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Abstract Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.

Abstract Background Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a “real-time” measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load. Methods The present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen. Results Regression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis. Conclusions Our results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials. Trial registration NexGen EBA study (NCT02371681)

Abstract Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration of treatment. The purpose of this study was to demonstrate utility of a physiologically‐based pharmacokinetic modeling approach to predict plasma and lung concentrations of 11 compounds used or under development as TB therapies (bedaquiline [and N‐desmethyl bedaquiline], clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, pyrazinamide, rifampicin, and rifapentine). Model accuracy was assessed by comparison of simulated plasma pharmacokinetic parameters with healthy volunteer data for compounds administered alone or in combination. Eighty‐four percent (area under the curve [AUC]) and 91% (maximum concentration [Cmax]) of simulated mean values were within 1.5‐fold of the observed data and the simulated drug‐drug interaction ratios were within 1.5‐fold (AUC) and twofold (Cmax) of the observed data for nine (AUC) and eight (Cmax) of the 10 cases. Following satisfactory recovery of plasma concentrations in healthy volunteers, model accuracy was assessed further (where patients’ with TB data were available) by comparing clinical data with simulated lung concentrations (9 compounds) and simulated lung: plasma concentration ratios (7 compounds). The 5th–95th percentiles for the simulated lung concentration data recovered between 13% (isoniazid and pyrazinamide) and 88% (pyrazinamide) of the observed data points (Am J Respir Crit Care Med, 198, 2018, 1208; Nat Med, 21, 2015, 1223; PLoS Med, 16, 2019, e1002773). The impact of uncertain model parameters, such as the fraction of drug unbound in lung tissue mass (fumass), is discussed. Additionally, the variability associated with the patient lung concentration data, which was sparse and included extensive within‐subject, interlaboratory, and experimental variability (as well interindividual variability) is reviewed. All presented models are transparently documented and are available as open‐source to aid further research.

In diesem Artikel werden Handlungsoptionen und -spielräume wissenschaftlicher Bibliotheken im Kontext eines sich durch die Digitalisierung verändernden Aufgaben- und Anforderungsspektrums thematisiert. Dieses Themenfeld wird durch die Linse der Berufsgruppe der wissenschaftlichen Bibliothekar*innen bzw. Fachreferent*innen betrachtet. Bestehenden Strukturen, insbesondere den Fachreferaten, kommt in diesem Prozess eine besondere Rolle zu, bieten sie doch Chancen, neue Themen effizient und gezielt an der eigenen Einrichtung einzubinden. Durch die Übernahme neuer Aufgaben durch die Fachreferent*innen besteht jedoch der Bedarf einer Selbstvergewisserung, um adäquat auf neue Situationen reagieren zu können. Anhand des Beispiels Forschungsdatenmanagement (FDM) an der Universitätsbibliothek der LMU (UB der LMU) werden Möglichkeiten aufgezeigt, wie eine Kooperation zwischen FDM-Beratung, Fachreferaten und Forschenden aussehen kann. Welche Rolle spielen dabei Konzepte wie „Embedded Librarian“ oder „Data Literacy“? Und wie können Fachreferent*innen einbezogen werden, um die FDM-Strukturen der eigenen Einrichtung erfolgreich weiterzuentwickeln?

This paper introduces the automation measurement software FlexSensor for capturing resonant spectra, an innovative and extensible software program developed explicitly for measuring and evaluating wafer-level Silicon Photonic (SiPh) circuits. Wafer-level Silicon Photonics allows the integration of numerous optical components and structures on a single wafer. However, researchers and engineers need precise and repeatable measurements to characterize them and face significant challenges when dealing with large numbers of complex systems on a single wafer. A toolchain gap hampers the measuring of such highly integrated photonic structures: While the setup necessitates the integration of an optimized hardware and software toolchain, there is neither software nor a standardized way to implement a reproducible measurement routine for a massive set of measurements.FlexSensor allows integration and control of external hardware (tunable lasers, analog–digital converters) and supports measurement data storage and evaluation. The software enables researchers and engineers to efficiently analyze the spectral response of photonic structures and facilitate rapid measuring.

