Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils

Pathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. The emergence of disease-specific tau aggregate structures termed tau strains, however, remains elusive. Here we show that full-length tau protein can be aggregated in the absence of co-factors into seeding-competent amyloid fibrils that sequester RNA. Using a combination of solid-state NMR spectroscopy and biochemical experiments we demonstrate that the co-factor-free amyloid fibrils of tau have a rigid core that is similar in size and location to the rigid core of tau fibrils purified from the brain of patients with corticobasal degeneration. In addition, we demonstrate that the N-terminal 30 residues of tau are immobilized during fibril formation, in agreement with the presence of an N-terminal epitope that is specifically detected by antibodies in pathological tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that the co-factor-free tau fibrils strongly sequester RNA. Taken together the study provides a critical advance to reveal the molecular factors that guide aggregation towards disease-specific tau strains

Globular domain of the prion protein needs to be unlocked by domain swapping to support prion protein conversion

Prion diseases are fatal transmissible neurodegenerative diseases affecting many mammalian species. The normal prion protein (PrP) converts into a pathological aggregated form, PrPSc, which is enriched in the β-sheet structure. While the high resolution structure of the normal PrP was determined, the structure of the converted form of PrP remains inaccessible to high resolution techniques. In order to map the PrP conversion process we introduced disulfide bridges into different positions within the globular domain of PrP, tethering selected secondary structure elements. The majority of tethered PrP mutants exhibited increased thermodynamic stability, nevertheless they converted efficiently. Only the disulfides which tether subdomain B1-H1-B2 to subdomain H2-H3 prevented PrP conversion in vitro and in prion infected cell cultures. Reduction of disulfides recovered the ability of these mutants to convert, demonstrating that the separation of subdomains is an essential step in conversion. Formation of disulfide-linked proteinase K-resistant dimers in fibrils composed of a pair of single cysteine mutants supports the model based on domain-swapped dimers as the building blocks of prion fibrils. In contrast to previously proposed structural models of PrPSc suggesting conversion of large secondary structure segments, we provide evidence for the conservation of secondary structure elements of the globular domain upon PrP conversion. Previous studies already showed that dimerization is the rate-limiting step in PrP conversion. We show that separation and swapping of subdomains of the globular domain is necessary for conversion. Therefore, we propose that domain-swapped dimer of PrP precedes amyloid formation and represents a potential target for therapeutic intervention

Pump-power-driven mode switching in a microcavity device and its relation to Bose-Einstein condensation

TL, DV, and HAML contributed equally to this work. DV is grateful for support from the Studienstiftung des Deutschen Volkes. We acknowlege funding from the European Research Council under the European Union's Seventh Framework ERC Grant Agreeement No. 615613 and from the German Research Foundation (DFG) via Project No. Re2974/3-1 and the Research Unit FOR2414.We investigate the switching of the coherent emission mode of a bimodal microcavity device, occurring when the pump power is varied. We compare experimental data to theoretical results and identify the underlying mechanism based on the competition between the effective gain, on the one hand, and the intermode kinetics, on the other. When the pumping is ramped up, above a threshold, the mode with the largest effective gain starts to emit coherent light, corresponding to lasing. In contrast, in the limit of strong pumping, it is the intermode kinetics that determines which mode acquires a large occupation and shows coherent emission. We point out that this latter mechanism is akin to the equilibrium Bose-Einstein condensation of massive bosons. Thus, the mode switching in our microcavity device can be viewed as a minimal instance of Bose-Einstein condensation of photons. Moreover, we show that the switching from one cavity mode to the other always occurs via an intermediate phase where both modes are emitting coherent light and that it is associated with both superthermal intensity fluctuations and strong anticorrelations between both modes.Publisher PDFPeer reviewe

Visual masking and the dynamics of human perception, cognition, and consciousness A century of progress, a contemporary synthesis, and future directions

The 1990s, the “decade of the brain,” witnessed major advances in the study of visual perception, cognition, and consciousness. Impressive techniques in neurophysiology, neuroanatomy, neuropsychology, electrophysiology, psychophysics and brain-imaging were developed to address how the nervous system transforms and represents visual inputs. Many of these advances have dealt with the steady-state properties of processing. To complement this “steady-state approach,” more recent research emphasized the importance of dynamic aspects of visual processing. Visual masking has been a paradigm of choice for more than a century when it comes to the study of dynamic vision. A recent workshop (http://lpsy.epfl.ch/VMworkshop/), held in Delmenhorst, Germany, brought together an international group of researchers to present state-of-the-art research on dynamic visual processing with a focus on visual masking. This special issue presents peer-reviewed contributions by the workshop participants and provides a contemporary synthesis of how visual masking can inform the dynamics of human perception, cognition, and consciousness

