Why the idea of framework propositions cannot contribute to an understanding of delusions

One of the tasks that recent philosophy of psychiatry has taken upon itself is to extend the range of understanding to some of those aspects of psychopathology that Jaspers deemed beyond its limits. Given the fundamental difficulties of offering a literal interpretation of the contents of primary delusions, a number of alternative strategies have been put forward including regarding them as abnormal versions of framework propositions described by Wittgenstein in On Certainty. But although framework propositions share some of the apparent epistemic features of primary delusions, their role in partially constituting the sense of inquiry rules out their role in helping to understand delusions

Resonant interaction between runaway electrons and the toroidal magnetic field ripple in TCV

This work explains the anomalously high runaway electron (RE) pitch angles inferred in the flat-top of dedicated Tokamak à Configuration Variable (TCV) experiments. Kinetic modelling shows that the resonant interaction between the gyromotion of the electrons and the toroidal magnetic field ripple will give rise to strong pitch angle scattering in TCV. The resulting increase in synchrotron radiation power losses acts as a RE energy barrier. These observations are tested experimentally by a magnetic field ramp-down, which gradually reduces the resonant parallel momentum at which the REs interact with the ripple. Resulting changes in synchrotron emission geometry and intensity are observed using three multi-spectral camera imaging systems, viewing the RE beam at distinct spatial angles in multiple wavelength ranges. Experimental reconstructions of the RE distribution in momentum- and real-space are consistent with kinetic model predictions.</p

Identification and in vivo characterization of a brain-penetrating nanobody

BACKGROUND: Preclinical models to determine blood to brain transport ability of therapeutics are often ambiguous. In this study a method is developed that relies on CNS target-engagement and is able to rank brain-penetrating capacities. This method led to the discovery of an anti-transferrin receptor nanobody that is able to deliver a biologically active peptide to the brain via receptor-mediated transcytosis. METHODS: Various nanobodies against the mouse transferrin receptor were fused to neurotensin and injected peripherally in mice. Neurotensin is a neuropeptide that causes hypothermia when present in the brain but is unable to reach the brain from the periphery. Continuous body temperature measurements were used as a readout for brain penetration of nanobody-neurotensin fusions after its peripheral administration. Full temperature curves were analyzed using two-way ANOVA with Dunnett multiple comparisons tests. RESULTS: One anti-transferrin receptor nanobody coupled to neurotensin elicited a drop in body temperature following intravenous injection. Epitope binning indicated that this nanobody bound a distinct transferrin receptor epitope compared to the non-crossing nanobodies. This brain-penetrating nanobody was used to characterize the in vivo hypothermia model. The hypothermic effect caused by neurotensin is dose-dependent and could be used to directly compare peripheral administration routes and various nanobodies in terms of brain exposure. CONCLUSION: This method led to the discovery of an anti-transferrin receptor nanobody that can reach the brain via receptor-mediated transcytosis after peripheral administration. This method could be used to assess novel proteins for brain-penetrating capabilities using a target-engaging readout

The muscle fiber type–fiber size paradox: hypertrophy or oxidative metabolism?

An inverse relationship exists between striated muscle fiber size and its oxidative capacity. This relationship implies that muscle fibers, which are triggered to simultaneously increase their mass/strength (hypertrophy) and fatigue resistance (oxidative capacity), increase these properties (strength or fatigue resistance) to a lesser extent compared to fibers increasing either of these alone. Muscle fiber size and oxidative capacity are determined by the balance between myofibrillar protein synthesis, mitochondrial biosynthesis and degradation. New experimental data and an inventory of critical stimuli and state of activation of the signaling pathways involved in regulating contractile and metabolic protein turnover reveal: (1) higher capacity for protein synthesis in high compared to low oxidative fibers; (2) competition between signaling pathways for synthesis of myofibrillar proteins and proteins associated with oxidative metabolism; i.e., increased mitochondrial biogenesis via AMP-activated protein kinase attenuates the rate of protein synthesis; (3) relatively higher expression levels of E3-ligases and proteasome-mediated protein degradation in high oxidative fibers. These observations could explain the fiber type–fiber size paradox that despite the high capacity for protein synthesis in high oxidative fibers, these fibers remain relatively small. However, it remains challenging to understand the mechanisms by which contractile activity, mechanical loading, cellular energy status and cellular oxygen tension affect regulation of fiber size. Therefore, one needs to know the relative contribution of the signaling pathways to protein turnover in high and low oxidative fibers. The outcome and ideas presented are relevant to optimizing treatment and training in the fields of sports, cardiology, oncology, pulmonology and rehabilitation medicine

Characterisation of detachment in the MAST-U Super-X divertor using multi-wavelength imaging of 2D atomic and molecular emission processes

In this work, we provide the first 2D spatially resolved description of radiative detachment in MAST-U Super-X L-mode divertor plasmas. The Super-X magnetic configuration was designed to achieve reduced heat- and particle loads at the divertor target compared to conventional exhaust solutions. We use filtered camera imaging to reconstruct 2D emissivity profiles in the poloidal plane for multiple atomic and molecular emission lines and bands. A set of deuterium fuelling scans is discussed that, together, span attached to deeply detached divertor states observed in MAST-U. Emissivity profiles facilitate separate analysis of locked-mode induced split branches of the scrape-off layer. Molecular deuterium Fulcher band emission front tracking reveals that the deuterium electron-impact ionisation front, for which it serves a proxy, detaches at different upstream electron densities in the split branches. Upon detachment of this ionisation front, Balmer emission attributed to molecular activated recombination appears near-target. We report a simultaneous radial broadening of the emission leg, consistent with previous SOLPS-ITER modelling. With increased fuelling this emission region detaches, implying electron temperatures below ∼ 1 eV. In this phase, 2D Balmer line ratio reconstruction indicates an onset of volumetric direct electron-ion recombination near-target. At the highest fuelling rates this emission region moves off-target, suggesting a drop in near-wall electron density accompanying the low temperatures.</p

Endo-prosthesis, a femoral head prosthesis and an acetabulum prosthesis

A prosthesis for insertion into a long bone includes a stem which has been shaped so as to evenly distribute low stress to the bone. A synthetic resinous sheath surrounds the stem which effects a contact surface between the stem and the bone. The prosthesis includes an extension which extends outwardly of the bone and has a ball and socket thereon.</p