Abstract Cuing or executing a task impacts processing pathways for task-relevant information. While there is ample evidence that processing associated with task execution changes with practice, such evidence regarding cue-induced task preparation is scarce. Here we explored practice-related changes of processing pathways by task cuing in order to assess the plasticity of task preparation. We first developed and validated a new method for the study of practice-related changes, the effect course analysis. The effect course analysis is a model-free, non-parametric method designed to reveal effect changes within an experimental session on a continuous time scale. Then we applied this method to a new study in which cued task sets were supposed to remain activated during assessment of task-relevant pathways, as potential task execution was postponed at the end of the trial. The results showed that, with little practice, task cuing amplified task-relevant pathways, whereas this effect vanished with practice, suggesting that practice prompts fundamental changes of how task cues are used for task preparation. Hence, if one cannot be certain that cognitive processing is stationary, investigating the time course of experimental effects appears to be crucial to determine how cognitive processing is influenced by practice.

Wechselwirkung ist ein zentrales, übergreifendes Konzept im Bereich Ökologie. Nahrungsbeziehungen in Ökosystemen eignen sich besonders, um das Konzept Wechselwirkung in der Sekundarstufe I beispielhaft einzuführen. Studien zeigen, dass Lernenden die elaborierte Beschreibung von Nahrungsbeziehungen schwerfällt und sie oftmals nur direkte Wechselwirkungen beschreiben. In der Forschungsliteratur wird ein Bedarf an unterrichtlichen Strategien benannt, mit deren Hilfe Schüler:innen aufbauend auf ihre bisherigen Konzepte fachlich angemessenere entwickeln können und dabei Nahrungsbeziehungen auch als indirekte und zyklische Wechselwirkungen erklären. Das Projekt entwickelt auf Basis von Conceptual Change-Texts ein innovatives Lernmedium: Conceptual Change-Stories. Diese greifen Konstruktionsprinzipien von Conceptual Change-Texts auf, bieten aber durch die narrative Textgestaltung vereinfachte Zugänge zum Verstehen von Nahrungsbeziehungen als Wechsel-wirkungen. In der vorliegenden Studie wird die Wirkung der Conceptual Change-Stories auf die Beschreibungen von Nah-rungsbeziehungen bei Schüler:innen der Klassenstufe 6 untersucht. Die Ergebnisse liefern Anhaltspunkte zur (Weiter-) Entwicklung von Conceptual Change-Stories. Erste Ergebnisse deuten an, dass Conceptual Change-Stories ein geeignetes Lern-medium darstellen können, um Wechselwirkungen im Nahrungsnetz verstehbar zu machen.

Integrated photonic sensors have gained significant attention for biosensing applications. An especially potent design is the polarimetric waveguide interferometer, which utilizes polarization diversity for effective self-referencing. However, its implementations are held back by the need for bulky free-space optics or unreliable waveguide junctions for polarization handling. To overcome these limitations, we propose a novel concept for a compact photonic system that employs edge couplers to excite both polarizations from an optical fiber and an in-line polarizer to obtain the phase information in the fiber-based readout. Additionally, we improve the waveguide design methodology to minimize the limit of detection through balancing sensitivity with optical loss. To this end, we create a unified perturbative approach based on atomic force microscopy and ellipsometry data to model sensitivity, surface-roughness-induced scattering, absorption, and radiation. We then incorporate the coupling efficiency into a figure of merit for the combined system. Thus, we optimize the geometry of a strip waveguide on a CMOS-foundry-sourced silicon nitride platform for biosensing. Through exhaustive screening of the design space, we discover that polarization diversity simultaneously leverages high sensitivity and low overlap with sidewall roughness. Further, we present designs that eliminate the phase signal from two major noise sources: thermal and bulk refractive index fluctuations. Finally, we provide design recommendations and achieve a 5.2-fold improvement over a comparable bimodal waveguide interferometer. Thus, our aim is to design a robust, compact, sensitive, and cost-effective polarimetric waveguide interferometer through an efficient concept and an optimized design.

