Bill to Professor Silver, 13 May 1963

Professional correspondenc

The Mu3e Data Acquisition

The Mu3e experiment aims to find or exclude the lepton flavor violating decay μ+→e+e−e+ with a sensitivity of one in 10 16 muon decays. The first phase of the experiment is currently under construction at the Paul Scherrer Institute (PSI, Switzerland), where beams with up to 10 8 muons per second are available. The detector will consist of an ultra-thin pixel tracker made from High-Voltage Monolithic Active Pixel Sensors (HV-MAPS) , complemented by scintillating tiles and fibers for precise timing measurements. The experiment produces about 100Gbit/s of zero-suppressed data, which are transported to a filter farm using a network of field programmable gate arrays (FPGAs) and fast optical links. On the filter farm, tracks and three-particle vertices are reconstructed using highly parallel algorithms running on graphics processing units, leading to a reduction of the data to 100 Mbyte/s for mass storage and offline analysis. This article introduces the system design and hardware implementation of the Mu3e data acquisition and filter farm

Amount of Information Needed for Model Choice in Approximate Bayesian Computation

Approximate Bayesian Computation (ABC) has become a popular technique in evolutionary genetics for elucidating population structure and history due to its flexibility. The statistical inference framework has benefited from significant progress in recent years. In population genetics, however, its outcome depends heavily on the amount of information in the dataset, whether that be the level of genetic variation or the number of samples and loci. Here we look at the power to reject a simple constant population size coalescent model in favor of a bottleneck model in datasets of varying quality. Not only is this power dependent on the number of samples and loci, but it also depends strongly on the level of nucleotide diversity in the observed dataset. Whilst overall model choice in an ABC setting is fairly powerful and quite conservative with regard to false positives, detecting weaker bottlenecks is problematic in smaller or less genetically diverse datasets and limits the inferences possible in non-model organism where the amount of information regarding the two models is often limited. Our results show it is important to consider these limitations when performing an ABC analysis and that studies should perform simulations based on the size and nature of the dataset in order to fully assess the power of the study

Humic Substances Enhance Chlorothalonil Phototransformation via Photoreduction and Energy Transfer

ABSTRACT: The photodegradation of chlorothalonil, a polychlorinated aromatic fungicide widely used in agriculture, was investigated under ultraviolet–visible irradiation in the presence and absence of different humic substances that significantly enhance the chlorothalonil phototransformation. On the basis of a kinetic model, an analytical study, the effect of scavengers, the chlorothalonil phosphorescence measurement, and varying irradiation conditions, it was possible to demonstrate that this accelerating effect is due to their capacity to reduce the chlorothalonil triplet state via H-donor reaction and to energy transfer from the triplet humic to ground state chlorothalonil. Energy transfer occurs at wavelengths below 450 nm and accounts for up to 30% of the reaction in deoxygenated medium upon irradiation with polychromatic light (300–450 nm). This process is more important with Elliott humic and fulvic acids and with humic acids extracted from natural carbonaceous material than with Nordic NOM and Pahokee peat humic acids. The obtained results are of high relevance to understanding the processes involved in chlorothalonil phototransformation and the photoreactivity of humic substances. Chlorothalonil is one of the rare molecules shown to react by energy transfer from excited humic substances

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction

NMR and in silico studies of fucosylated chondroitin sulfate (fCS) and its interactions with selectins

