Enhancing Variant Prioritization in VarFish through On-Premise Computational Facial Analysis.

Genomic variant prioritization is crucial for identifying disease-associated genetic variations. Integrating facial and clinical feature analyses into this process enhances performance. This study demonstrates the integration of facial analysis (GestaltMatcher) and Human Phenotype Ontology analysis (CADA) within VarFish, an open-source variant analysis framework. Challenges related to non-open-source components were addressed by providing an open-source version of GestaltMatcher, facilitating on-premise facial analysis to address data privacy concerns. Performance evaluation on 163 patients recruited from a German multi-center study of rare diseases showed PEDIA's superior accuracy in variant prioritization compared to individual scores. This study highlights the importance of further benchmarking and future integration of advanced facial analysis approaches aligned with ACMG guidelines to enhance variant classification.

A High Temperature Harvestorer Based on a Photovoltaic Cell and an Oxygen Ion Battery.

Hybrid devices for combined energy harvesting and storage, i.e., harvestorers, are attractive solutions for powering small autonomous devices (e.g., "smart appliances", Internet of things nodes), which are ever more prominent as the digitalization and technologization of our society progresses. A concept for a high temperature (HT) harvestorer is presented, and the operational characteristics of a prototype device are discussed. It is based on photovoltaic (PV) energy harvesting and HT electrochemical energy storage. The HT-PV cells employ SrTiO3/La0.9Sr0.1CrO3-δ heterojunctions for energy harvesting and produce photovoltages up to 1 V and photocurrents of several mA cm-2 upon UV illumination at 350 °C. Electrochemical energy storage is realized by oxygen ion battery (OIB), a device based on mixed ionic and electronic conducting oxide thin film electrodes and an yttria stabilized zirconia electrolyte. The OIB exhibits capacities of up to 11 mC cm-2 (3 µA h cm-2) at 0.6 V (350 °C). A prototype harvestorer device was fabricated by integrating an HT-PV and an OIB cell into one device. This harvestorer was operated over several cycles consisting of harvesting and storing energy under illumination, followed by retrieval of the stored energy without illumination. Up to 3.5 mJ cm-2 (1 µW h cm-2) was stored with energy efficiencies up to 67%. Approaches for further optimization are discussed.

Closed-Pore Formation in Oxygen Electrodes for Solid Oxide Electrolysis Cells Investigated by Impedance Spectroscopy.

Electrochemical impedance spectroscopy was used to investigate the chemical capacitance of La0.6Sr0.4CoO3-δ (LSC) thin-film electrodes under anodic polarization (i.e., in the electrolysis mode). For this purpose, electrodes with different microstructures were prepared via pulsed-laser deposition. Analysis of dense electrodes and electrodes with open porosity revealed decreasing chemical capacitances with increasing anodic overpotentials, as expected from defect chemical considerations. However, extremely high chemical capacitance peaks with values in the range of 104 F/cm3 at overpotentials of >140 mV were obtained after annealing for several hours in synthetic air and/or after applying high anodic bias voltages of >750 mV. From the results of several surface analysis techniques and transmission electron microscopy, it is concluded that closed pores develop upon both of these treatments: (i) During annealing, initially open pores get closed by SrSO4, which forms due to strontium segregation in measurement gases with minute traces of sulfur. (ii) The bias treatment causes mechanical failure and morphological changes including closed pores in the bulk of dense films. Under anodic polarization, high-pressure oxygen accumulates in those closed pores, and this causes the capacitance peak. Model calculations based on a real-gas equation allow us to properly predict the experimentally obtained capacitance increase. We demonstrate that analysis of the chemical capacitance of oxygen electrodes in solid oxide electrolysis cells can thus be used as a nondestructive observation tool to detect and quantify closed porosity with a lower detection limit between 10-4 and 10-3.

Formation and Detection of High-Pressure Oxygen in Closed Pores of La0.6Sr0.4CoO3-δ Solid Oxide Electrolysis Anodes.