Remote emission sensing (RES) is a state-of-the-art technique for monitoring thousands of vehicles on the road every day to detect high emitters. Modern commercial RES systems use absorption spectroscopy to measure the ratio of pollutants to CO2 from vehicle exhaust gases. In this work, we present an approach to enable direct concentration measurements by spectroscopic techniques in RES through measurement of the absorption path length. Our gas schlieren imaging sensor (GSIS) system operates on the principle of background-oriented schlieren (BOS) imaging in combination with advanced image processing and deep learning techniques to calculate detected exhaust plume sizes. We performed a qualitative as well as a quantitative analysis of vehicle exhaust and plume dimensions with the GSIS system. We present the system details and results from the GSIS system in the lab in comparison to a BOS model based on flow simulations, the results from characterization measurements in the lab with defined gas mixtures and temperatures, and the results from measurements on the road from different vehicles.

Damit (angehende) Lehrkräfte digitale Medien zukünftig im Fachunterricht einsetzen, müssen sie im Rahmen des Lehramtsstudiums digitalisie-rungsbezogene Kompetenzen erwerben. Zwar beschreiben diverse Modelle solche Kompetenzen für die Lehrer*innenbildung, jedoch erweist es sich als Herausforderung, diese Kompetenzen in die Curricula universitärer Lehrveranstaltungen zu integrieren. Um Studium und Lehre in entsprechender Weise zu verändern, bedarf es eines Vorgehens, das nicht lediglich „top-down“-Steuerungsansätze des Change-Managements auf Hochschulen überträgt, sondern stattdessen deren organisationale Eigenheiten ernst nimmt und relevante Akteur*innen im Sinne eines „bottom-up“-Veränderungsprozesses einbezieht. Ein solches Vorgehen zur Veränderung universitärer Studienprogramme (im Sinne der Integration digitalisierungsbezogener Kompetenzen in Ausbildungsziele) wurde im Rahmen des Projekts „BiodigitaliS“ entwickelt. Dies erfolgte unter Bezug auf das Modell der Pädagogischen Hochschulentwicklung und unter Verwendung des Kompetenzrahmens „DiKoLAN“. Die Konzeption des Vorgehens sowie die Ergebnisse seiner Durchführung am Standort Leipzig werden im vorliegenden Beitrag beschrieben. Unter Berücksichtigung der Kontextbedingungen am Standort (Struktur und Organisation des Lehrangebots, Voraussetzungen und Bedarfe Studierender) und unter starkem Einbezug der Lehrenden konnten digitalisierungsbezogene Kompetenzen umfassender, gezielt und systematisch in die Ausbildungsziele bestehender biologiedidaktischer Lehrveranstaltungen integriert werden. Mit den formulierten Ausbildungszielen liefert das Vorgehen eine Grundlage für die Gestaltung und Evaluation von Hochschullehre zur Förderung digitalisierungsbezogener Kompetenzen. Vor dem Hintergrund der Ergebnisse wird im Beitrag ein Verfahren zur Integration digitalisierungsbezogener Kompetenzen in die Ausbildungsziele universitärer Lehre (IKAL-Verfahren) vorgestellt und anhand von Leitlinien für nachhaltige Veränderungen von Hochschullehre diskutiert. Abschließend erfolgt ein Ausblick auf die Übertragbarkeit des Verfahrens auf hochschulische Lehrveranstaltungen in anderen Bereichen.

Abstract Objective Cross-species comparative genomics requires access to accurate homology data across the entire range of annotated genes. The Alliance of Genome Resources (AGR) provides an open-source and comprehensive database of homology data calculated using a wide array of algorithms at differing stringencies to elucidate orthologous relationships. However, the current AGR application program interface (API) is limited to five homology endpoints for nine species. While AGR provides a robust resource for several canonical species, its utility can be greatly enhanced by increased filtering and data processing options and incorporating additional species. Results Here, we describe a novel API tool, AON, that expands access to the AGR orthology resource by creating a data structure that supports 50 additional endpoints. More importantly, it provides users with a framework for adding bespoke endpoints, custom species, and additional orthology data. We demonstrate AON’s functionality by incorporating the service into the GeneWeaver ecosystem for supporting cross-species data analysis.

