Distinct mechanisms survey the structural integrity of HLA-B*27:05 intracellularly and at the surface

HLA-B*27:05 is associated with the development of autoimmune spondyloarthropathies, but the precise causal relationship between the MHC haplotype and disease pathogenesis is yet to be elucidated. Studies focusing on the structure and cellular trafficking of HLA-B*27:05 implicate several links between the onset of inflammation and the unusual conformations of the molecule inside and at the surface of antigen presenting cells. Several lines of evidence emphasize the emergence of those unnatural protein conformations under conditions where peptide loading onto B*27:05 is impaired. To understand how cellular factors distinguish between poorly loaded molecules from the optimally loaded ones, we have investigated the intracellular transport, folding, and cell surface expression of this particular B27 subtype. Our findings show that B*27:05 is structurally unstable in the absence of peptide, and that an artificially introduced disulfide bond between residues 84 and 139 conferred enhanced conformational stability to the suboptimally loaded molecules. Empty or suboptimally loaded B*27:05 can escape intracellular retention and arrive at the cell surface leading to the appearance of increased number of β2m-free heavy chains. Our study reveals a general mechanism found in the early secretory pathways of murine and human cells that apply to the quality control of MHC class I molecules, and it highlights the allotype-specific structural features of HLA-B*27:05 that can be associated with aberrant antigen presentation and that might contribute to the etiology of disease

Agnostic detection of large-scale weather patterns in the northern hemisphere: from blockings to teleconnections

Detecting recurrent weather patterns and understanding the transitions between such regimes are key to advancing our knowledge on the low-frequency variability of the atmosphere and have important implications in terms of weather and climate-related risks. We adapt an analysis pipeline inspired by Markov State Modelling and detect in an unsupervised manner the dominant winter mid-latitude Northern Hemisphere weather patterns in the Atlantic and Pacific sectors, defined by the slowest decaying modes of a suitable projection on a discrete basis of the weather dynamics. When focusing on a longitudinal window of 60$^\circ$, we recognise, first and foremost, a longitude-dependent estimate of the slowest relaxation times, which are often related with transitions between blocked regimes and zonal flow. We analyze in detail the Atlantic and Pacific sectors, finding, additionally, clear evidence of the strong connection between blockings in the two regions. When the analysis is performed in a broader geographical region of the Atlantic sector, we detect teleconnection patterns like the North Atlantic Oscillation and a large-scale mode of variability alternating between Scandinavian and Greenland blocking. The approach proposed here has great potential for intercomparing climate models and for assessing the impact of climate change on the low-frequency variability of the atmosphere.Comment: 14 pages, 4 figures, plus supplementary materia

Local Support Assembly of the ATLAS Pixel Detector

The barrel part of the ATLAS pixel detector will consist of 112 carbon-carbon structures called "staves" with 13 hybrid detector modules being glued on each stave. The demands on the glue joints are high, both in terms of mechanical precision and thermal contact. To achieve this precision a custom-made semi-automated mounting machine has been constructed in Wuppertal, which provides a precision in the order of tens of microns. As this is the last stage of the detector assembly providing an opportunity for stringent tests, a detailed procedure has been defined for assessing both mechanical and electrical properties. This note gives an overview of the procedure for affixation and tests, and summarizes the first results of the production.Comment: 6 pages, 8 figure

Fatigue Assessment of Wire and Arc Additively Manufactured Ti-6Al-4V

Wire and arc additively manufactured (WAAM) parts and structures often present internal defects, such as gas pores, and cause irregularities in the manufacturing process. In order to describe and assess the effect of internal defects in fatigue design, this research study investigates the fatigue strength of wire arc additive manufactured structures covering the influence of imperfections, particularly gas pores. Single pass WAAM structures are manufactured using titanium alloy Ti-6Al-4V and round fatigue, tensile specimen are extracted. Tensile tests and uniaxial fatigue tests with a load stress ratio of R = 0.1 were carried out, whereby fatigue test results are used for further assessments. An extensive fractographic and metallographic fracture surface analysis is utilized to characterize and measure crack-initiating defects. As surface pores as well as bulk pores are detected, a stress intensity equivalent ∆Keqv transformation approach is presented in this study. Thereby, the defect size of the surface pore is transformed to an increased defect size, which is equivalent to a bulk pore. Subsequently, the fatigue strength assessment method by Tiryakioğlu, commonly used for casting processes, is applied. For this method, a cumulative Gumbel extreme value distribution is utilized to statistically describe the defect size. The fitted distribution with modified data reveals a better agreement with the experimental data than unmodified. Additionally, the validation of the model shows that the usage of the ∆K modified data demonstrates better results, with a slight underestimation of up to about −7%, compared to unmodified data, with an overestimation of up to about 14%, comparing the number of load cycles until failure. Hence, the presented approach applying a stress intensity equivalent transformation of surface to bulk pores facilitates a sound fatigue strength assessment of WAAM Ti-6Al-4V structures

