Targeting tauopathy with engineered tau-degrading intrabodies

BACKGROUND: The accumulation of pathological tau is the main component of neurofibrillary tangles and other tau aggregates in several neurodegenerative diseases, referred to as tauopathies. Recently, immunotherapeutic approaches targeting tau have been demonstrated to be beneficial in decreasing tauopathy in animal models. We previously found that passive immunotherapy with anti-tau antibody to human tau or expression of an anti-tau secreted single-chain variable fragment (scFv) in the central nervous system of a mouse model of tauopathy decreased but did not remove all tau-associated pathology. Although these and other studies demonstrate that conventional immunotherapeutic approaches targeting tau can influence tau pathogenesis, the majority of pathological tau remains in the cytosol of cells, not typically accessible to an extracellular antibody. Therefore, we reasoned targeting intracellular tau might be more efficacious in preventing or decreasing tauopathy. METHODS: By utilizing our anti-tau scFv, we generated anti-tau intrabodies for the expression in the cytosol of neurons. To enhance the degradation capacity of conventional intrabodies, we engineered chimeric anti-tau intrabodies fused to ubiquitin harboring distinct mutations that shuttle intracellular tau for either the proteasome or lysosomal mediated degradation. To evaluate the efficacy in delaying or eliminating tauopathy, we expressed our tau degrading intrabodies or controls in human tau transgenic mice by adeno-associated virus prior to overt tau pathology and after tau deposition. RESULTS: Our results demonstrate, the expression of chimeric anti-tau intrabodies significantly reduce tau protein levels in primary neuronal cultures expression human tau relative to a non-modified anti-tau intrabody. We found the expression of engineered tau-degrading intrabodies destined for proteasomal-mediated degradation are more effective in delaying or eliminating tauopathy than a conventional intrabody in aged human tau transgenic mice. CONCLUSION: This study, harnesses the strength of intrabodies that are amendable for targeting specific domains or modifications with the cell-intrinsic mechanisms that regulate protein degradation providing a new immunotherapeutic approach with potentially improved efficacy

Condiciones orgánicas y correlaciones de fuerza del movimiento estudiantil chileno.: Una aproximación desde la Confech (2011-2015)*

This paper aims at analyzing the organizational changes in the Confederation of Chilean Students (CONFECH) in the period 2011-2015 and the complexities of the process of institutionalization in the context of the government of Sebastián Piñera and the subsequent administration of Michelle Bachelet. It argues, in the main, that the processes of growth and fragmentation of space CONFECH have generated an increase in the cost of decision-making and collective coordination has become more complex political management capacity of the Executive Board

{\it Ab initio} 27Al^{27}Al NMR chemical shifts and quadrupolar parameters for Al2O3Al_2O_3 phases and their precursors

The Gauge-Including Projector Augmented Wave (GIPAW) method, within the Density Functional Theory (DFT) Generalized Gradient Approximation (GGA) framework, is applied to compute solid state NMR parameters for $^{27}Al$ in the $\alpha$, $\theta$, and $\kappa$ aluminium oxide phases and their gibbsite and boehmite precursors. The results for well-established crystalline phases compare very well with available experimental data and provide confidence in the accuracy of the method. For $\gamma$-alumina, four structural models proposed in the literature are discussed in terms of their ability to reproduce the experimental spectra also reported in the literature. Among the considered models, the $Fd\bar{3}m$ structure proposed by Paglia {\it et al.} [Phys. Rev. B {\bf 71}, 224115 (2005)] shows the best agreement. We attempt to link the theoretical NMR parameters to the local geometry. Chemical shifts depend on coordination number but no further correlation is found with geometrical parameters. Instead our calculations reveal that, within a given coordination number, a linear correlation exists between chemical shifts and Born effective charges

The current population of benchmark brown dwarfs

The number of brown dwarfs (BDs) now identified tops 700. Yet our understanding of these cool objects is still lacking, and models are struggling to accurately reproduce observations. What is needed is a method of calibrating the models, BDs whose properties (e.g. age, mass, distance, metallicity) that can be independently determined can provide such calibration. The ability to calculate properties based on observables is set to be of vital importance if we are to be able to measure the properties of fainter, more distant populations of BDs that near-future surveys will reveal, for which ground based spectroscopic studies will become increasingly difficult. We present here the state of the current population of age benchmark brown dwarfs.Comment: 2 pages, 1 figure, to appear in the conference proceedings "New Technologies for Probing the Diversity of Brown Dwarfs and Exoplanets", Shanghai, 19-24 July, 200

