Background: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CDI, MRI, and butyrophilin 3AI. Such T cells, referred to as donor... Show moreBackground: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CDI, MRI, and butyrophilin 3AI. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MRI-restricted MAIT cells, CDth-restricted glucose monomycolate (GMM)-specific T cells, CDth-restricted NKT cells, and gamma delta T cells, in vaccination against Mycobacterium tuberculosis. Methods: We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults. Findings: BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CDth-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CDId-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of gamma delta T cells as well as a novel subset of CD26(+)CDI6I(+)TRAVI-2(-) IFN-gamma-expressing CD4(+) T cells in infants. Interpretation: Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies. Copyright (C) 2022 The Authors. Published by Elsevier B.V. Show less
Background: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under... Show moreBackground: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.Methods: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions.Results: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (+/- 4.61) in younger adult subjects and 14.3 h (+/- 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes.Conclusion: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. Show less
Context-dependency effects on memory exist, whereby people’s context influences their ability to accurately recall items from memory. This effect was not previously studied when considering virtual... Show moreContext-dependency effects on memory exist, whereby people’s context influences their ability to accurately recall items from memory. This effect was not previously studied when considering virtual reality as an environmental context. We show that adverse effects on recall of memorized items exist when changing between virtual and real environments. The effect was not present when memorizing and recall were both done in VR; it appears to be caused by the change of environmental context. This previously unknown effect may impact how we use VR for memorization tasks, particularly when accurate recall of memorized information in a real environment is important. In a memory-recall experiment (n = 51) participants that underwent a context change involving VR after memorizing performed significantly worse on 24-h later item recall than those who did not change context (17% lower accuracy, p < 0.001). In particular memorizing in VR as opposed to a real environment lowers accuracy of recall in a real environment (24% lower, p = 0.001). Show less
Exploring novel environments enhances learning in animals. Due to differing traditions, research into the effects of spatial novelty on learning in humans is scarce. Recent developments of... Show moreExploring novel environments enhances learning in animals. Due to differing traditions, research into the effects of spatial novelty on learning in humans is scarce. Recent developments of affordable and fMRI-compatible virtual reality (VR) and mobile EEG systems can help bridge the gap between the two literatures. One promising study showed that spatial novelty also promotes learning in humans. It still remains largely unknown, however, which aspect of novelty underlies the beneficial effect on memory, as novelty, expectations, and volition are often confounded in animal studies. In humans, these factors can be experimentally manipulated, but such studies are currently lacking. Future studies in humans could combine pharmacological interventions, neuroimaging and VR or use mobile EEG to help elucidate whether the plasticity enhancing mechanisms observed in animals, also exist in humans. When the aspects of exploring a novel environment underlying beneficial memory effects have been identified, effective novelty-exposure interventions could be designed to improve learning and counteract age-related memory decline. Show less
Although useful, digital screens have not yet replaced physical books. The printed book offers three concurrent psychological advantages that explain its puzzling resilience: (1) Better learning... Show moreAlthough useful, digital screens have not yet replaced physical books. The printed book offers three concurrent psychological advantages that explain its puzzling resilience: (1) Better learning and remembering are associated with the physical act of moving through the space of printed pages, which stimulates the visuo-spatial sketchpad component of working memory; (2) since reading is based on temporal, sequential processing, the fixed frame of reference of printed pages and their fixed shape are great aids to memory; (3) the properties of paper and the standard design of a printed book guarantee that it will always function properly: one day, a year, or many centuries later. One reads the same words on screen or in print, but the context in which the symbols are read is very different. The digital book appears and vanishes. The physical book – where kinesthetic experience is more vivid – remains as an actual, remembered space. Show less
Stijntjes, M.; Craen, A.J.M. de; Grond, J. van der; Meskers, C.G.M.; Slagboom, P.E.; Maier, A.B. 2016
The Doublecortin-Like Kinase (DCLK) gene is involved in neuronal migration during development. Through alternative splicing the DCLK gene also produces a transcript called Ca2+/calmodulin dependent... Show moreThe Doublecortin-Like Kinase (DCLK) gene is involved in neuronal migration during development. Through alternative splicing the DCLK gene also produces a transcript called Ca2+/calmodulin dependent protein kinase (CaMK)-related peptide (CARP) that is expressed exclusively during adulthood in response to neuronal activity. The function of CARP, however, is poorly understood. To study CARP function, we have generated transgenic mice with over-expression of the CARP transcript in, amongst other brain areas, the hippocampus. We aimed to characterize possible behavioral adaptations of these mice by using a Pavlovian fear conditioning approach. This type of fear conditioning, in which both the hippocampus and amygdala are critically involved, allows studying the formation and extinction of fear related memories. We here report on the behavioral adaptations of two distinct transgenic lines: one with high levels of CARP in the hippocampus and amygdala, whilst the other has high levels of CARP in the hippocampal formation, but not in the amygdala. We tested both mouse lines separately by comparing them to their wild-type littermate controls. We provide evidence suggesting consolidation of contextual fear memories is strengthened in mice of both transgenic lines. (C) 2010 Elsevier Inc. All rights reserved. Show less