The chemical capacitance of La0.6Sr0.4CoO3-δ (LSC) thin film microelectrodes with different microstructures was investigated upon varying anodic DC voltages. Dense and porous electrodes (open porosity) were prepared by using different parameters during pulsed laser deposition (PLD). Furthermore, electrodes with closed porosity were fabricated by depositing a dense capping layer on a porous film. Electrochemical impedance spectroscopy (EIS) was performed in synthetic air at 460 and 608 °C with anodic DC voltages up to 440 mV. Chemical capacitance values of the electrodes were derived from the obtained spectra. While the chemical capacitance of dense and porous electrodes decreased as expected with increasing anodic overpotential, electrodes with closed pores exhibited very unusual peaks with extremely high values of >8000 F/cm3 at overpotentials of >100 mV. We demonstrate that this huge capacitance increase agrees very well with calculated chemical capacitances deduced from a real gas equation. Hence, we conclude that the formation of highly pressurized oxygen (up to gas pressures of ∼104 bar) in closed pores is responsible for this strong capacitive effect at anodic overpotentials. Such measurements can thus detect and quantify the buildup of high internal gas pressures in closed pores at the anode side of solid oxide electrolysis cells.

In situ techniques reveal the true capabilities of SOFC cathode materials and their sudden degradation due to omnipresent sulfur trace impurities.

In this study, five different mixed conducting cathode materials were grown as dense thin films by pulsed laser deposition (PLD) and characterized via in situ impedance spectroscopy directly after growth inside the PLD chamber (i-PLD). This technique enables quantification of the oxygen reduction kinetics on pristine and contaminant-free mixed conducting surfaces. The measurements reveal excellent catalytic performance of all pristine materials with polarization resistances being up to two orders of magnitude lower than those previously reported in the literature. For instance, on dense La0.6Sr0.4CoO3-δ thin films, an area specific surface resistance of ∼0.2 Ω cm2 at 600 °C in synthetic air was found, while values usually >1 Ω cm2 are measured in conventional ex situ measurement setups. While surfaces after i-PLD measurements were very clean, ambient pressure X-ray photoelectron spectroscopy (AP-XPS) measurements found that all samples measured in other setups were contaminated with sulfate adsorbates. In situ impedance spectroscopy during AP-XPS revealed that already trace amounts of sulfur present in high purity gases accumulate quickly on pristine surfaces and lead to strongly increased surface polarization resistances, even before the formation of a SrSO4 secondary phase. Accordingly, the inherent excellent catalytic properties of this important class of materials were often inaccessible so far. As a proof of concept, the fast kinetics observed on sulfate-free surfaces were also realized in ex situ measurements with a gas purification setup and further reduces the sulfur concentration in the high purity gas.

The Digital Transformation of Mental Health Care and Psychotherapy - A Market and Research Maturity Analysis.

Digital technology trends for mental health, instantiated with only emerging use cases or already established applications, offer significant potential to improve clinical therapy and care. In this paper, we identify five major trends, mHealth/eHealth, telehealth, artificial intelligence (AI), big data, and biosensors/wearables; describe seven specific technology use cases for mental health care and psychotherapy; and provide an overview of their maturity in practice.

Combining electron spin resonance spectroscopy with scanning tunneling microscopy at high magnetic fields.

The continuous increase in storage densities and the desire for quantum memories and computers push the limits of magnetic characterization techniques. Ultimately, a tool that is capable of coherently manipulating and detecting individual quantum spins is needed. Scanning tunneling microscopy (STM) is the only technique that unites the prerequisites of high spatial and energy resolution, low temperature, and high magnetic fields to achieve this goal. Limitations in the available frequency range for electron spin resonance STM (ESR-STM) mean that many instruments operate in the thermal noise regime. We resolve challenges in signal delivery to extend the operational frequency range of ESR-STM by more than a factor of two and up to 100 GHz, making the Zeeman energy the dominant energy scale at achievable cryogenic temperatures of a few hundred millikelvin. We present a general method for augmenting existing instruments into ESR-STM to investigate spin dynamics in the high-field limit. We demonstrate the performance of the instrument by analyzing inelastic tunneling in a junction driven by a microwave signal and provide proof of principle measurements for ESR-STM.

GestaltMatcher facilitates rare disease matching using facial phenotype descriptors.