The order parameter-entropy relation in some universal classes: experimental evidence

The asymptotic behaviour near phase transitions can be suitably characterized by the scaling of $\Delta s/Q^2$ with $\epsilon=1-T/T_c$, where $\Delta s$ is the excess entropy and $Q$ is the order parameter. As $\Delta s$ is obtained by integration of the experimental excess specific heat of the transition $\Delta c$, it displays little experimental noise so that the curve $\log(\Delta s/Q^2)$ versus $\log\epsilon$ is better constrained than, say, $\log\Delta c$ versus $\log\epsilon$. The behaviour of $\Delta s/Q^2$ for different universality classes is presented and compared. In all cases, it clearly deviates from being a constant. The determination of this function can then be an effective method to distinguish asymptotic critical behaviour. For comparison, experimental data for three very different systems, Rb2CoF4, Rb2ZnCl4 and SrTiO3, are analysed under this approach. In SrTiO3, the function $\Delta s/Q^2$ does not deviate within experimental resolution from a straight line so that, although Q can be fitted with a non mean-field exponent, the data can be explained by a classical Landau mean-field behaviour. In contrast, the behaviour of $\Delta s/Q^2$ for the antiferromagnetic transition in Rb2CoF4 and the normal-incommensurate phase transition in Rb2ZCl4 is fully consistent with the asymptotic critical behaviour of the universality class corresponding to each case. This analysis supports, therefore, the claim that incommensurate phase transitions in general, and the A$_2$BX$_4$ compounds in particular, in contrast with most structural phase transitions, have critical regions large enough to be observable.Comment: 13 pp. 9 ff. 2 tab. RevTeX. Submitted to J. Phys.: Cond. Matte

Transcriptomic analysis of the hepatic response to stress in the red cusk-eel (Genypterus chilensis): Insights into lipid metabolism, oxidative stress and liver steatosis

Indexación: Scopus.Teleosts exhibit a broad divergence in their adaptive response to stress, depending on the magnitude, duration, and frequency of stressors and the species receiving the stimulus. We have previously reported that the red cusk-eel (Genypterus chilensis), an important marine farmed fish, shows a physiological response to stress that results in increased skeletal muscle atrophy mediated by over-expression of components of the ubiquitin proteasome and autophagy-lysosomal systems. To better understand the systemic effects of stress on the red cusk-eel metabolism, the present study assessed the transcriptomic hepatic response to repetitive handling-stress. Using high-Throughput RNA-seq, 259 up-regulated transcripts were found, mostly associated with angiogenesis, gluconeogenesis, and triacylglyceride catabolism. Conversely, 293 transcripts were down-regulated, associated to cholesterol biosynthesis, PPARα signaling, fatty acid biosynthesis, and glycolysis. This gene signature was concordant with hepatic metabolite levels and hepatic oxidative damage. Moreover, the increased plasmatic levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase) and AP (alkaline phosphatase), as well as liver histology suggest stress-induced liver steatosis. This study offers an integrative molecular and biochemical analysis of the hepatic response to handling-stress, and reveals unknown aspects of lipid metabolism in a non-model teleost.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.017644

Avalanche criticality in the martensitic transition of Cu67.64Zn16.71Al15.65 shape-memory alloy: a calorimetric and acoustic emission study

The first-order diffusionless structural transition in Cu67.64Zn16.71Al15.65 is characterized by jerky propagation of phase fronts related to the appearance of avalanches. In this paper, we describe a full analysis of this avalanche behavior using calorimetric heat-flux measurements and acoustic emission measurements. Two different propagation modes, namely, smooth front propagation and jerky avalanches, were observed in extremely slow measurements with heating and cooling rates as low as a few 10−3 K/h. Avalanches show criticality where each avalanche leads to a spike in the heat flux. Their statistical analysis leads to a power law [P(E)∼E−ε, where P(E)dE is the probability to observe an avalanche with energy E in an interval between E and E+dE] with an energy exponent of ε=2.15±0.15 in excellent agreement with the results of acoustic emission measurements. Avalanches appear to be more common for heating rates faster than 5×10−3 K/h whereas smooth front propagation occurs in all calorimetric measurements and (almost) exclusively for slower heating rates. Repeated cooling runs were taken after a waiting time of 1 month (and an intermediate heating run). Correlations between the avalanche sequences of the two cooling runs were found for the strongest avalanche peaks but not for the full sequence of avalanches. The memory effect is hence limited to strong avalanches