is stored predominantly in the lungs, bones, liver, kidneys and brain. The toxicity of aluminium in humans is briefly summarised, highlighting links and possible causal relationships between a high aluminium body burden and a number of neurological disorders and disease states. Aluminium salts have been used as depot-adjuvants successfully in essential prophylactic vaccinations for almost 100 years, with a convincing positive benefit-risk assessment which remains unchanged. However, allergen-specific immunotherapy commonly consists of administering a long-course programme of subcutaneous injections using preparations of relevant allergens. Regulatory authorities currently set aluminium limits for vaccines per dose, rather than per treatment course. Unlike prophylactic vaccinations, numerous injections with higher proportions of aluminium-adjuvant per injection are applied in subcutaneous immunotherapy (SCIT) and will significantly contribute to a higher cumulative life dose of aluminium. While the human body may cope robustly with a daily aluminium overload from the environment, regulatory cumulative threshold values in immunotherapy need further addressing. Based on the current literature, predisposing an individual to an unusually high level of aluminium, such as through subcutaneous immunotherapy, has the potential to form focal accumulations in the body with the propensity to exert forms of toxicity. Particularly in relation to longer-term health effects, the safety of aluminium adjuvants in immunotherapy remains unchallenged by health authorities – evoking the need for more consideration, guidance, and transparency on what is known and not known about its safety in long-course therapy and what measures can be taken to prevent or minimise its risks. The possibility of providing an effective means of measuring aluminium accumulation in patients undergoing long-term SCIT treatment as well as reducing their aluminium body burden is discussed.

The concept of adjuvants or adjuvant systems, used in vaccines, exploit evolutionary relationships associated with how the immune system may initially respond to a foreign antigen or pathogen, thus mimicking natural exposure. This is particularly relevant during the non-specific innate stage of the immune response; as such, the quality of this response may dictate specific adaptive responses and conferred memory/protection to that specific antigen or pathogen. Therefore, adjuvants may optimise this response in the most appropriate way for a specific disease. The most commonly used traditional adjuvants are aluminium salts; however, a biodegradable adjuvant, MCT ® , was developed for application in the niche area of allergy immunotherapy (AIT), also in combination with a TLR-4 adjuvant—Monophosphoryl Lipid A (MPL ® )—producing the first adjuvant system approach for AIT in the clinic. In the last decade, the use and effectiveness of MCT ® across a variety of disease models in the preclinical setting highlight it as a promising platform for adjuvant systems, to help overcome the challenges of modern vaccines. A consequence of bringing together, for the first time, a unified view of MCT ® mode-of-action from multiple experiments and adjuvant systems will help facilitate future rational design of vaccines while shaping their success.

In this review, we outline and reflect on the important differences between allergen-specific immunotherapy for inhalant allergies (i.e., aeroallergens) and venom-specific immunotherapy (VIT), with a special focus on Venomil® Bee and Wasp. Venomil® is provided as a freeze-dried extract and a diluent to prepare a solution for injection for the treatment of patients with IgE-mediated allergies to bee and/or wasp venom and for evaluating the degree of sensitivity in a skin test. While the materials that make up the product have not changed, the suppliers of raw materials have changed over the years. Here, we consolidate relevant historical safety and efficacy studies that used products from shared manufacture supply profiles, i.e., products from Bayer or Hollister–Stier. We also consider the characterization and standardization of venom marker allergens, providing insights into manufacturing controls that have produced stable and consistent quality profiles over many years. Quality differences between products and their impacts on treatment outcomes have been a current topic of discussion and further research. Finally, we review the considerations surrounding the choice of depot adjuvant most suitable to augmenting VIT.

Background Induction of strong T cell responses, in particular cytotoxic T cells, is a key for the generation of efficacious therapeutic cancer vaccines which yet, remains a major challenge for the vaccine developing world. Here we demonstrate that it is possible to harness the physiological properties of the lymphatic system to optimize the induction of a protective T cell response. Indeed, the lymphatic system sharply distinguishes between nanoscale and microscale particles. The former reaches the fenestrated lymphatic system via diffusion, while the latter either need to be transported by dendritic cells or form a local depot. Methods Our previously developed cucumber-mosaic virus-derived nanoparticles termed (CuMV TT -VLPs) incorporating a universal Tetanus toxoid epitope TT830–843 were assessed for their draining kinetics using stereomicroscopic imaging. A nano-vaccine has been generated by coupling p33 epitope as a model antigen to CuMV TT -VLPs using bio-orthogonal Cu-free click chemistry. The CuMV TT -p33 nano-sized vaccine has been next formulated with the micron-sized microcrystalline tyrosine (MCT) adjuvant and the formed depot effect was studied using confocal microscopy and trafficking experiments. The immunogenicity of the nanoparticles combined with the micron-sized adjuvant was next assessed in an aggressive transplanted murine melanoma model. The obtained results were compared to other commonly used adjuvants such as B type CpGs and Alum. Results Our results showed that CuMV TT -VLPs can efficiently and rapidly drain into the lymphatic system due to their nano-size of ~ 30 nm. However, formulating the nanoparticles with the micron-sized MCT adjuvant of ~ 5 μM resulted in a local depot for the nanoparticles and a longer exposure time for the immune system. The preclinical nano-vaccine CuMV TT -p33 formulated with the micron-sized MCT adjuvant has enhanced the specific T cell response in the stringent B16F10p33 murine melanoma model. Furthermore, the micron-sized MCT adjuvant was as potent as B type CpGs and clearly superior to the commonly used Alum adjuvant when total CD8 + , specific p33 T cell response or tumour protection were assessed. Conclusion The combination of nano- and micro-particles may optimally harness the physiological properties of the lymphatic system. Since the nanoparticles are well defined virus-like particles and the micron-sized adjuvant MCT has been used for decades in allergen-specific desensitization, this approach may readily be translated to the clinic.