Many monogenic disorders cause a characteristic facial morphology. Artificial intelligence can support physicians in recognizing these patterns by associating facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this 'supervised' approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we developed GestaltMatcher, an encoder for portraits that is based on a deep convolutional neural network. Photographs of 17,560 patients with 1,115 rare disorders were used to define a Clinical Face Phenotype Space, in which distances between cases define syndromic similarity. Here we show that patients can be matched to others with the same molecular diagnosis even when the disorder was not included in the training set. Together with mutation data, GestaltMatcher could not only accelerate the clinical diagnosis of patients with ultra-rare disorders and facial dysmorphism but also enable the delineation of new phenotypes.

Investigating oxygen reduction pathways on pristine SOFC cathode surfaces by in situ PLD impedance spectroscopy.

The oxygen exchange reaction mechanism on truly pristine surfaces of SOFC cathode materials (La0.6Sr0.4CoO3-δ = LSC, La0.6Sr0.4FeO3-δ = LSF, (La0.6Sr0.4)0.98Pt0.02FeO3-δ = Pt:LSF, SrTi0.3Fe0.7O3-δ = STF, Pr0.1Ce0.9O2-δ = PCO and La0.6Sr0.4MnO3-δ = LSM) was investigated employing in situ impedance spectroscopy during pulsed laser deposition (i-PLD) over a wide temperature and p(O2) range. Besides demonstrating the often astonishing catalytic capabilities of the materials, it is possible to discuss the oxygen exchange reaction mechanism based on experiments on clean surfaces unaltered by external degradation processes. All investigated materials with at least moderate ionic conductivity (i.e. all except LSM) exhibit polarization resistances with very similar p(O2)- and T-dependences, mostly differing only in absolute value. In combination with non-equilibrium measurements under polarization and defect chemical model calculations, these results elucidate several aspects of the oxygen exchange reaction mechanism and refine the understanding of the role oxygen vacancies and electronic charge carriers play in the oxygen exchange reaction. It was found that a major part of the effective activation energy of the surface exchange reaction, which is observed during equilibrium measurements, originates from thermally activated charge carrier concentrations. Electrode polarization was therefore used to control defect concentrations and to extract concentration amended activation energies, which prove to be drastically different for oxygen incorporation and evolution (0.26 vs. 2.05 eV for LSF).

Cation non-stoichiometry in Fe:SrTiO3 thin films and its effect on the electrical conductivity.

The interplay of structure, composition and electrical conductivity was investigated for Fe-doped SrTiO3 thin films prepared by pulsed laser deposition. Structural information was obtained by reciprocal space mapping while solution-based inductively-coupled plasma optical emission spectroscopy and positron annihilation lifetime spectroscopy were employed to reveal the cation composition and the predominant point defects of the thin films, respectively. A severe cation non-stoichiometry with Sr vacancies was found in films deposited from stoichiometric targets. The across plane electrical conductivity of such epitaxial films was studied in the temperature range of 250-720 °C by impedance spectroscopy. This revealed a pseudo-intrinsic electronic conductivity despite the substantial Fe acceptor doping, i.e. conductivities being several orders of magnitude lower than expected. Variation of PLD deposition parameters causes some changes of the cation stoichiometry, but the films still have conductivities much lower than expected. Targets with significant Sr excess (in the range of several percent) were employed to improve the cation stoichiometry in the films. The use of 7% Sr-excess targets resulted in near-stoichiometric films with conductivities close to the stoichiometric bulk counterpart. The measurements show that a fine-tuning of the film stoichiometry is required in order to obtain acceptor doped SrTiO3 thin films with bulk-like properties. One can conclude that, although reciprocal space maps give a first hint whether or not cation non-stoichiometry is present, conductivity measurements are more appropriate for assessing SrTiO3 film quality in terms of cation stoichiometry.

CADA: phenotype-driven gene prioritization based on a case-enriched knowledge graph.

