Stable Polyglutamine Dimers Can Contain β-Hairpins with Interdigitated Side Chains But Not α-Helices, β-Nanotubes, β-Pseudohelices, or Steric Zippers

AbstractA common thread connecting nine fatal neurodegenerative protein aggregation diseases is an abnormally expanded polyglutamine tract found in the respective proteins. Although the structure of this tract in the large mature aggregates is increasingly well described, its structure in the small early aggregates remains largely unknown. As experimental evidence suggests that the most toxic species along the aggregation pathway are the small early ones, developing strategies to alleviate disease pathology calls for understanding the structure of polyglutamine peptides in the early stages of aggregation. Here, we present a criterion, grounded in available experimental data, that allows for using kinetic stability of dimers to assess whether a given polyglutamine conformer can be on the aggregation path. We then demonstrate that this criterion can be assessed using present-day molecular dynamics simulations. We find that although the α-helical conformer of polyglutamine is very stable, dimers of α-helices lack the kinetic stability necessary to support further oligomerization. Dimers of steric zipper, β-nanotube, and β-pseudohelix conformers are also too short-lived to initiate aggregation. The β-hairpin-containing conformers, instead, invariably form very stable dimers when their side chains are interdigitated. Combining these findings with the implications of recent solid-state NMR data on mature fibrils, we propose a possible pathway for the initial stages of polyglutamine aggregation, in which β-hairpin-containing conformers act as templates for fibril formation

Optimal percolation in correlated multilayer networks with overlap

Multilayer networks have been found to be prone to abrupt cascading failures under random and targeted attacks, but most of the targeting algorithms proposed so far have been mainly tested on uncorrelated systems. Here we show that the size of the critical percolation set of a multilayer network is substantially affected by the presence of inter-layer degree correlations and edge overlap. We provide extensive numerical evidence which confirms that the state-of-the-art optimal percolation strategies consistently fail to identify minimal percolation sets in synthetic and real-world correlated multilayer networks, thus overestimating their robustness. We propose two new targeting algorithms, based on the local estimation of path disruptions away from a given node, and a family of Pareto-efficient strategies that take into account both intra-layer and inter-layer heuristics, and can be easily extended to multiplex networks with an arbitrary number of layers. We show that these strategies consistently outperform existing attacking algorithms, on both synthetic and real-world multiplex networks, and provide some interesting insights about the interplay of correlations and overlap in determining the hyperfragility of real-world multilayer networks. Overall, the results presented in the paper suggest that we are still far from having fully identified the salient ingredients determining the robustness of multiplex networks to targeted attacks.Comment: 14 pages, 9 figures, 1 tabl

Pareto optimality in multilayer network growth

We model the formation of multi-layer transportation networks as a multi-objective optimization process, where service providers compete for passengers, and the creation of routes is determined by a multi-objective cost function encoding a trade-off between efficiency and competition. The resulting model reproduces well real-world systems as diverse as airplane, train and bus networks, thus suggesting that such systems are indeed compatible with the proposed local optimization mechanisms. In the specific case of airline transportation systems, we show that the networks of routes operated by each company are placed very close to the theoretical Pareto front in the efficiency-competition plane, and that most of the largest carriers of a continent belong to the corresponding Pareto front. Our results shed light on the fundamental role played by multi-objective optimization principles in shaping the structure of large-scale multilayer transportation systems, and provide novel insights to service providers on the strategies for the smart selection of novel routes

Interaction of small size wave packet with hadron target

We calculate in QCD the cross section for the scattering of an energetic small-size wave packet off a hadron target. We use our results to study the small-$\sigma$ behaviour of $P_{\pi}(\sigma)$, the distribution over cross section for the pion, in the leading $\alpha_{s}$-order.Comment: Revised version of the report CEBAF-TH-96-0

Androgen deprivation and SARS-CoV-2 in men with prostate cancer

Non peer reviewe

Semiclassical theory of spin-orbit interactions using spin coherent states

We formulate a semiclassical theory for systems with spin-orbit interactions. Using spin coherent states, we start from the path integral in an extended phase space, formulate the classical dynamics of the coupled orbital and spin degrees of freedom, and calculate the ingredients of Gutzwiller's trace formula for the density of states. For a two-dimensional quantum dot with a spin-orbit interaction of Rashba type, we obtain satisfactory agreement with fully quantum-mechanical calculations. The mode-conversion problem, which arose in an earlier semiclassical approach, has hereby been overcome.Comment: LaTeX (RevTeX), 4 pages, 2 figures, accepted for Physical Review Letters; final version (v2) for publication with minor editorial change

Towards an unified description of total and diffractive structure functions at HERA in the QCD dipole picture

It is argued that the QCD dipole picture allows to build an unified theoretical description -based on BFKL dynamics- of the total and diffractive nucleon structure functions. This description is in qualitative agreement with the present collection of data obtained by the H1 collaboration. More precise theoretical estimates, in particular the determination of the normalizations and proton transverse momentum behaviour of the diffractive components, are shown to be required in order to reach definite conclusions.Comment: latex file with 5 encapsulated figures, 19 page

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltage-dependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1

Optimized sound diffusers based on sonic crystals using a multiobjective evolutionary algorithm

Sonic crystals have been demonstrated to be good candidates to substitute for conventional diffusers in order to overcome the need for extremely thick structures when low frequencies have to be scattered, however, their performance is limited to a narrow band. In this work, multiobjective evolutionary algorithms are used to extend the bandwidth to the whole low frequency range. The results show that diffusion can be significantly increased. Several cost functions are considered in the paper, on the one hand to illustrate the flexibility of the optimization and on the other hand to demonstrate the problems associated with the use of certain cost functions. A study of the robustness of the optimized diffusers is also presented, introducing a parameter that can help to choose among the best candidates. Finally, the advantages of the use of multiobjective optimization in comparison with conventional optimizations are discussed.This work was partially supported by the Spanish "Ministerio de Economia y Competitividad" under the projects TEC2015-68076-R and DPI2015-71443-R.Redondo, J.; Sánchez Pérez, JV.; Blasco, X.; Herrero Durá, JM.; Vorlander, M. (2016). Optimized sound diffusers based on sonic crystals using a multiobjective evolutionary algorithm. Journal of the Acoustical Society of America. 139(5):2807-2814. doi:10.1121/1.4948580S28072814139