The role of water in the primary nucleation of protein amyloid aggregation

The understanding of the complex conformational landscape of amyloid aggregation and its modulation by relevant physicochemical and cellular factors is a prerequisite for elucidating some of the molecular basis of pathology in amyloid related diseases, and for developing and evaluating effective disease-specific therapeutics to reduce or eliminate the underlying sources of toxicity in these diseases. Interactions of proteins with solvating water have been long considered to be fundamental in mediating their function and folding; however, the relevance of water in the process of protein amyloid aggregation has been largely overlooked. Here, we provide a perspective on the role water plays in triggering primary amyloid nucleation of intrinsically disordered proteins (IDPs) based on recent experimental evidences. The initiation of amyloid aggregation likely results from the synergistic effect between both protein intermolecular interactions and the properties of the water hydration layer of the protein surface. While the self-assembly of both hydrophobic and hydrophilic IDPs would be thermodynamically favoured due to large water entropy contributions, large desolvation energy barriers are expected, particularly for the nucleation of hydrophilic IDPs. Under highly hydrating conditions, primary nucleation is slow, being facilitated by the presence of nucleation-active surfaces (heterogeneous nucleation). Under conditions of poor water activity, such as those found in the interior of protein droplets generated by liquid-liquid phase separation, however, the desolvation energy barrier is significantly reduced, and nucleation can occur very rapidly in the bulk of the solution (homogeneous nucleation), giving rise to structurally distinct amyloid polymorphs. Water, therefore, plays a key role in modulating the transition free energy of amyloid nucleation, thus governing the initiation of the process, and dictating the type of preferred primary nucleation and the type of amyloid polymorph generated, which could vary depending on the particular microenvironment that the protein molecules encounter in the cell

Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies; 35244787

Protein misfolding is a general hallmark of protein deposition diseases, such as Alzheimer’s disease or Parkinson’s disease, in which different types of aggregated species (oligomers, protofibrils and fibrils) are generated by the cells. Despite widespread interest, the relationship between oligomers and fibrils in the aggregation process and spreading remains elusive. A large variety of experimental evidences supported the idea that soluble oligomeric species of different proteins might be more toxic than the larger fibrillar forms. Furthermore, the lack of correlation between the presence of the typical pathological inclusions and disease sustained this debate. However, recent data show that the ß-sheet core of the a-Synuclein (aSyn) fibrils is unable to establish persistent interactions with the lipid bilayers, but they can release oligomeric species responsible for an immediate dysfunction of the recipient neurons. Reversibly, such oligomeric species could also contribute to pathogenesis via neuron-to-neuron spreading by their direct cell-to-cell transfer or by generating new fibrils, following their neuronal uptake. In this Review, we discuss the various mechanisms of cellular dysfunction caused by aSyn, including oligomer toxicity, fibril toxicity and fibril spreading. © 2022, The Author(s)

Towards a microscopic construction of flavour vacua from a space-time foam model

The effect on flavour oscillations of simple expanding background space-times, motivated by some D-particle foam models, is calculated for a toy-model of bosons with flavour degrees of freedom. The presence of D-particle defects in the space-time, which can interact non trivially (via particle capture) with flavoured particles in a flavour non-preserving way, generates mixing in the effective field theory of low-energy string excitations. Moreover, the recoil of the D-particle defect during the capture/scattering process implies Lorentz violation, which however may be averaged to zero in isotropic D-particle populations, but implies non-trivial effects in correlators. Both features imply that the flavoured mixed state sees a non-trivial flavour (Fock-space) vacuum of a type introduced earlier by Blasone and Vitiello in a generic context of theories with mixing. We discuss the orthogonality of the flavour vacua to the usual Fock vacua and the effect on flavour oscillations in these backgrounds. Furthermore we analyse the equation of state of the Flavour vacuum, and find that, for slow expansion rates induced by D particle recoil, it is equivalent to that of a cosmological constant. Some estimates of these novel non-perturbative contribution to the vacuum energy are made. The contribution vanishes if the mass difference and the mixing angle of the flavoured states vanish.Comment: 27 pages RevTex, 2 eps figures incorporate