In situ grown palladium nanoparticles on polyester fabric as easy-separable and recyclable catalyst for Suzuki-Miyaura reaction

Palladium nanoparticles supported on low-melting polyester (Pd/LMPET) fabric were prepared through a microwave irradiation assisted method. In this way, in situ growth of Pd nanoparticles onto an easy to handle material was initiated and proceeded. The results of the characterization revealed that the palladium nanoparticles were well-dispersed on the surfaces of the polyester fibers. The Pd/LMPET fabrics were then employed in the Suzuki-Miyaura coupling. They exhibited excellent catalytic activity in ethanol/water under air atmosphere at 50 °C. Importantly, the Pd/LMPET fabrics could be separated from reaction mixture conveniently and they can still maintain good activity after 8 cycles without Pd leaching. © 2021 The Author

Correction: Distinct mechanisms survey the structural integrity of HLA-B*27:05 intracellularly and at the surface

[This corrects the article DOI: 10.1371/journal.pone.0200811.]

Bayesian synthetic likelihood for stochastic models with applications in mathematical finance

We present a Bayesian synthetic likelihood method to estimate both the parameters and their uncertainty in systems of stochastic differential equations. Together with novel summary statistics the method provides a generic and model-agnostic estimation procedure and is shown to perform well even for small observational data sets and biased observations of latent processes. Moreover, a strategy for assessing the goodness of the model fit to the observational data is provided. The combination of the aforementioned features differentiates our approach from other well-established estimation methods. We would like to stress the fact that the algorithm is pleasingly parallel and thus well suited for implementation on modern computing hardware. We test and compare the method to maximum likelihood, filtering and transition density estimation methods on a number of practically relevant examples from mathematical finance. Additionally, we analyze how to treat the lack-of-fit in situations where the model is biased due to the necessity of using proxies in place of unobserved volatility

FoldAffinity: Binding affinities from nDSF experiments

Differential scanning fluorimetry (DSF) using the inherent fluorescence of proteins (nDSF) is a popular technique to evaluate thermal protein stability in different conditions (e.g. buffer, pH). In many cases, ligand binding increases thermal stability of a protein and often this can be detected as a clear shift in nDSF experiments. Here, we evaluate binding affinity quantification based on thermal shifts. We present four protein systems with different binding affinity ligands, ranging from nM to high μM. Our study suggests that binding affinities determined by isothermal analysis are in better agreement with those from established biophysical techniques (ITC and MST) compared to apparent Kds obtained from melting temperatures. In addition, we describe a method to optionally fit the heat capacity change upon unfolding (Δ Cp) during the isothermal analysis. This publication includes the release of a web server for easy and accessible application of isothermal analysis to nDSF data.Fil: Niebling, Stephan. Centre for Structural Systems Biology; Alemania. European Molecular Biology Laboratory; AlemaniaFil: Burastero, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. European Molecular Biology Laboratory; AlemaniaFil: Bürgi, Jérôme. European Molecular Biology Laboratory; AlemaniaFil: Günther, Christian. European Molecular Biology Laboratory; AlemaniaFil: Defelipe, Lucas Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. European Molecular Biology Laboratory; AlemaniaFil: Sander, Simon. Universitat Hamburg; AlemaniaFil: Gattkowski, Ellen. Universitat Hamburg; AlemaniaFil: Anjanappa, Raghavendra. Universitat Bremen. School of Engineering and Science Jacobs; AlemaniaFil: Wilmanns, Matthias. European Molecular Biology Laboratory; Alemania. Universitat Hamburg; AlemaniaFil: Springer, Sebastian. Universitat Bremen. School of Engineering and Science Jacobs; AlemaniaFil: Tidow, Henning. Universitat Hamburg; AlemaniaFil: García Alai, María. European Molecular Biology Laboratory; Alemania. Centre for Structural Systems Biology; Alemani