Sequence-based prediction for vaccine strain selection and identification of antigenic variability in foot-and-mouth disease virus

Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence - by controlling for phylogenetic structure - for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease

The Interaction of αB-Crystallin with Mature α-Synuclein Amyloid Fibrils Inhibits Their Elongation

αB-Crystallin is a small heat-shock protein (sHsp) that is colocalized with α-synuclein (αSyn) in Lewy bodies—the pathological hallmarks of Parkinson's disease—and is an inhibitor of αSyn amyloid fibril formation in an ATP-independent manner in vitro. We have investigated the mechanism underlying the inhibitory action of sHsps, and here we establish, by means of a variety of biophysical techniques including immunogold labeling and nuclear magnetic resonance spectroscopy, that αB-crystallin interacts with αSyn, binding along the length of mature amyloid fibrils. By measurement of seeded fibril elongation kinetics, both in solution and on a surface using a quartz crystal microbalance, this binding is shown to strongly inhibit further growth of the fibrils. The binding is also demonstrated to shift the monomer-fibril equilibrium in favor of dissociation. We believe that this mechanism, by which a sHsp interacts with mature amyloid fibrils, could represent an additional and potentially generic means by which at least some chaperones protect against amyloid aggregation and limit the onset of misfolding diseases

Electrolyte‐gated organic field‐effect transistors with high operational stability and lifetime in practical electrolytes

A key component of organic bioelectronics is electrolyte‐gated organic field‐effect transistors (EG‐OFETs), which have recently been used as sensors to demonstrate label‐free, single‐molecule detection. However, these devices exhibit limited stability when operated in direct contact with aqueous electrolytes. Ultrahigh stability is demonstrated to be achievable through the utilization of a systematic multifactorial approach in this study. EG‐OFETs with operational stability and lifetime several orders of magnitude higher than the state of the art have been fabricated by carefully controlling a set of intricate stability‐limiting factors, including contamination and corrosion. The indacenodithiophene‐co‐benzothiadiazole (IDTBT) EG‐OFETs exhibit operational stability that exceeds 900 min in a variety of widely used electrolytes, with an overall lifetime exceeding 2 months in ultrapure water and 1 month in various electrolytes. The devices were not affected by electrical stress‐induced trap states and can remain stable even in voltage ranges where electrochemical doping occurs. To validate the applicability of our stabilized device for biosensing applications, the reliable detection of the protein lysozyme in ultrapure water and in a physiological sodium phosphate buffer solution for 1500 min was demonstrated. The results show that polymer‐based EG‐OFETs are a viable architecture not only for short‐term but also for long‐term biosensing applications

Event shapes in e+e- annihilation and deep inelastic scattering

This article reviews the status of event-shape studies in e+e- annihilation and DIS. It includes discussions of perturbative calculations, of various approaches to modelling hadronisation and of comparisons to data.Comment: Invited topical review for J.Phys.G; 40 pages; revised version corrects some nomenclatur

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta‐analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive–compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta‐analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First‐degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Nonparametric identification of regulatory interactions from spatial and temporal gene expression data

<p>Abstract</p> <p>Background</p> <p>The correlation between the expression levels of transcription factors and their target genes can be used to infer interactions within animal regulatory networks, but current methods are limited in their ability to make correct predictions.</p> <p>Results</p> <p>Here we describe a novel approach which uses nonparametric statistics to generate ordinary differential equation (ODE) models from expression data. Compared to other dynamical methods, our approach requires minimal information about the mathematical structure of the ODE; it does not use qualitative descriptions of interactions within the network; and it employs new statistics to protect against over-fitting. It generates spatio-temporal maps of factor activity, highlighting the times and spatial locations at which different regulators might affect target gene expression levels. We identify an ODE model for <it>eve </it>mRNA pattern formation in the <it>Drosophila melanogaster </it>blastoderm and show that this reproduces the experimental patterns well. Compared to a non-dynamic, spatial-correlation model, our ODE gives 59% better agreement to the experimentally measured pattern. Our model suggests that protein factors frequently have the potential to behave as both an activator and inhibitor for the same <it>cis</it>-regulatory module depending on the factors' concentration, and implies different modes of activation and repression.</p> <p>Conclusions</p> <p>Our method provides an objective quantification of the regulatory potential of transcription factors in a network, is suitable for both low- and moderate-dimensional gene expression datasets, and includes improvements over existing dynamic and static models.</p

Effect of ageing on the microstructural evolution in a new design of maraging steels with carbon

A new maraging steel, based on carbide precipitation, is described. Two alloys were designed namely Fe-10Mn-0.25C-2Cr-1Mo wt% (2CrMo) and Fe-10Mn-0.25C-1Cr-2Mo wt% (Cr2Mo). These compositions were chosen to achieve ultra-high strength and high tensile elongation; the former and latter are promoted through the simulatenous precipitation of Cr- and Mo-rich carbides and Mn-rich reverted austenite. The alloys were manufactured through the standard melting, casting and hot working route. Following a solution treatment at 870 °C and quench, which gave a fully martensitic structure, the alloys were aged for various times at 510 °C. The microstructure and tensile properties were investigated in detail as a function of ageing time. The microstructure observed was dominated by micron scale and nanometre scale Mn segregation which determined the local Ac3 temperature. Austenite reversion occurred in both alloys, peaking at 16 h in both cases. In the 2CrMo alloy, the reverted austenite was mainly globular in morphology due the Ac3 temperature being lower than the ageing temperature, but was acicular in the Cr2Mo with Ac3 similar to the ageing temperature of 510 °C. Moreover, acicular austenite was promoted by Mn segregation at martensite lath boundaries in Cr2Mo. In the 2CrMo steel, carbide precipitation (M3C and M7C3) occurred during heating to the ageing temperature, but the carbides gradually dissolved with further ageing. In contrast, in the Cr2Mo alloy, precipitation of carbides (M7C3 and M2C) occurred during ageing, the volume fraction of which increased with ageing time. In both alloys a TRIP effect was observed, but the extent of this was greater for the Cr2Mo alloy. The complex microstructure obtained after 16 h led to an excellent combination of strength of 1.3 GPa and elongation of 18%. Physics-based models for the microstructure in martensite, precipitation kinetics, as well as for TRIP in austenite were employed to explain and predict the individual strengthtening contributions of the microstructure to the total strength, confirming that the maximum strength-elongation relationship found after 16 h is due to an optimal combination of a slightly overaged - but still strong- martensite and 30% of reverted austenite, for increased work hardening and ductility