This thesis describes structural studies on the interactions between the fucosylated chondroitin sulfate (fCS) oligosaccharides and human proteins known as selectins. fCS is a carbohydrate obtained from sea cucumbers, that can be classified as a branched glycosaminoglycan (GAG). It has attracted much attention due to its anti-coagulant, anti-inflammatory, antimetastatic and anti-HIV properties and its structure was previously determined by NMR. Selectins constitute a family of proteins involved in cell adhesion processes, such as inflammation, attachment of viral particles and migration of tumour cells. fCS oligosaccharides have been shown to bind to selectins, which is likely a reason behind their biological activity. However, the mechanism of this interaction is currently unknown. The initial part of the thesis describes the experimental work on expression and purification of the recombinant L- and P-selectin constructs in Pichia pastoris, Escherichia coli and HEK 293 cells. The aim of these experiments was to produce two constructs for each selectin, a single domain construct, consisting of the C-type lectin domain only, and a double domain construct, consisting of both the C-type lectin and the EGF-like domains. The intention was that the recombinant proteins would be labelled with 13C and 15N to allow for the in-depth structural NMR studies on the fCS-selectin interaction. Various experimental approaches have been explored, including the use of different cell lines, modifications to construct design, as well as alterations to expression and purification conditions. Although it was not possible to produce soluble selectin constructs in either bacterial or yeast cells, protein expression tests in HEK293 cells, performed in collaboration with the Oxford Protein Production facility (OPPF), led to production of a soluble L-selectin construct, consisting of the L-selectin C-type lectin domain. The produced L-selectin construct, as well as two commercially available constructs of the Land P-selectin extracellular domains, were used in the Saturation Transfer Difference (STD) NMR experiments to provide new information about the nature of the fCS-selectin binding. The STD experiments allowed to identify the regions within the fCS oligosaccharides that are in direct contact with the protein and likely play an important role in this interaction. Experiments on different protein constructs allowed the comparison of fCS binding to P-selectin and to two different recombinant constructs of L-selectin. Results of these studies suggest that the binding occurs via a similar mechanism for both L- and P-selectins and that the fCS oligosaccharides bind to one-domain L-selectin construct with similar affinity as to a larger construct, consisting of the entire extracellular region of the protein. Alongside the experimental work, theoretical in silico studies on the fCS-selectin binding were undertaken as part of this project. The existing X-ray structures of selectin complexes were subjected to Molecular Dynamics (MD) simulations, which allowed to explore the dynamic behaviour of E-selectin upon binding to sialyl Lewis x (sLex). It was found that sLex forms a more favourable interaction with the extended conformation of E-selectin and that the protein in this conformation is characterised by a high degree of interdomain flexibility, with a new type of interdomain movement observed in the MD studies on this complex. In further in silico studies, the fCS oligosaccharides were docked to the existing P-selectin structures. The docking tests were performed on the computationally produced fCS trisaccharides with fucose branches either 2,4 or 3,4-sulfated. Results were evaluated with MD simulations and analysed in the light of current knowledge of selectin-ligand binding and the STD NMR experimental results. The in silico studies allowed to identify a subset of P-selectin residues that are likely involved in the interaction with fCS oligosaccharides in vivo. The conformational behaviour of P-selectin upon binding to fCS was also explored and it was found that the interdomain hinge is flexible during this interaction and allows transition from bent to extended conformational state. Finally, a new NMR method was developed to facilitate the studies of complex carbohydrates, incorporating the concepts of G-matrix Fourier Transform (GFT) NMR into 2D HSQC and 2D HSQC-TOCSY experiments. The method allows to separate peaks in the regions of high spectral overlap, providing information that can simplify the assignment process. The new experiments facilitated the structural evaluation of a sample containing a mixture of oligosaccharides resulting from the depolymerisation of fCS polysaccharide

Rifapentine access in Europe: growing concerns over key tuberculosis treatment component

[No abstract available]Support statement: C. Lange is supported by the German Center of Infection Research (DZIF). All other authors have no funding to declare for this study. Funding information for this article has been deposited with the Crossref Funder Registry

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Correction: Volume53, Issue5 Page 762-762 DOI: 10.1038/s41588-021-00832-z Published MAY 2021Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequencyPeer reviewe

Technical design of the phase I Mu3e experiment

The Mu3e experiment aims to find or exclude the lepton flavour violating decay $\mu \rightarrow eee$ at branching fractions above $10^{-16}$. A first phase of the experiment using an existing beamline at the Paul Scherrer Institute (PSI) is designed to reach a single event sensitivity of $2\cdot 10^{-15}$. We present an overview of all aspects of the technical design and expected performance of the phase~I Mu3e detector. The high rate of up to $10^{8}$ muon decays per second and the low momenta of the decay electrons and positrons pose a unique set of challenges, which we tackle using an ultra thin tracking detector based on high-voltage monolithic active pixel sensors combined with scintillating fibres and tiles for precise timing measurements.Comment: 114 pages, 185 figures. Submitted to Nuclear Instruments and Methods A. Edited by Frank Meier Aeschbacher This version has many enhancements for better readability and more detail