A current challenge in realising clean road transport is non-exhaust emissions. Important advances regarding measurement systems, including well-defined characterisation techniques, as well as regulation, will be made in the next few years. In this work, we present the detailed results of particle emission analyses, consisting of aerosol (size distribution, particle number (PN), and mass (PM)) and electron microscopy (EM) measurements, under different load conditions on a test bed for a wheel suspension and brakes. Standard tyres and brakes from serial production were tested with a high-load driving cycle, while particle measurements were conducted by gravimetric measurements and with a TSI SMPS, a TSI APS, and a GRIMM OPS. Furthermore, samples were analysed by electron microscopy. A bimodal particle size distribution (PSD) was obtained with an SMPS, with peaks at 20 nm and around 400 nm. The results of an EM analysis of >1400 single particles from the electrostatic sampler match the PSD results. The EM analysis also showed ultrafine particles, mainly containing O, Fe, Si, Ba, Mg, and S, and also fractal particles with high-C fractions. Our results suggest, in agreement with the previously published literature, that particulate emissions are related to the brake disc temperature and occur in significant amounts above a threshold temperature.

Abstract Humidity sensors are used in many applications. The design of fast sensors that can operate in explosive environments is a difficult task. Therefore, current research efforts aim at combining reliability, sensitivity and high sensing speed. The use of structured ultrathin hydrogels perfectly meets these requirements. Nanostructures are directly fabricated with a two‐photon‐polymerisation (2PP) 3D printer to use them as templates for hydrogels. After the 3D printing multiple templates are coated with ultrathin films of poly(2‐hydroxyethyl‐methacrylate) (pHEMA) using initiated chemical vapor deposition (iCVD). p(HEMA) is a humidity responsive hydrogel which changes its thickness by orders of magnitude depending on the ambient conditions. The 3D printed structures are optimized to give both a fast response time, and an optical read‐out method for visible wavelengths. Upon hydrogel swelling, the height of the nanostructure pillars increases, keeping their periodicity constant. This induces a change in intensity of the first ‐order refraction peak, which can be easily measured also at low humidity levels. The humidity response of the nanostructures is measured and an influence for different hydrogel thicknesses and humidity flow rates is observed. The ultrathin film with the lowest thickness of 50 nm shows the fastest response to relative humidity, which is much faster than commercial sensors with 8 s response time.

Summary: Arthropod-borne viruses (arboviruses) transmitted by Aedes aegypti mosquitoes are an increasing threat to global health. The small interfering RNA (siRNA) pathway is considered the main antiviral immune pathway of insects, but its effective impact on arbovirus transmission is surprisingly poorly understood. Here, we use CRISPR-Cas9-mediated gene editing in vivo to mutate Dicer2, a gene encoding the RNA sensor and key component of the siRNA pathway. The loss of Dicer2 enhances early viral replication and systemic viral dissemination of four medically significant arboviruses (chikungunya, Mayaro, dengue, and Zika viruses) representing two viral families. However, Dicer2 mutants and wild-type mosquitoes display overall similar levels of vector competence. In addition, Dicer2 mutants undergo significant virus-induced mortality during infection with chikungunya virus. Together, our results define a multifaceted role for Dicer2 in the transmission of arboviruses by Ae. aegypti mosquitoes and pave the way for further mechanistic investigations.

Abstract Aims Although the prevalence of coronary artery disease (CAD) is high among patients with atrial fibrillation (AF), studies on stress perfusion cardiac magnetic resonance (CMR) imaging frequently exclude patients with AF, and its prognostic and diagnostic value in high‐risk patients with suspected or known CAD remains unclear. Methods and results In this longitudinal cohort study, we included 164 consecutive patients with AF during vasodilator perfusion CMR. Diagnostic value was evaluated regarding invasive coronary angiography in a subset of patients. We targeted a follow‐up of >5 years and used CMR results as stratification, and the primary outcome was major adverse cardiac events [MACE, cardiovascular (CV) death and myocardial infarction (MI)]. Secondary outcomes included late coronary revascularization or stroke and the components of the primary outcome. Of the whole cohort (73.8% male, mean age 72.2 years ± 7.8 SD), 99.4% were successfully scanned (163/164 patients). Median CHA2DS2‐VASc score was 4 [interquartile range (IQR) 3–5], and median 10‐year risk for CV events based on SMART risk score was high (24%, IQR 16–32%). Thirty‐two patients (19.6%) presented with ischaemia and 52 patients (31.9%) with late gadolinium enhancement (LGE). A combination of LGE and inducible ischaemia was present in 20 patients (12.3%). Diagnostic accuracy was 86.2% [confidence interval (CI) 68.3–96.1%]. The median follow‐up was 6.6 years (IQR 3.6–7.8). Ischaemia in vasodilator perfusion CMR was significantly associated with the occurrence of MACE [P

