Mucosal‐associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non‐lineage‐specific (surrogate) markers such as ...anti‐TRAV1‐2, CD161, IL‐18Rα and CD26. The development of MR1‐Ag tetramers now permits the specific identification of MAIT cells based on T‐cell receptor specificity. Here, we compare these approaches for identifying MAIT cells and show that surrogate markers are not always accurate in identifying these cells, particularly the CD4+ fraction. Moreover, while all MAIT cell subsets produced comparable levels of IFNγ, TNF and IL‐17A, the CD4+ population produced more IL‐2 than the other subsets. In a human ontogeny study, we show that the frequencies of most MR1 tetramer+ MAIT cells, with the exception of CD4+ MAIT cells, increased from birth to about 25 years of age and declined thereafter. We also demonstrate a positive association between the frequency of MAIT cells and other unconventional T cells including Natural Killer T (NKT) cells and Vδ2+ γδ T cells. Accordingly, this study demonstrates that MAIT cells are phenotypically and functionally diverse, that surrogate markers may not reliably identify all of these cells, and that their numbers are regulated in an age‐dependent manner and correlate with NKT and Vδ2+ γδ T cells.
This study uses MR1 tetramers to enumerate and phenotypically characterize human blood MAIT cells, and subsets thereof based on CD4 and CD8 expression. Furthermore MR1 tetramers are compared to the commonly used mAb‐based MAIT cell identification techniques.
We have conducted pulling and bending tests on individual carbon nanotubes in-situ in a transition electron microscope. Based on our observation of the force required to break the tube, a tensile ...strength of 0.15 TPa was computed. From corresponding bending studies on such nanotubes, the Young's modulus was estimated to be 0.9 TPa (0.8 TPa after ‘sub continuum’ corrections). These results suggest a strength that is a large fraction of the elastic modulus, although previous measurements of their elastic stiffness have yielded higher modulus values, by as much as a factor of 2. The result does indicate that individual nanotubes can fail as essentially defect-free materials. Furthermore, we observed no obvious reduction in cross-sectional area prior to the failure. In addition, the bending experiments revealed a remarkable flexibility in these tubes. These unique properties support the potential of nanotubes as reinforcement fibers in structural materials.
A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2+ T cell receptors (TCRs) that are activated by riboflavin metabolite-based antigens (Ag) presented by the ...MHC-I related molecule, MR1. Whether the MR1-restricted T cell repertoire and associated Ag responsiveness extends beyond these cells remains unclear. Here, we describe MR1 autoreactivity and folate-derivative reactivity in a discrete subset of TRAV1-2+ MAIT cells. This recognition was attributable to CDR3β loop-mediated effects within a consensus TRAV1-2+ TCR-MR1-Ag footprint. Furthermore, we have demonstrated differential folate- and riboflavin-derivative reactivity by a diverse population of “atypical” TRAV1-2− MR1-restricted T cells. We have shown that TRAV1-2− T cells are phenotypically heterogeneous and largely distinct from TRAV1-2+ MAIT cells. A TRAV1-2− TCR docks more centrally on MR1, thereby adopting a markedly different molecular footprint to the TRAV1-2+ TCR. Accordingly, diversity within the MR1-restricted T cell repertoire leads to differing MR1-restricted Ag specificity.
•Identification of TRAV1-2− MR1 restricted T cells•Characterization of autoreactive and folate-derivative-reactive MAIT cells•Folate-derivative responsiveness and autoreactivity mediated by CDR3β hypervariability•Structure determination of a TRAV1-2− TCR-MR1-antigen complex
MAIT cells, defined by an invariant TRAV1-2+ TCR α-chain, respond to riboflavin-based metabolites presented by MR1. Rossjohn, Godfrey, and colleagues describe atypical TRAV1-2+ and TRAV1-2− MR1 restricted T cells that can be activated by riboflavin and folate derivatives, and provide a molecular basis underpinning their interactions.
Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier ...lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence supports the efficacy of preventive interventions on persons with intact cognition and high dementia risk. We report recommendations for the deployment of second-generation memory clinics (Brain Health Services) whose mission is evidence-based and ethical dementia prevention in at-risk individuals. The cornerstone interventions consist of (i) assessment of genetic and potentially modifiable risk factors including brain pathology, and risk stratification, (ii) risk communication with ad-hoc protocols, (iii) risk reduction with multi-domain interventions, and (iv) cognitive enhancement with cognitive and physical training. A roadmap is proposed for concept validation and ensuing clinical deployment.
The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. ...Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies.
Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests.
535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β = - 0.22, OR = 0.80, p < .05), more prior study visits (β = - 0.93, OR = 0.40, p < .001), and positive family history of dementia (β = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PC
= 27.4%, PC
= 9.0%, X
= 10.56, p = .001), and loss of research interest (PC
= 46.3%, PC
= 16.5%, X
= 32.34, p < .001).
The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site.
The spectrum of broad and overlapping nucleon excitations can be greatly clarified by use of a polarized photon beam incident on a polarized target in meson photoproduction experiments. At Jefferson ...Lab, a program of such measurements has made use of the Jefferson Lab FROzen Spin Target (FROST). An overview of preliminary results are presented.
Amyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative ...European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and 'Small and Medium-sized enterprises' (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population.
In the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with
Fflutemetamol or
Fflorbetaben radiotracers was performed and quantified using the Centiloid (CL) method.
AMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BP
), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aβ burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine.
The AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.
This paper reports a study of self-assessment practices in 10 organisations. The research was carried out by semi-structured interviews directed towards a range of issues related to the process, ...practice and management of self-assessment. Amongst the findings are that organisations are becoming more aware of the role of self-assessment in influencing strategy and are including the outputs of self-assessment in their business planning process, and self-assessment is seen as making the organisation a more viable commodity. It was also found that the potential of self-assessment for analysing organisational performance and identifying areas for improvement is underestimated by managers. On the other hand, it is pointed out that the increasing commercial aspects of self-assessment and the Quality Award process is diluting their effects. Based on the findings, two matrices have been developed which define the organisational and TQM related characteristics that an organisation should exhibit before adopting a particular approach to self-assessment.
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