Zika virus (ZIKV) is a flavivirus similar to Dengue virus (DENV) in terms of transmission and clinical manifestations, and usually both viruses are found to co-circulate. ZIKV is usually transmitted by mosquitoes bites, but may also be transmitted by blood transfusion, via the maternal–foetal route, and sexually. After 2015, when the most extensive outbreak of ZIKV had occurred in Brazil and subsequently spread throughout the rest of South America, it became evident that ZIKV infection during the first trimester of pregnancy was associated with microcephaly and other neurological complications in newborns. As a result, the development of a vaccine against ZIKV became an urgent goal. A major issue with DENV vaccines, and therefore likely also with ZIKV vaccines, is the induction of antibodies that fail to neutralize the virus properly and cause antibody-dependent enhancement (ADE) of the infection instead. It has previously been shown that antibodies against the third domain of the envelope protein (EDIII) induces optimally neutralizing antibodies with no evidence for ADE for other viral strains. Therefore, we generated a ZIKV vaccine based on the EDIII domain displayed on the immunologically optimized Cucumber mosaic virus (CuMVtt) derived virus-like particles (VLPs) formulated in dioleoyl phosphatidylserine (DOPS) as adjuvant. The vaccine induced high levels of specific IgG after a single injection. The antibodies were able to neutralise ZIKV without enhancing infection by DENV in vitro. Thus, the here described vaccine based on EDIII displayed on VLPs was able to stimulate production of antibodies specifically neutralizing ZIKV without potentially enhancing disease caused by DENV.

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.

An emerging issue in movement neurosciences is whether haptic feedback influences the nature of the information supporting a simulated grasping response (i.e., pantomime-grasping). In particular, recent work by our group contrasted pantomime-grasping responses performed with (i.e., PH+ trials) and without (i.e., PH- trials) terminal haptic feedback in separate blocks of trials. Results showed that PH- trials were mediated via relative visual information. In contrast, PH+ trials showed evidence of an absolute visuo-haptic calibration-a finding attributed to an error signal derived from a comparison between expected and actual haptic feedback (i.e., an internal forward model). The present study examined whether advanced knowledge of haptic feedback availability influences the aforementioned calibration process. To that end, PH- and PH+ trials were completed in separate blocks (i.e., the feedback schedule used in our group's previous study) and a block wherein PH- and PH+ trials were randomly interleaved on a trial-by-trial basis (i.e., random feedback schedule). In other words, the random feedback schedule precluded participants from predicting whether haptic feedback would be available at the movement goal location. We computed just-noticeable-difference (JND) values to determine whether responses adhered to, or violated, the relative psychophysical principles of Weber's law. Results for the blocked feedback schedule replicated our group's previous work, whereas in the random feedback schedule PH- and PH+ trials were supported via relative visual information. Accordingly, we propose that a priori knowledge of haptic feedback is necessary to support an absolute visuo-haptic calibration. Moreover, our results demonstrate that the presence and expectancy of haptic feedback is an important consideration in contrasting the behavioral and neural properties of natural and simulated grasping.

The presentation of a remote - but not proximal - distractor concurrent with target onset increases prosaccade reaction times (RT) (i.e., the remote distractor effect: RDE). The competitive integration model asserts that the RDE represents the time required to resolve the conflict for a common saccade threshold between target- and distractor-related saccade generating commands in the superior colliculus. To our knowledge however, no previous research has examined whether remote and proximal distractors differentially influence antisaccade RTs. This represents a notable question because antisaccades require decoupling of the spatial relations between stimulus and response (SR) and therefore provide a basis for determining whether the sensory- and/or motor-related features of a distractor influence response planning. Participants completed pro- and antisaccades in a target-only condition and conditions wherein the target was concurrently presented with a proximal or remote distractor. As expected, prosaccade RTs elicited a reliable RDE. In contrast, antisaccade RTs were increased independent of the distractor's spatial location and the magnitude of the effect was comparable across each distractor location. Thus, distractor-related antisaccade RT costs are not accounted for by a competitive integration between conflicting saccade generating commands. Instead, we propose that a visual distractor increases uncertainty related to the evocation of the response-selection rule necessary for decoupling SR relations.

When an individual grasps a physical object, the visuomotor system is able to specify grip aperture via absolute visual information. In contrast, grasping to a location previously occupied by an object (i.e., pantomime-grasping) results in the specification of grip aperture via relative visual information. The basis for the dissociable visual codes is thought to reflect that pantomime-grasping is a perception-based task. It is, however, important to recognize that grasping a physical object and pantomime-grasping differ not only in terms of their visuospatial properties but also with respect to the availability of haptic feedback: Grasping a physical object provides haptic cues derived from touching the object, whereas no such feedback is available in a traditional pantomime-grasping task. As such, we examined whether haptic feedback influences the information supporting a pantomime-grasp performed after a 1000-ms visual delay. Participants completed responses in each of the three tasks: (1) grasping a physical object, (2) traditional pantomime-grasping wherein the to-be-grasped object was removed from the grasping environment and (3) pantomime-grasping wherein the experimenter placed the object between participants’ thumb and forefinger once they had completed their response (i.e., pantomime-grasping with haptic feedback). Just-noticeable-difference (JND) scores were computed to determine whether responses adhered to or violated the psychophysical (i.e., relative) principles of Weber’s law. JNDs for the traditional pantomime-grasping task adhered to Weber’s law, whereas JNDs for grasping a physical object and for pantomime-grasping with haptic feedback violated the law. Thus, we propose that convergent visual and haptic cues support the absolute specification of object size in a pantomime-grasping task. Furthermore, our results highlight the important role of multisensory cue integration in a target-defined grasping task.