Adsorption Isotherms of Hydrogen: The Role of Thermal Fluctuations

It is shown that experimentally obtained isotherms of adsorption on solid substrates may be completely reconciled with Lifshitz theory when thermal fluctuations are taken into account. This is achieved within the framework of a solid-on-solid model which is solved numerically. Analysis of the fluctuation contributions observed for hydrogen adsorption onto gold substrates allows to determine the surface tension of the free hydrogen film as a function of film thickness. It is found to decrease sharply for film thicknesses below seven atomic layers.Comment: RevTeX manuscript (3 pages output), 3 figure

Distinct Timing Mechanisms Produce Discrete and Continuous Movements

The differentiation of discrete and continuous movement is one of the pillars of motor behavior classification. Discrete movements have a definite beginning and end, whereas continuous movements do not have such discriminable end points. In the past decade there has been vigorous debate whether this classification implies different control processes. This debate up until the present has been empirically based. Here, we present an unambiguous non-empirical classification based on theorems in dynamical system theory that sets discrete and continuous movements apart. Through computational simulations of representative modes of each class and topological analysis of the flow in state space, we show that distinct control mechanisms underwrite discrete and fast rhythmic movements. In particular, we demonstrate that discrete movements require a time keeper while fast rhythmic movements do not. We validate our computational findings experimentally using a behavioral paradigm in which human participants performed finger flexion-extension movements at various movement paces and under different instructions. Our results demonstrate that the human motor system employs different timing control mechanisms (presumably via differential recruitment of neural subsystems) to accomplish varying behavioral functions such as speed constraints

Anti-prion drug mPPIg5 inhibits PrP(C) conversion to PrP(Sc).

Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. The 'protein only hypothesis' advocates that PrP(Sc), an abnormal isoform of the cellular protein PrP(C), is the main and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminate PrPSc in cell culture models. Of particular interest are synthetic polymers known as dendrimers which possess the unique ability to eliminate PrP(Sc) in both an intracellular and in vitro setting. The efficacy and mode of action of the novel anti-prion dendrimer mPPIg5 was investigated through the creation of a number of innovative bio-assays based upon the scrapie cell assay. These assays were used to demonstrate that mPPIg5 is a highly effective anti-prion drug which acts, at least in part, through the inhibition of PrP(C) to PrP(Sc) conversion. Understanding how a drug works is a vital component in maximising its performance. By establishing the efficacy and method of action of mPPIg5, this study will help determine which drugs are most likely to enhance this effect and also aid the design of dendrimers with anti-prion capabilities for the future

Disentangling neural processing of masked and masking stimulus by means of event-related contralateral – ipsilateral differences of EEG potentials

In spite of the excellent temporal resolution of event-related EEG potentials (ERPs), the overlapping potentials evoked by masked and masking stimuli are hard to disentangle. However, when both masked and masking stimuli consist of pairs of relevant and irrelevant stimuli, one left and one right from fixation, with the side of the relevant element varying between pairs, effects of masked and masking stimuli can be distinguished by means of the contralateral preponderance of the potentials evoked by the relevant elements, because the relevant elements may independently change sides in masked and masking stimuli. Based on a reanalysis of data from which only selected contralateral-ipsilateral effects had been previously published, the present contribution will provide a more complete picture of the ERP effects in a masked-priming task. Indeed, effects evoked by masked primes and masking targets heavily overlapped in conventional ERPs and could be disentangled to a certain degree by contralateral-ipsilateral differences. Their major component, the N2pc, is interpreted as indicating preferential processing of stimuli matching the target template, which process can neither be identified with conscious perception nor with shifts of spatial attention. The measurements showed that the triggering of response preparation by the masked stimuli did not depend on their discriminability, and their priming effects on the processing of the following target stimuli were qualitatively different for stimulus identification and for response preparation. These results provide another piece of evidence for the independence of motor-related and perception-related effects of masked stimuli

Electrophysiological activation by masked primes: Independence of prime-related and target-related activities

Visual stimuli that are made invisible by metacontrast masking (primes) have a marked influence on behavioral and psychophysiological measures such as reaction time (RT) and the lateralized readiness potential (LRP). 4 experiments are reported that shed light on the effects that masked primes have on the LRP. Participants had a go-nogo task in which the prime was associated with 1 of 2 responses even if the target required participants to refrain from responding. To analyze the electrophysiological responses, we computed the LRP and applied an averaging method separating the activation due to the prime and the target. The results demonstrated that (a) masked primes activate responses even in a nogo situation, (b) this prime-related activation is independent of masking, (c) and is also independent of whether prime and target require the same responses (congruent condition) or different responses (incongruent condition)