Abstract Background Investigations of evolution knowledge and acceptance and their relation are central to evolution education research. Ambiguous results in this field of study demonstrate a variety of measuring issues, for instance differently theorized constructs, or a lack of standardized methods, especially for cross-country comparisons. In particular, meaningful comparisons across European countries, with their varying cultural backgrounds and education systems, are rare, often include only few countries, and lack standardization. To address these deficits, we conducted a standardized European survey, on 9200 first-year university students in 26 European countries utilizing a validated, comprehensive questionnaire, the “Evolution Education Questionnaire”, to assess evolution acceptance and knowledge, as well as influencing factors on evolution acceptance. Results We found that, despite European countries’ different cultural backgrounds and education systems, European first-year university students generally accept evolution. At the same time, they lack substantial knowledge about it, even if they are enrolled in a biology-related study program. Additionally, we developed a multilevel-model that determines religious faith as the main influencing factor in accepting evolution. According to our model, knowledge about evolution and interest in biological topics also increase acceptance of evolution, but to a much lesser extent than religious faith. The effect of age and sex, as well as the country’s affiliation, students’ denomination, and whether or not a student is enrolled in a biology-related university program, is negligible. Conclusions Our findings indicate that, despite all their differences, most of the European education systems for upper secondary education lead to acceptance of evolution at least in university students. It appears that, at least in this sample, the differences in knowledge between countries reflect neither the extent to which school curricula cover evolutionary biology nor the percentage of biology-related students in the country samples. Future studies should investigate the role of different European school curricula, identify particularly problematic or underrepresented evolutionary concepts in biology education, and analyze the role of religious faith when teaching evolution.

AimTo develop and evaluate a new approach for spatially variant and tissue-dependent positron range (PR) correction (PRC) during the iterative PET image reconstruction.Materials and MethodsThe PR distributions of three radionuclides (18F, 68Ga, and 124I) were simulated using the GATE (GEANT4) framework in different material compositions (lung, water, and bone). For every radionuclide, the uniform PR kernel was created by mapping the simulated 3D PR point cloud to a 3D matrix with its size defined by the maximum PR in lung (18F) or water (68Ga and 124I) and the PET voxel size. The spatially variant kernels were composed from the uniform PR kernels by analyzing the material composition of the surrounding medium for each voxel before implementation as tissue-dependent, point-spread functions into the iterative image reconstruction. The proposed PRC method was evaluated using the NEMA image quality phantom (18F, 68Ga, and 124I); two unique PR phantoms were scanned and evaluated following OSEM reconstruction with and without PRC using different metrics, such as contrast recovery, contrast-to-noise ratio, image noise and the resolution evaluated in terms of full width at half maximum (FWHM).ResultsThe effect of PRC on 18F-imaging was negligible. In contrast, PRC improved image contrast for the 10-mm sphere of the NEMA image quality phantom filled with 68Ga and 124I by 33 and 24%, respectively. While the effect of PRC was less noticeable for the larger spheres, contrast recovery still improved by 5%. The spatial resolution was improved by 26% for 124I (FWHM of 4.9 vs. 3.7 mm).ConclusionFor high energy positron-emitting radionuclides, the proposed PRC method helped recover image contrast with reduced noise levels and with improved spatial resolution. As such, the PRC approach proposed here can help improve the quality of PET data in clinical practice and research.

Temperature is a crucial factor for the safe operation of lithium-ion batteries. During operation, the internal temperature rises above the external temperature due to poor inner thermal conductivity. Various sensors have been proposed to detect the internal temperature, including fiber Bragg grating sensors. However, to the authors’ knowledge, there is no detailed description of the encapsulation of the fiber Bragg grating sensor in the literature to shield it from strain. In this study, different encapsulation methods for strain compensation were compared to find the encapsulation material most compatible with the electrolyte. For this, we stored the proposed sensors with different encapsulation methods in ethylene carbonate:ethyl methyl carbonate (EC:EMC) 3:7 with LiPF6 (lithium hexafluorophosphate) electrolyte and applied temperature changes. After evaluating the sensor encapsulation methods in terms of handling, diameter, uncertainty, usability, and hysteresis behavior, the most suitable sensor encapsulation was found to be a fused silica capillary with polyimide coating.