Many rare syndromes can be well described and delineated from other disorders by a combination of characteristic symptoms. These phenotypic features are best documented with terms of the Human Phenotype Ontology (HPO), which are increasingly used in electronic health records (EHRs), too. Many algorithms that perform HPO-based gene prioritization have also been developed; however, the performance of many such tools suffers from an over-representation of atypical cases in the medical literature. This is certainly the case if the algorithm cannot handle features that occur with reduced frequency in a disorder. With Cada, we built a knowledge graph based on both case annotations and disorder annotations. Using network representation learning, we achieve gene prioritization by link prediction. Our results suggest that Cada exhibits superior performance particularly for patients that present with the pathognomonic findings of a disease. Additionally, information about the frequency of occurrence of a feature can readily be incorporated, when available. Crucial in the design of our approach is the use of the growing amount of phenotype-genotype information that diagnostic labs deposit in databases such as ClinVar. By this means, Cada is an ideal reference tool for differential diagnostics in rare disorders that can also be updated regularly.

Narrative review of metabolomics in cardiovascular disease.

Cardiovascular diseases are accompanied by disorders in the cardiac metabolism. Furthermore, comorbidities often associated with cardiovascular disease can alter systemic and myocardial metabolism contributing to worsening of cardiac performance and health status. Biomarkers such as natriuretic peptides or troponins already support diagnosis, prognosis and treatment of patients with cardiovascular diseases and are represented in international guidelines. However, as cardiovascular diseases affect various pathophysiological pathways, a single biomarker approach cannot be regarded as ideal to reveal optimal clinical application. Emerging metabolomics technology allows the measurement of hundreds of metabolites in biological fluids or biopsies and thus to characterize each patient by its own metabolic fingerprint, improving our understanding of complex diseases, significantly altering the management of cardiovascular diseases and possibly personalizing medicine. This review outlines current knowledge, perspectives as well as limitations of metabolomics for diagnosis, prognosis and treatment of cardiovascular diseases such as heart failure, atherosclerosis, ischemic and non-ischemic cardiomyopathy. Furthermore, an ongoing research project tackling current inconsistencies as well as clinical applications of metabolomics will be discussed. Taken together, the application of metabolomics will enable us to gain more insights into pathophysiological interactions of metabolites and disease states as well as improving therapies of patients with cardiovascular diseases in the future.

How To Get Mechanistic Information from Partial Pressure-Dependent Current-Voltage Measurements of Oxygen Exchange on Mixed Conducting Electrodes.

The oxygen incorporation and evolution reaction on mixed conducting electrodes of solid oxide fuel or electrolysis cells involves gas molecules as well as ionic and electronic point defects in the electrode. The defect concentrations depend on the gas phase and can be modified by the overpotential. These interrelationships make a mechanistic analysis of partial pressure-dependent current-voltage experiments challenging. In this contribution it is described how to exploit this complex situation to unravel the kinetic roles of surface adsorbates and electrode point defects. Essential is a counterbalancing of oxygen partial pressure and dc electrode polarization such that the point defect concentrations in the electrode remain constant despite varying the oxygen partial pressure. It is exemplarily shown for La0.6Sr0.4FeO3-δ (LSF) thin film electrodes on yttria-stabilized zirconia how mechanistically relevant reaction orders can be obtained from current-voltage curves, measured in a three-electrode setup. This analysis strongly suggests electron holes as the limiting defect species for the oxygen evolution on LSF and reveals the dependence of the oxygen incorporation rate on the oxygen vacancy concentration. A virtual independence of the reaction rate from the oxygen partial pressure was empirically found for moderate oxygen pressures. This effect, however, arises from a counterbalancing of defect and adsorbate concentration changes.

Voltage and partial pressure dependent defect chemistry in (La,Sr)FeO3-δ thin films investigated by chemical capacitance measurements.

La0.6Sr0.4FeO3-δ (LSF) thin films of different thickness were prepared by pulsed laser deposition on yttria stabilized zirconia (YSZ) and characterized by using three electrode impedance spectroscopy. Electrochemical film capacitance was analyzed in relation to oxygen partial pressure (0.25 mbar to 1 bar), DC polarization (0 m to -600 m) and temperature (500 to 650 °C). For most measurement parameters, the chemical bulk capacitance dominates the overall capacitive properties and the corresponding defect chemical state depends solely on the oxygen chemical potential inside the film, independent of atmospheric oxygen pressure and DC polarization. Thus, defect chemical properties (defect concentrations and defect formation enthalpies) could be deduced from such measurements. Comparison with LSF defect chemical bulk data from the literature showed good agreement for vacancy formation energies but suggested larger electronic defect concentrations in the films. From thickness-dependent measurements at lower oxygen chemical potentials, an additional capacitive contribution could be identified and attributed to the LSF|YSZ interface. Deviations from simple chemical capacitance models at high pressures are most probably due to defect interactions.