Yukawa Coupling Structure in Intersecting D-brane Models

The structure of Yukawa coupling matrices is investigated in type IIA T^6/(Z_2 x Z_2) orientifold models with intersecting D-branes. Yukawa coupling matrices are difficult to be realistic in the conventional models in which the generation structure emerges by the multiple intersection of D-branes in the factorized T^6 = T^2 x T^2 x T^2. We study the new type of flavor structure, where Yukawa couplings are dynamically generated, and show this type of models lead to nontrivial structures of Yukawa coupling matrices, which can be realistic.Comment: 9 pages, 2 figure

Understanding shock dynamics in the inner heliosphere with modeling and type II radio data: A statistical study

We study two methods of predicting interplanetary shock location and strength in the inner heliosphere: (1) the ENLIL simulation and (2) the kilometric type II (kmTII) prediction. To evaluate differences in the performance of the first method, we apply two sets of coronal mass ejections (CME) parameters from the cone-model fitting and flux-rope (FR) model fitting as input to the ENLIL model for 16 halo CMEs. The results show that the ENLIL model using the actual CME speeds from FR-fit provided an improved shock arrival time (SAT) prediction. The mean prediction errors for the FR and cone-model inputs are 4.90±5.92 h and 5.48±6.11 h, respectively. A deviation of 100 km s−1 from the actual CME speed has resulted in a SAT error of 3.46 h on average. The simulations show that the shock dynamics in the inner heliosphere agrees with the drag-based model. The shock acceleration can be divided as two phases: a faster deceleration phase within 50 Rs and a slower deceleration phase at distances beyond 50 Rs. The linear-fit deceleration in phase 1 is about 1 order of magnitude larger than that in phase 2. When applying the kmTII method to 14 DH-km CMEs, we found that combining the kmTII method with the ENLIL outputs improved the kmTII prediction. Due to a better modeling of plasma density upstream of shocks and the kmTII location, we are able to provide a more accurate shock time-distance and speed profiles. The mean kmTII prediction error using the ENLIL model density is 6.7±6.4 h; it is 8.4±10.4 h when the average solar wind plasma density is used. Applying the ENLIL density has reduced the mean kmTII prediction error by ∼2 h and the standard deviation by 4.0 h. Especially when we applied the combined approach to two interacting events, the kmTII prediction error was drastically reduced from 29.6 h to −4.9 h in one case and 10.6 h to 4.2 h in the other. Furthermore, the results derived from the kmTII method and the ENLIL simulation, together with white-light data, provide a valuable validation of shock formation location and strength. Such information has important implications for solar energetic particle acceleration.Fil: Xie, H.. NASA. Goddard Space Flight Center; Estados Unidos. Department of Physics. Catholic University of America; Estados UnidosFil: St. Cyr, O.C.. NASA. Goddard Space Flight Center; Estados UnidosFil: Gopalswamy, N.. NASA. Goddard Space Flight Center; Estados UnidosFil: Odstrcil, D.. George Mason University. Department of Computational and Data Sciences; Estados UnidosFil: Cremades Fernandez, Maria Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Tecnológica Nacional. Facultad Regional de Mendoza; Argentin

Computing Yukawa Couplings from Magnetized Extra Dimensions

We compute Yukawa couplings involving chiral matter fields in toroidal compactifications of higher dimensional super-Yang-Mills theory with magnetic fluxes. Specifically we focus on toroidal compactifications of D=10 super-Yang-Mills theory, which may be obtained as the low-energy limit of Type I, Type II or Heterotic strings. Chirality is obtained by turning on constant magnetic fluxes in each of the 2-tori. Our results are general and may as well be applied to lower D=6,8 dimensional field theories. We solve Dirac and Laplace equations to find out the explicit form of wavefunctions in extra dimensions. The Yukawa couplings are computed as overlap integrals of two Weyl fermions and one complex scalar over the compact dimensions. In the case of Type IIB (or Type I) string theories, the models are T-dual to (orientifolded) Type IIA with D6-branes intersecting at angles. These theories may have phenomenological relevance since particular models with SM group and three quark-lepton generations have been recently constructed. We find that the Yukawa couplings so obtained are described by Riemann theta-functions, which depend on the complex structure and Wilson line backgrounds. Different patterns of Yukawa textures are possible depending on the values of these backgrounds. We discuss the matching of these results with the analogous computation in models with intersecting D6-branes. Whereas in the latter case a string computation is required, in our case only field theory is needed.Comment: 73 pages, 9 figures. Using JHEP3.cls. Typos and other minor corrections fixed. References adde

