Genome Interpretation Using In Silico Predictors of Variant Impact

Estimating the effects of variants found in disease driver genes opens the door to personalized therapeutic opportunities. Clinical associations and laboratory experiments can only characterize a tiny fraction of all the available variants, leaving the majority as variants of unknown significance (VUS). In silico methods bridge this gap by providing instant estimates on a large scale, most often based on the numerous genetic differences between species. Despite concerns that these methods may lack reliability in individual subjects, their numerous practical applications over cohorts suggest they are already helpful and have a role to play in genome interpretation when used at the proper scale and context. In this review, we aim to gain insights into the training and validation of these variant effect predicting methods and illustrate representative types of experimental and clinical applications. Objective performance assessments using various datasets that are not yet published indicate the strengths and limitations of each method. These show that cautious use of in silico variant impact predictors is essential for addressing genome interpretation challenges

Further investigations of the deep double donor magnesium in silicon

The deep double donor levels of substitutional chalcogen impurities in silicon have unique optical properties which may enable a spin/photonic quantum technology. The interstitial magnesium impurity (Mg$_i$) in silicon is also a deep double donor but has not yet been studied in the same detail as have the chalcogens. In this study we look at the neutral and singly ionized Mg$_i$ absorption spectra in natural silicon and isotopically enriched 28-silicon in more detail. The 1s(A$_1$) to 1s(T$_2$) transitions, which are very strong for the chalcogens and are central to the proposed spin/photonic quantum technology, could not be detected. We observe the presence of another double donor (Mg$_{i*}$) that may result from Mg$_i$ in a reduced symmetry configuration, most likely due to complexing with another impurity. The neutral species of Mg$_{i*}$ reveal unusual low lying ground state levels detected through temperature dependence studies. We also observe a shallow donor which we identify as a magnesium-boron pair

A Mg-pair isoelectronic bound exciton identified by its isotopic fingerprint in 28^{28}Si

We use the greatly improved optical linewidths provided by highly enriched $^{28}$Si to study a photoluminescence line near 1017 meV previously observed in the luminescence spectrum of natural Si diffused with Mg, and suggested to result from the recombination of an isoelectronic bound exciton localized at a Mg-pair center. In $^{28}$Si this no-phonon line is found to be comprised of five components whose relative intensities closely match the relative abundances of Mg-pairs formed by random combinations of the three stable isotopes of Mg, thus confirming the Mg-pair hypothesis. We further present the results of temperature dependence studies of this center that reveal unusual and as yet unexplained behaviour.Comment: 5 pages, 4 figure

Reduced Drying Time of Anodes for Lithium-Ion Batteries through Simultaneous Multilayer Coating

The extended process chain starting from slurry mixing up to the operative lithium-ion battery requires a deep understanding of each individual process step and knowledge of the interaction of the different process steps with each other. In particular, the intertwining of slurry mixing and drying determines the microstructure of the electrode, which in turn affects the performance of the cell. Herein, a scalable multilayer approach is used to tailor electrodes with improved mechanical and electrochemical properties, which disclose their advantages especially at high drying rates. Cryogenic broad ion beam scanning electron microscopy (Cryo-BIB-SEM) micrographs are used to reveal the influences of different process parameters, like slurry formulation, mixing device, and properties of the active material on the intrinsic network between active particles and binders in graphite-based anode slurries. By a chosen combination of these slurries in a multilayer electrode, a tenfold acceleration of the drying time with favorable mechanical and electrochemical properties for full cells derived from these anodes is demonstrated

PINK1 regulated mitophagy is evident in skeletal muscles

PINK1, mutated in familial forms of Parkinson’s disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions

A macro-level analysis of the socio-economic impacts of climate change driven water scarcity : incorporating behavioural and resilience aspects

Recognising the urgent need to address water scarcity resulting from climate change, there is a growing push to enhance the resilience of water (and related) systems. For instance, policymakers are now urging companies to shift from short-term focused strategies towards long-term approaches to effectively manage water scarcity. This paper utilises a custom-built dynamic multisectoral model to assess the socio-economic impacts at a macro-level of temporary water scarcity. The focus of the analysis is to identify the effects that varying levels of investment foresight may have on economic resilience. Specifically, the model incorporates often overlooked factors such as behavioural and resilience aspects. By considering these key elements, a more comprehensive understanding of the system-wide implications of water scarcity on the broader economy is provided. The analysis shows how firms' foresight, or lack thereof, impacts their response to water scarcity and the subsequent impact on the economy. Sector-specific analyses shed light on the potential negative impacts of water scarcity on sectors like agriculture, food, and electricity production and distribution. Yet, the analysis also reveals that certain sectors can benefit from competitiveness effects, which can mitigate the adverse economic implications of water scarcity. However, it should be noted that these sectors may contribute to a catch-up effect on water use. The policy recommendations arising from this research emphasise the promotion of anticipation and preparedness among firms. It is crucial to prioritise resilience-building measures in all sectors, whether they directly rely on water or not

Coaxial end-launched and microstrip to partial H-plane waveguide transitions

Conventional rectangular waveguides are commonly used for high power and other microwave and millimeter-wave applications. Their use at lower frequencies has been limited by their bulky nature. A new type of compact waveguide called a partial H-plane waveguide has previously been proposed that has only one quarter of the cross-sectional area of a conventional waveguide. However, only limited information relating to the feeding of such waveguides is available. This paper presents two types of transitions to partial H-plane waveguides from the coaxial and microstrip transmission mediums. Additionally, in the coaxial case, the transition is end-launched to offer collinear properties. The development of both transitions is discussed and optimized designs presented with simulated and measured results over -band (3.95–5.85 GHz).http://ieeexplore.ieee.org/xpl/RecentIssue.jsp?punumber=22hb201