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Different tau biomarkers become abnormal at different stages of Alzheimer’s disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in tau-PET, cortical thickness and cognitive decline in amyloid-β-positive individuals with elevated CSF p-tau levels (P+) but subthreshold Tau-PET retention (T−). To this end, individuals without dementia (i.e. cognitively unimpaired or mild cognitive impairment, n = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF p-tau217 and 18F-RO948 (Tau) PET, yielding groups of tau-concordant-negative (A+P−T−; n = 30), tau-discordant (i.e. A+P+T−; n = 48) and tau-concordant-positive (A+P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in tau-PET was faster in the A+P+T− group than in the control and A+P−T− groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A+P+T− group showed a slower rate of increase in tau-PET compared to the A+P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A+P+T− and A+P−T− groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A+P+T− biomarker profile in persons without dementia is associated with an isolated effect on increased tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring the effects of interventions with disease-modifying agents on tau accumulation in early Alzheimer’s disease, and for examining the emergence of tau aggregates in Alzheimer’s disease. Further, we suggest updating the AT(N) criteria for Alzheimer’s disease biomarker classification to APT(N).

According to transactional stress theory (TST), the extent to which entrepreneurs cope with errors by engaging in error damage control or ruminating about disengaging from their business goals depends on whether they interpret action errors as predominantly challenging or threatening. Using latent profile analysis (LPA), the current study investigates the existence of latent profiles of challenge and threat appraisal of entrepreneurial errors and their relationship with error damage control and rumination about business goal disengagement in a sample of 649 entrepreneurs. The results identify five appraisal profiles characterized by different challenge and threat appraisal intensities. The levels of error damage control and rumination about business goal disengagement differed between the profiles. Specifically, entrepreneurs high in challenge and threat appraisal showed higher levels of both forms of coping than those low in appraisal. Entrepreneurs falling into a high challenge and low threat appraisal profile exhibited the lowest level of business goal disengagement. Still, they showed similar levels of error damage control to those high on challenge and threat appraisal. Implications for the further development of TST and the development of effective error management interventions are discussed.

Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer’s disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer’s disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer’s and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighborhood – the Anterior-Temporal and Posterior-Medial brain networks – in normal agers, individuals with preclinical Alzheimer’s disease, and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer’s disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted ‘U-shaped’ relationship between functional connectivity and Alzheimer’s stage. According to our results, the preclinical phase of Alzheimer’s disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbors in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer’s disease. Instead, patients with symptomatic Alzheimer’s disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (1) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (2) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and, (3) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer’s disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging vs. Alzheimer’s disease.

Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods.Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere.Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA-binding protein 43 (TDP-43) and α-synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP-43 and α-synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35.We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases.Neurodegenerative disorders are associated with co-occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.

In the Multi beam source (MBS) of our Multi Beam Scanning Electron Microscope (MBSEM), an aperture lens array (ALA) splits the emission cone of the Schottky field emitter into multiple beamlets. When the apertures in the ALA are close to each other, the ALA can introduce aberrations to these beamlets through the electrostatic interaction of neighbouring apertures with each aperture's lens field. When the apertures are arranged in a square grid pattern, the aberration causes fourfold astigmatism. The effect on the beam spot is analyzed through a combination of 3D simulations and experimental validation. To counterbalance the fourfold astigmatism, a correction scheme is proposed in which a slightly non-round profile is applied to the aperture lenses.

In this contribution we investigate the conceptual coherence of penal substitution and its moral validity. After assessing two opposing modern contributions (Stevin Porter and Mark Murphy), we turn to Reformed and medieval scholasticism (Owen, Van Mastricht, and Duns Scotus). This scholastic manoeuvre sheds additional light on the analytic questions at issue. Following Owen and Scotus in their use of a relational analysis of guilt and its punishment, we argue that penal substitution is conceptually and morally coherent, albeit not univocally vis-a-vis ordinary punishment. Absent from the case of substitution is personal deservedness; herein we follow Murphy. However, this leaves open the conceptual possibility of representative deservedness (pace Murphy).