Characterization of pairs of toxic and nontoxic misfolded protein oligomers elucidates the structural determinants of oligomer toxicity in protein misfolding diseases

Conspectus: The aberrant misfolding and aggregation of peptides and proteins into amyloid aggregates occurs in over 50 largely incurable protein misfolding diseases. These pathologies include Alzheimer’s and Parkinson’s diseases, which are global medical emergencies owing to their prevalence in increasingly aging populations worldwide. Although the presence of mature amyloid aggregates is a hallmark of such neurodegenerative diseases, misfolded protein oligomers are increasingly recognized as of central importance in the pathogenesis of many of these maladies. These oligomers are small, diffusible species that can form as intermediates in the amyloid fibril formation process or be released by mature fibrils after they are formed. They have been closely associated with the induction of neuronal dysfunction and cell death. It has proven rather challenging to study these oligomeric species because of their short lifetimes, low concentrations, extensive structural heterogeneity, and challenges associated with producing stable, homogeneous, and reproducible populations. Despite these difficulties, investigators have developed protocols to produce kinetically, chemically, or structurally stabilized homogeneous populations of protein misfolded oligomers from several amyloidogenic peptides and proteins at experimentally ameneable concentrations. Furthermore, procedures have been established to produce morphologically similar but structurally distinct oligomers from the same protein sequence that are either toxic or nontoxic to cells. These tools offer unique opportunities to identify and investigate the structural determinants of oligomer toxicity by a close comparative inspection of their structures and the mechanisms of action through which they cause cell dysfunction. This Account reviews multidisciplinary results, including from our own groups, obtained by combining chemistry, physics, biochemistry, cell biology, and animal models for pairs of toxic and nontoxic oligomers. We describe oligomers comprised of the amyloid-β peptide, which underlie Alzheimer’s disease, and α-synuclein, which are associated with Parkinson’s disease and other related neurodegenerative pathologies, collectively known as synucleinopathies. Furthermore, we also discuss oligomers formed by the 91-residue N-terminal domain of [NiFe]-hydrogenase maturation factor from E. coli, which we use as a model non-disease-related protein, and by an amyloid stretch of Sup35 prion protein from yeast. These oligomeric pairs have become highly useful experimental tools for studying the molecular determinants of toxicity characteristic of protein misfolding diseases. Key properties have been identified that differentiate toxic from nontoxic oligomers in their ability to induce cellular dysfunction. These characteristics include solvent-exposed hydrophobic regions, interactions with membranes, insertion into lipid bilayers, and disruption of plasma membrane integrity. By using these properties, it has been possible to rationalize in model systems the responses to pairs of toxic and nontoxic oligomers. Collectively, these studies provide guidance for the development of efficacious therapeutic strategies to target rationally the cytotoxicity of misfolded protein oligomers in neurodegenerative conditions

El Quijote en las escuelas

Estudio premiado por la Asociación provincial de maestros de escuelas públicas de Barcelona, en el Certamen literario conmemorativo del 3er. centenario de la publicación de "El Quijote

An Asymmetric Cone Model for Halo Coronal Mass Ejections

Due to projection effects, coronagraphic observations cannot uniquely determine parameters relevant to the geoeffectiveness of CMEs, such as the true propagation speed, width, or source location. The Cone Model for Coronal Mass Ejections (CMEs) has been studied in this respect and it could be used to obtain these parameters. There are evidences that some CMEs initiate from a flux-rope topology. It seems that these CMEs should be elongated along the flux-rope axis and the cross section of the cone base should be rather elliptical than circular. In the present paper we applied an asymmetric cone model to get the real space parameters of frontsided halo CMEs (HCMEs) recorded by SOHO/LASCO coronagraphs in 2002. The cone model parameters are generated through a fitting procedure to the projected speeds measured at different position angles on the plane of the sky. We consider models with the apex of the cone located at the center and surface of the Sun. The results are compared to the standard symmetric cone model