Lightweight, Room-Temperature CO2 Gas Sensor Based on Rare-Earth Metal-Free Composites-An Impedance Study.

We report a light, flexible, and low-power poly(ionic liquid)/alumina composite CO2 sensor. We monitor the direct-current resistance changes as a function of CO2 concentration and relative humidity and demonstrate fast and reversible sensing kinetics. Moreover, on the basis of the alternating-current impedance measurements we propose a sensing mechanism related to proton conduction and gas diffusion. The findings presented herein will promote the development of organic/inorganic composite CO2 gas sensors. In the future, such sensors will be useful for numerous practical applications ranging from indoor air quality control to the monitoring of manufacturing processes.

The Chemical Capacitance as a Fingerprint of Defect Chemistry in Mixed Conducting Oxides.

The oxygen stoichiometry of mixed conducting oxides depends on the oxygen chemical potential and thus on the oxygen partial pressure in the gas phase. Also voltages may change the local oxygen stoichiometry and the amount to which such changes take place is quantified by the chemical capacitance of the sample. Impedance spectroscopy can be used to probe this chemical capacitance. Impedance measurements on different oxides ((La,Sr)FeO3-δ = LSF, Sr(Ti,Fe)O3-δ = STF, and Pb(Zr,Ti)O3 = PZT) are presented, and demonstrate how the chemical capacitance may affect impedance spectra in different types of electrochemical cells. A quantitative analysis of the spectra is based on generalized equivalent circuits developed for mixed conducting oxides by J. Jamnik and J. Maier. It is discussed how defect chemical information can be deduced from the chemical capacitance.

JANE: efficient mapping of prokaryotic ESTs and variable length sequence reads on related template genomes.

BACKGROUND: ESTs or variable sequence reads can be available in prokaryotic studies well before a complete genome is known. Use cases include (i) transcriptome studies or (ii) single cell sequencing of bacteria. Without suitable software their further analysis and mapping would have to await finalization of the corresponding genome. RESULTS: The tool JANE rapidly maps ESTs or variable sequence reads in prokaryotic sequencing and transcriptome efforts to related template genomes. It provides an easy-to-use graphics interface for information retrieval and a toolkit for EST or nucleotide sequence function prediction. Furthermore, we developed for rapid mapping an enhanced sequence alignment algorithm which reassembles and evaluates high scoring pairs provided from the BLAST algorithm. Rapid assembly on and replacement of the template genome by sequence reads or mapped ESTs is achieved. This is illustrated (i) by data from Staphylococci as well as from a Blattabacteria sequencing effort, (ii) mapping single cell sequencing reads is shown for poribacteria to sister phylum representative Rhodopirellula Baltica SH1. The algorithm has been implemented in a web-server accessible at http://jane.bioapps.biozentrum.uni-wuerzburg.de. CONCLUSION: Rapid prokaryotic EST mapping or mapping of sequence reads is achieved applying JANE even without knowing the cognate genome sequence.

New aspects on the preparation of [11C]Methionine--a simple and fast online approach without preparative HPLC.

At present, most data available on PET imaging of brain tumors using amino acids are based on l-[S-methyl-11C]methionine (MET). This radiopharmaceutical accurately delineates tumor extent, sometimes even better than CT. Since MET is playing such an important role for PET, a potent preparation method for this radiotracer allowing frequent syntheses for PET routine is desirable. Therefore, a simple disposable synthesis module was conceived without HPLC purification. Using a solid supported [11C]methylation on Al2O3 leads to the simplification of the preparation requiring only filtration for separation of precursor and MET. The presented method is able to produce high purity MET in excellent yields enough to serve several consecutive patients.