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n= 68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n= 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau (n= 186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area (BA)35 structurally covaried within the AT network while the parahippocampal cortex (PHC) covaried within the PM network. In addition, these networks are differentially associated with relative tau and amyloid burden, with higher tau levels in AT than in PM and higher amyloid levels in PM than in AT. Our results also suggest differences in the relative burden of tau species. The current results provide further support for the notion that two distinct MTL networks display differential alterations in the context of AD. These findings have important implications for disease spread and the cognitive manifestations of AD.SIGNIFICANCE STATEMENTThe current study provides further support for the notion that two distinct medial temporal lobe (MTL) networks, i.e., anterior-temporal (AT) and the posterior-medial (PM), display differential alterations in the context of Alzheimer's disease (AD). Importantly, neurodegeneration appears to occur within these networks in a dissociable manner marked by their covariance patterns. In addition, the AT and PM networks are also differentially associated with relative tau and amyloid burden, and perhaps differences in the relative burden of tau species [e.g., neurofibriliary tangles (NFTs) vs tau in neuritic plaques]. These findings, in the context of a growing literature consistent with the present results, have important implications for disease spread and the cognitive manifestations of AD in light of the differential cognitive processes ascribed to them.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images., In this commentary, we outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies. This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images.

Molybdenum and rhodium are foreseen to be utilized in ITER for the light reflecting, plasma facing components called first mirrors (FMs). In this work, the plasma and impurity conditions which FMs are expected to be subjected to were simulated experimentally, while monitoring their reflectivity. Experiments include deuterium plasma exposure with tungsten–carbon and tungsten–aluminum impurities, where aluminum was employed as a proxy for beryllium. The surface composition and morphology of the mirrors were characterized with XPS and SEM. When carbon was present in the plasma, the molybdenum surface became carbidized, while this effect was not observed for rhodium. Aluminum impurities were deposited as oxides, whereas tungsten was either oxidized or carbidized depending on the presence of carbon in the plasma. SEM results show the deposits to be amorphous. The mirrors in erosion conditions showed no critical decrease in the reflectivity, whereas the degradation was severe in net deposition conditions involving carbon. Cleaning techniques have to be developed for mirrors in deposition conditions, which should be part of ITER’s routine operation.

The effects of low flux, low temperature deuterium plasma (LTP) exposure on nanocrystalline rhodium (Rh) films are investigated. The exposures do not cause any surface damage on the nanoscale and the specific electrical resistivity of the films remains invariant during exposures. However, the spectral reflectivity of Rh decreases during exposure and recovers very slowly during subsequent storage in high vacuum. This drop in the reflectivity can be associated with a formation of a subsurface rhodium deuteride (RhD x , x ≤ 2), which has optical constants different to those of Rh. After air storage of the exposed samples, the Rh surface gets depopulated of deuterium adsorbates due to a catalytic reaction taking place between oxygen and deuterium, which results in a diffusion of the incorporated deuterium first to the surface and then into the air. Consequently, the reflectivity is rapidly recovered. Comparison of the ultraviolet photoelectron spectroscopy (UPS) measurements performed before and after plasma exposure reveals an increase in the work function which is attributed to deuterium adsorbates on the surface. Changes in the valence band structure were also observed with UPS measurements, lending support to the suggestion of subsurface RhD x formation. Deuterium atoms in Rh are electron donors filling the 4d states above the Fermi level, thus reducing optical transitions.

Metallic mirrors are foreseen to play a crucial role for all optical diagnostics in ITER. Therefore, the development of reliable techniques for the production of mirrors which are able to maintain their optical properties in the harsh ITER environment is highly important. By applying magnetron sputtering and evaporation techniques, rhodium and molybdenum films have been prepared for tokamak tests. The films were characterised in terms of chemical composition, surface roughness, crystallite structure, reflectivity and adhesion. No impurities were detected on the surface after deposition. The effects of deposition parameters and substrate temperature on the resulting crystallite structure, surface roughness and hence on the reflectivity, were investigated. The films are found to exhibit nanometric crystallites with a dense columnar structure. Open boundaries between the crystallite columns, which are sometimes present after evaporation, are found to reduce the reflectivity as compared to rhodium or molybdenum references.

Low aspect ratio plasmas in devices such as the mega ampere spherical tokamak (MAST) are characterized by strong toroidicity, strong shaping and self fields, low magnetic field, high beta, large plasma flow and high intrinsic E × B flow shear. These characteristics have important effects on plasma behaviour, provide a stringent test of theories and scaling laws and offer new insight into underlying physical processes, often through the amplification of effects present in conventional tokamaks (e.g. impact of fuelling source and magnetic geometry on H-mode access). The enhancement of neoclassical effects makes MAST ideal for the study of particle pinch processes and neoclassical resistivity corrections, which can be assessed with unique accuracy. MAST data have an important influence on scaling laws for confinement and H-mode threshold power, exerting strong leverage on the form of these scaling laws (e.g. scaling with aspect ratio, beta, magnetic field, etc). The high intrinsic flow shear is conducive to transport barrier formation by turbulence suppression. Internal transport barriers are readily formed in MAST with both co- and counter-NBI, and electron and ion thermal diffusivities have been reduced to the ion neoclassical level. The strong variation in toroidal field (~ × 5 in MAST) between the inboard and outboard plasma edges, provides a useful test of edge models prompting, for example, a comparison of inboard and outboard scrape-off-layer transport to highlight magnetic field effects. Low aspect ratio plasmas are also an ideal testing ground for plasma instabilities, such as neoclassical tearing modes, edge localized modes (ELMs) and Alfven eigenmodes, which are readily generated due to the supra-Alfvenic ion population. Examples of how MAST is providing new insights into such instabilities (e.g. ELM structure) are described.

A set of seven polycrystalline mirror samples retrieved from the JET tokamak has been cleaned in vacuum using a pulsed laser system. The surfaces of samples exposed to plasma during 2008–2009 campaigns as part of the second phase of a comprehensive first mirror test contained a mixture of carbon, beryllium and tritium. For this reason, the samples were treated in a vacuum chamber constructed specially for this purpose. In some cases mirrors show an increase of the specular reflectivity after cleaning, though beryllium and carbon deposits were not fully removed. Additionally, three samples coated in PISCES-B with a 110–120 nm beryllium layer were subjected to laser cleaning tests as well.

A set of seven polycrystalline mirror samples retrieved from the JET tokamak have been cleaned in vacuum using a pulsed laser system. The samples were exposed between 2008- 2009 as part of the second phase of a comprehensive first mirror test and contain a mixture of carbon, beryllium and tritium. For this reason, the samples were treated in a vacuum chamber especially constructed for this purpose. Additionally, three samples coated in PISCES-B with a 110-120nm beryllium layer were cleaned as well. The results are quite positive, most mirrors showing a substantial increase of the specular reflectivity after cleaning. The ones that do not appear to have been damaged already prior to cleaning.

A laser ablation system has been constructed and used to determine the damage threshold of stainless steel, rhodium and single-, poly- and nanocrystalline molybdenum in vacuum, at a number of wavelengths between 220 and 1064 nm using 5 ns pulses. All materials show an increase of the damage threshold with decreasing wavelength below 400 nm. Tests in a nitrogen atmosphere showed a decrease of the damage threshold by a factor of two to three. Cleaning tests have been performed in vacuum on stainless steel samples after applying mixed Al/W/C/D coatings using magnetron sputtering. In situ XPS analysis during the cleaning process as well ex situ reflectivity measurements demonstrate near complete removal of the coating and a substantial recovery of the reflectivity. The first results also show that the reflectivity obtained through cleaning at 532 nm may be further increased by additional exposure to UV light, in this case 230 nm, an effect which is attributed to the removal of tungsten dust from the surface., 19 pages, 16 figures

An in situ spectroscopic reflectometry system has been built to investigate the evolution of the specular reflectivity spectrum of ITER first mirror samples during plasma exposure. Results are presented for three different types of molybdenum mirror samples that were exposed to deuterium plasma, including single crystalline, nanocrystalline, and polycrystalline molybdenum. The results show good agreement with ex situ measurements of the reflectivity spectrum before and after exposure and extend the results obtained in previous experiments.

The 1973 Trojan survey of a region close to the preceding Lagrangian point is discussed in this paper. This region consists of four overlapping fields and one field for the photometric calibration, centered on Selected Area 68. Orbital elements of most of the 1504 asteroids found have been published in the Minor Planet Circulars. Among these are 5 Hungaria-type asteroids, 12 of the Hilda type and 55 Trojans. The accuracy of the orbits is somewhat lower than in the Palomar-Leiden survey of 1960, because of the shorter arc in the present investigation. A discussion of the degree of completeness of this material shows that the (photographic) magnitude interval 19.5–20.0 is only 50% complete; to obtain completeness down to magnitude 20.0 the number of found Trojans brighter than this limit has to be increased by 9. In combination with the surveys of 1960 and 1965 an improved distribution of the number of Trojans as a function of distance to the preceding Lagrangian point (L4) has been constructed. A preliminary discussion, including the result on L5, yields a value of 2.0 for the ratio of Trojans around L4 and L5, along the ecliptic. The L5 Trojans appear to be deficient in orbits of small inclination. Taking this into account we find this ratio again to be 2.0 for the total Trojan clouds around L4 and L5. Possibly, however, high-inclination Trojans were systematically overlooked in this survey. If this would be true, the ratio N (L4)/ N (L5) is increased to 2.3. The uncertainty of these numbers can be estimated to be ±0.5.