Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.

BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy

Recursive Definitions of Monadic Functions

Using standard domain-theoretic fixed-points, we present an approach for defining recursive functions that are formulated in monadic style. The method works both in the simple option monad and the state-exception monad of Isabelle/HOL's imperative programming extension, which results in a convenient definition principle for imperative programs, which were previously hard to define. For such monadic functions, the recursion equation can always be derived without preconditions, even if the function is partial. The construction is easy to automate, and convenient induction principles can be derived automatically.Comment: In Proceedings PAR 2010, arXiv:1012.455

張州雑志の世界

Cities are increasingly exposed to extreme climate events such as floods and droughts. Land use change is also expected to reduce the availability of green spaces and intensify extreme heat events. Given these pressures on the quality of life of urban dwellers, there is a great need to improve the integrated management of water to enable sustainable development of rapidly growing cities and improve human well-being. A promising way to make urban communities more liveable is to invest in green water technologies, that is, decentralised and low-energy water supply, wastewater and stormwater solutions, to foster the transition to more sustainable and resilient cities. However, the adoption of multifunctional water technologies is a complex issue that requires cross-disciplinary approaches, demanding innovative thinking and practice. Despite the increasing body of literature on the benefits of decentralised water technologies, several barriers to their adoption remain. This paper uses an agent-based model that integrates social and environmental factors, as well as economic evaluation of water services provided by water technologies to assess the decision-making of two types of agents. The model is applied to evaluate incentive-based strategies to increase the adoption of rainwater tanks in Melbourne, a city that has suffered from severe droughts over the last decades. The model shows that using economic evaluation may not be adequate to understand the dynamics of rainwater tank uptake. Social factors such as public education might have played a role on decisions of households. This tool will be further tested and validated to explore policies and robust strategies to enable sustainable water management in rapidly developing cities.</p

Tandem X-ray absorption spectroscopy and scattering forin situtime-resolved monitoring of gold nanoparticle mechanosynthesis

Current time-resolvedin situapproaches limit the scope of mechanochemical investigations possible. Here we develop a new, general approach to simultaneously follow the evolution of bulk atomic and electronic structure during a mechanochemical synthesis. This is achieved by coupling two complementary synchrotron-based X-ray methods: X-ray absorption spectroscopy (XAS) and X-ray diffraction. We apply this method to investigate the bottom-up mechanosynthesis of technologically important Au micro and nanoparticles in the presence of three different reducing agents, hydroquinone, sodium citrate, and NaBH4. Moreover, we show how XAS offers new insight into the early stage generation of growth species (e.g.monomers and clusters), which lead to the subsequent formation of nanoparticles. These processes are beyond the detection capabilities of diffraction methods. This combined X-ray approach paves the way to new directions in mechanochemical research of advanced electronic materials.Peer reviewe

The Green Bank Ammonia Survey (GAS): First Results of NH3 mapping the Gould Belt

We present an overview of the first data release (DR1) and first-look science from the Green Bank Ammonia Survey (GAS). GAS is a Large Program at the Green Bank Telescope to map all Gould Belt star-forming regions with $A_V \gtrsim 7$ mag visible from the northern hemisphere in emission from NH$_3$ and other key molecular tracers. This first release includes the data for four regions in Gould Belt clouds: B18 in Taurus, NGC 1333 in Perseus, L1688 in Ophiuchus, and Orion A North in Orion. We compare the NH$_3$ emission to dust continuum emission from Herschel, and find that the two tracers correspond closely. NH$_3$ is present in over 60\% of lines-of-sight with $A_V \gtrsim 7$ mag in three of the four DR1 regions, in agreement with expectations from previous observations. The sole exception is B18, where NH$_3$ is detected toward ~ 40\% of lines-of-sight with $A_V \gtrsim 7$ mag. Moreover, we find that the NH$_3$ emission is generally extended beyond the typical 0.1 pc length scales of dense cores. We produce maps of the gas kinematics, temperature, and NH$_3$ column densities through forward modeling of the hyperfine structure of the NH$_3$ (1,1) and (2,2) lines. We show that the NH$_3$ velocity dispersion, ${\sigma}_v$, and gas kinetic temperature, $T_K$, vary systematically between the regions included in this release, with an increase in both the mean value and spread of ${\sigma}_v$ and $T_K$ with increasing star formation activity. The data presented in this paper are publicly available.Comment: 33 pages, 27 figures, accepted to ApJS. Datasets are publicly available: https://dataverse.harvard.edu/dataverse/GAS_DR

Droplets I: Pressure-Dominated Sub-0.1 pc Coherent Structures in L1688 and B18

We present the observation and analysis of newly discovered coherent structures in the L1688 region of Ophiuchus and the B18 region of Taurus. Using data from the Green Bank Ammonia Survey (GAS), we identify regions of high density and near-constant, almost-thermal, velocity dispersion. Eighteen coherent structures are revealed, twelve in L1688 and six in B18, each of which shows a sharp "transition to coherence" in velocity dispersion around its periphery. The identification of these structures provides a chance to study the coherent structures in molecular clouds statistically. The identified coherent structures have a typical radius of 0.04 pc and a typical mass of 0.4 Msun, generally smaller than previously known coherent cores identified by Goodman et al. (1998), Caselli et al. (2002), and Pineda et al. (2010). We call these structures "droplets." We find that unlike previously known coherent cores, these structures are not virially bound by self-gravity and are instead predominantly confined by ambient pressure. The droplets have density profiles shallower than a critical Bonnor-Ebert sphere, and they have a velocity (VLSR) distribution consistent with the dense gas motions traced by NH3 emission. These results point to a potential formation mechanism through pressure compression and turbulent processes in the dense gas. We present a comparison with a magnetohydrodynamic simulation of a star-forming region, and we speculate on the relationship of droplets with larger, gravitationally bound coherent cores, as well as on the role that droplets and other coherent structures play in the star formation process.Comment: Accepted by ApJ in April, 201

iNNk: A Multi-Player Game to Deceive a Neural Network

This paper presents iNNK, a multiplayer drawing game where human players team up against an NN. The players need to successfully communicate a secret code word to each other through drawings, without being deciphered by the NN. With this game, we aim to foster a playful environment where players can, in a small way, go from passive consumers of NN applications to creative thinkers and critical challengers

Natural variations in the biofilm-associated protein BslA from the genus <i>Bacillus</i>

AbstractBslA is a protein secreted by Bacillus subtilis which forms a hydrophobic film that coats the biofilm surface and renders it water-repellent. We have characterised three orthologues of BslA from Bacillus amyloliquefaciens, Bacillus licheniformis and Bacillus pumilus as well as a paralogue from B. subtilis called YweA. We find that the three orthologous proteins can substitute for BslA in B. subtilis and confer a degree of protection, whereas YweA cannot. The degree to which the proteins functionally substitute for native BslA correlates with their in vitro biophysical properties. Our results demonstrate the use of naturally-evolved variants to provide a framework for teasing out the molecular basis of interfacial self-assembly.</jats:p

Ovarian Cancer Progression is Controlled by Phenotypic Changes in Dendritic Cells

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable antitumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity