Amyloid β 42 fibril structure based on small-angle scattering

Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer’s disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril structure may thus facilitate therapeutic development. We use small-angle scattering to provide information on the fibril cross-section dimension and shape for Aβ42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37 °C from pure recombinant Aβ42 peptide. Fitting the data using a continuum model reveals an elliptical cross-section and a peptide mass-per-unit length compatible with two filaments of two monomers, four monomers per plane. To provide a more detailed atomistic model, the data were fitted using as a starting state a high-resolution structure of the two-monomer arrangement in filaments from solid-state NMR (Protein Data Bank ID 5kk3). First, a twofold symmetric model including residues 11 to 42 of two monomers in the filament was optimized in terms of twist angle and local packing using Rosetta. A two-filament model was then built and optimized through fitting to the scattering data allowing the two N-termini in each filament to take different conformations, with the same conformation in each of the two filaments. This provides an atomistic model of the fibril with twofold rotation symmetry around the fibril axis. Intriguingly, no polydispersity as regards the number of filaments was observed in our system over separate samples, suggesting that the two-filament arrangement represents a free energy minimum for the Aβ42 fibril.

Optimization of the pre-starting state of athletes in rhythmic gymnastics at the initial stage of basic training

Against the background of intensifying competition in the international arena, the demands placed on female athletes in rhythmic gymnastics are growing, which requires the formation of female athletes' ability to self-control and self-regulation. The purpose of the article is to substantiate and develop an algorithm for optimizing the pre-start condition of young gymnasts at the stage of preliminary basic training. Research methods: analysis, systematization and generalization of data of scientific literature, methods of assessment of Spielberger-Khanin situational anxiety, statistical analysis. The study involved 10 gymnasts who train at the stage of basic preliminary training (8-12 years), who took part in the International Competition "Dmitrash Cup 2021". Result. It is proved that the average assessment of situational anxiety of young gymnasts in the pre-competition period is statistically significant (p <0.05) increases from 19.3 to 35.1 points. The most effective in the training process of gymnasts at the stage of initial basic training methods and techniques to combat the state of pre-start overstrain: psychological and pedagogical, hardware means of influence, methods of relaxation and mobilization and psychophysiological influences. An algorithm for optimizing the pre-start state of female athletes in rhythmic gymnastics at the initial stage of basic training, namely the establishment of the type of temperament of the athlete, the diagnosis of her pre-start state, the application of methods of regulation of pre-start states. The prospect of further research is the development of methods for optimizing the pre-start condition of athletes in rhythmic gymnastics and the formation of their skills of self-regulation in the training process at the stage of initial basic training.

Simulations of the Ultra-Fast Kinetics in Ni-Si-C Ternary Systems under Laser Irradiations

We present a method for the simulation of the kinetic evolution in the sub µs timescale for composite materials containing regions occupied by alloys, compounds, and mixtures belonging to the Ni-Si-C ternary system. Pulsed laser irradiation (pulses of the order of 100 ns) promotes this evolution. The simulation approach is formulated in the framework of the phase-field theory and it consists of a system of coupled non-linear partial differential equations (PDEs), which considers as variables the following fields: the laser electro-magnetic field, the temperature, the phase-field and the material (Ni, Si, C, C clusters and Ni-silicides) densities. The model integrates a large set of materials and reaction parameters which could also self-consistently depend on the model variables. A parameter calibration is also proposed, specifically suited for the wavelength of a widely used class of excimer lasers (? = 308 nm). The model is implemented on a proprietary laser annealing technology computer-aided design (TCAD) tool based on the finite element method (FEM). This integration allows, in principle, numerical solutions in systems of any dimension. Here we discuss the complex simulation trend in the one-dimensional case, considering as a starting state, thin films on 4H-SiC substrates, i.e., a configuration reproducing a technologically relevant case study. Simulations as a function of the laser energy density show an articulated scenario, also induced by the variables’ dependency of the materials’ parameters, for the non-melting, partial-melting and full-melting process conditions. The simulation results are validated by post-process experimental analyses of the microstructure and composition of the irradiated samples.

Peg solitaire on graphs with large maximum degree

In 2011, Beeler and Hoilman introduced the peg solitaire on graphs. The peg solitaire on a connected graph is a one-player combinatorial game starting with exactly one hole in a vertex and pegs in all other vertices and removing all pegs but exactly one by a sequence of jumps; for a path [Formula: see text], if there are pegs in [Formula: see text] and [Formula: see text] and exists a hole in [Formula: see text], then [Formula: see text] can jump over [Formula: see text] into [Formula: see text], and after that, the peg in [Formula: see text] is removed. A problem of interest in the game is to characterize solvable (respectively, freely solvable) graphs, where a graph is solvable (respectively, freely solvable) if for some (respectively, any) vertex [Formula: see text], starting with a hole [Formula: see text], a terminal state consisting of a single peg can be obtained from the starting state by a sequence of jumps. In this paper, we consider the peg solitaire on graphs with large maximum degree. In particular, we show the necessary and sufficient condition for a graph with large maximum degree to be solvable in terms of the number of pendant vertices adjacent to a vertex of maximum degree. It is a notable point that this paper deals with a question of Beeler and Walvoort whether a non-solvable condition of trees can be extended to other graphs.

Metabolic Dynamics in Escherichia coli-based Cell-Free Systems

The field of metabolic engineering has yielded remarkable accomplishments in using cells to produce valuable molecules, and cell-free expression (CFE) systems have the potential to push the field even further. However, CFE systems still face some outstanding challenges, including endogenous metabolic activity that is poorly understood yet has a significant impact on CFE productivity. Here, we use metabolomics to characterize the temporal metabolic changes in CFE systems and their constituent components, including significant metabolic activity in central carbon and amino acid metabolism. We find that while changing the reaction starting state via lysate pre-incubation impacts protein production, it has a comparatively small impact on metabolic state. We also demonstrate that changes to lysate preparation have a larger effect on protein yield and temporal metabolic profiles, though general metabolic trends are conserved. Finally, while we improve protein production through targeted supplementation of metabolic enzymes, we show that the endogenous metabolic activity is fairly resilient to these enzymatic perturbations. Overall, this work highlights the robust nature of CFE reaction metabolism as well as the importance of understanding the complex interdependence of metabolites and proteins in CFE systems to guide optimization efforts.

Stability of Imprinting and Differentiation Capacity in Naïve Human Cells Induced by Chemical Inhibition of CDK8 and CDK19

Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The naïve and primed states are the best characterized pluripotency states. Naïve pluripotent stem cells (PSCs) correspond to the early pre-implantation blastocyst and, in mice, constitute the optimal starting state for subsequent developmental applications. However, the stabilization of human naïve PSCs remains challenging because, after short-term culture, most current methods result in karyotypic abnormalities, aberrant DNA methylation patterns, loss of imprinting and severely compromised developmental potency. We have recently developed a novel method to induce and stabilize naïve human PSCs that consists in the simple addition of a chemical inhibitor for the closely related CDK8 and CDK19 kinases (CDK8/19i). Long-term cultured CDK8/19i-naïve human PSCs preserve their normal karyotype and do not show widespread DNA demethylation. Here, we investigate the long-term stability of allele-specific methylation at imprinted loci and the differentiation potency of CDK8/19i-naïve human PSCs. We report that long-term cultured CDK8/19i-naïve human PSCs retain the imprinting profile of their parental primed cells, and imprints are further retained upon differentiation in the context of teratoma formation. We have also tested the capacity of long-term cultured CDK8/19i-naïve human PSCs to differentiate into primordial germ cell (PGC)-like cells (PGCLCs) and trophoblast stem cells (TSCs), two cell types that are accessible from the naïve state. Interestingly, long-term cultured CDK8/19i-naïve human PSCs differentiated into PGCLCs with a similar efficiency to their primed counterparts. Also, long-term cultured CDK8/19i-naïve human PSCs were able to differentiate into TSCs, a transition that was not possible for primed PSCs. We conclude that inhibition of CDK8/19 stabilizes human PSCs in a functional naïve state that preserves imprinting and potency over long-term culture.

New Model-Based Manipulation Technique for Reshaping Deformable Linear Objects

In this article, we consider the problem of reshaping a deformable linear object (DLO) like wires, cables, ropes, and surgical sutures. The solution to this problem would be useful for many fields, especially industrial manufacturing, where the DLO manipulation is still frequently carried out by human workers. In this work, a new model-based manipulation technique for reshaping a DLO is addressed employing a sequence of grasping and releasing primitives performed by a single-armed robot equipped with a gripper. A decision process selects the optimal grasping point exploiting an error minimization approach and chooses the related releasing point. This decision process performs a spline interpolation between the error values obtained from candidate grasping points and chooses the optimal point that owns a minimum error. The multivariate dynamic spline model of the DLO is exploited for selecting the optimal grasping point and predicting the DLO behavior during the manipulation process. Because of its advantages over other integration methods, the symplectic integrator is utilized for iteratively solving the DLO dynamic model. Simulation results of reshaping a DLO lying on a table are presented to evaluate the proposed technique. These results illustrate the intermediate deformation steps which lead the DLO from its starting state to the desired one. They demonstrate that our proposed technique can efficiently manipulate the DLO into various shapes in few steps.

The Matthew effect in political science: head start and key reforms important for democratization

Are some countries better equipped from the onset of a democratization process to become democracies? We compared successful and failed episodes of liberalization over the period 1900 to 2018 to examine if starting state influences the probability of successful democratization. We show that liberalization in autocracies was more likely to succeed in countries that had the advantage of a better starting point concerning political institutions, GDP, and education. These more privileged countries could also carry out key reforms more rapidly, and were able to do so even in areas in which they had no initial advantage. This reveals a “Matthew effect” in political science: to countries that already have, more is given. This is a novel observation in political science that has important implications for current methodologies and policies.

Structure and contingency determine mutational hotspots for flower color evolution

Evolutionary genetic studies have uncovered abundant evidence for genomic hotspots of phenotypic evolution, as well as biased patterns of mutations at those loci. However, the theoretical basis for this concentration of particular types of mutations at particular loci remains largely unexplored. In addition, historical contingency is known to play a major role in evolutionary trajectories, but has not been reconciled with the existence of such hotspots. For example, do the appearance of hotspots and the fixation of different types of mutations at those loci depend on the starting state and/or on the nature and direction of selection? Here we use a computational approach to examine these questions, focusing the anthocyanin pigmentation pathway, which has been extensively studied in the context of flower color transitions. We investigate two transitions that are common in nature, the transition from blue to purple pigmentation and from purple to red pigmentation. Both sets of simulated transitions occur with a small number of mutations at just four loci and show strikingly similar peaked shapes of evolutionary trajectories, with the mutations of largest effect occurring early but not first. Nevertheless, the types of mutations (biochemical vs. regulatory) as well as their direction and magnitude are contingent on the particular transition. These simulated color transitions largely mirror findings from natural flower color transitions, which are known to occur via repeated changes at a few hotspot loci. Still, some types of mutations observed in our simulated color evolution are rarely observed in nature, suggesting that pleiotropic effects further limit the trajectories between color phenotypes. Overall, our results indicate that the branching structure of the pathway leads to a predictable concentration of evolutionary change at hotspot loci, but the types of mutations at these loci and their order is contingent on the evolutionary context.

ESTATE: A Lightweight and Low Energy Authenticated Encryption Mode

NIST has recently initiated a standardization project for efficient lightweight authenticated encryption schemes. SUNDAE, a candidate in this project, achieves optimal state size which results in low circuit overhead on top of the underlying block cipher. In addition, SUNDAE provides security in nonce-misuse scenario as well. However, in addition to the block cipher circuit, SUNDAE also requires some additional circuitry for multiplication by a primitive element. Further, it requires an additional block cipher invocation to create the starting state. In this paper, we propose a new lightweight and low energy authenticated encryption family, called ESTATE, that significantly improves the design of SUNDAE in terms of implementation costs (both hardware area and energy) and efficient processing of short messages. In particular, ESTATE does not require an additional multiplication circuit, and it reduces the number of block cipher calls by one. Moreover, it provides integrity security even under the release of unverified plaintext (or RUP) model. ESTATE is based on short-tweak tweakable block ciphers (or tBC, small ’t’ denotes short tweaks) and we instantiate it with two recently designed tBCs: TweAES and TweGIFT. We also propose a low latency variant of ESTATE, called sESTATE, that uses a round-reduced (6 rounds) variant of TweAES called TweAES-6. We provide comprehensive FPGA based hardware implementation for all the three instances. The implementation results depict that ESTATE_TweGIFT-128 (681 LUTs, 263 slices) consumes much lesser area as compared to SUNDAE_GIFT-128 (931 LUTs, 310 slices). When we moved to the AES variants, along with the area-efficiency (ESTATE_TweAES consumes 1901 LUTs, 602 slices while SUNDAE_AES-128 needs 1922 LUTs, 614 slices), we also achieve higher throughput for short messages (For 16-byte message, a throughput of 1251.10 and 945.36 Mbps for ESTATE_TweAES and SUNDAE_AES-128 respectively).