Summary: Inflammatory bowel diseases (IBDs) are genetically complex and exhibit significant inter-patient heterogeneity in disease presentation and therapeutic response. Here, we show that mouse models of IBD exhibit variable responses to inhibition of MK2, a pro-inflammatory serine/threonine kinase, and that MK2 inhibition suppresses inflammation by targeting inflammatory monocytes and neutrophils in murine models. Using a computational approach (TransComp-R) that allows for cross-species comparison of transcriptomic features, we identified an IBD patient subgroup that is predicted to respond to MK2 inhibition, and an independent preclinical model of chronic intestinal inflammation predicted to be non-responsive, which we validated experimentally. Thus, cross-species mouse-human translation approaches can help to identify patient subpopulations in which to deploy new therapies.

Background: Despite the ongoing global pandemic, the impact of COVID-19 on cardiac structure and function is still not completely understood. Myocarditis is a rare but potentially serious complication of other viral infections with variable recovery, and is, in some cases, associated with long-term cardiac remodeling and functional impairment.Aim: To assess myocardial injury in patients who recently recovered from an acute SARS-CoV-2 infection with advanced cardiac magnetic resonance imaging (CMR) and endomyocardial biopsy (EMB).Methods: In total, 32 patients with persistent cardiac symptoms after a COVID-19 infection, 22 patients with acute classic myocarditis not related to COVID-19, and 16 healthy volunteers were included in this study and underwent a comprehensive baseline CMR scan. Of these, 10 patients post COVID-19 and 13 with non-COVID-19 myocarditis underwent a follow-up scan. In 10 of the post-COVID-19 and 15 of the non-COVID-19 patients with myocarditis endomyocardial biopsy (EMB) with histological, immunohistological, and molecular analysis was performed.Results: In total, 10 (31%) patients with COVID-19 showed evidence of myocardial injury, eight (25%) presented with myocardial oedema, eight (25%) exhibited global or regional systolic left ventricular (LV) dysfunction, and nine (28%) exhibited impaired right ventricular (RV) function. However, only three (9%) of COVID-19 patients fulfilled updated CMR–Lake Louise criteria (LLC) for acute myocarditis. Regarding EMB, none of the COVID-19 patients but 87% of the non-COVID-19 patients with myocarditis presented histological findings in keeping with acute or chronic inflammation. COVID-19 patients with severe disease on the WHO scale presented with reduced biventricular longitudinal function, increased RV mass, and longer native T1 times compared with those with only mild or moderate disease.Conclusions: In our cohort, CMR and EMB findings revealed that SARS-CoV-2 infection was associated with relatively mild but variable cardiac involvement. More symptomatic COVID-19 patients and those with higher clinical care demands were more likely to exhibit chronic inflammation and impaired cardiac function compared to patients with milder forms of the disease.

Background and Objectives: A substantial portion of students report test anxiety, and those reporting low levels of self-efficacy seem to be especially affected. Previous research has indicated the relevance of mental images in the maintenance of anxiety disorders, however, no data are available with respect to test anxiety. In order to close this gap, the present study investigates the association between test anxiety, self-efficacy and mental images.Method: One hundred sixty-three university students completed an online survey. Test anxiety (PAF), general self-efficacy (WIRKALL-r), study-related self-efficacy (WIRK_STUD), intrusiveness of mental images (IFES), spontaneous use of imagery (SUIS) and vividness of imagery (VVIQ) were examined.Results: Test-related mental images were frequently reported among the surveyed students. Test anxiety showed a positive correlation with IFES and a negative correlation with self-efficacy. Mediation analyses showed that about one fifth of the influence of self-efficacy on test anxiety is mediated by IFES.Discussion: The present study gives first indication about an association between test anxiety, self-efficacy and mental images, even though the results are limited with respect to generalizability. Further investigations with respect to the impact of test-related mental images on the self-efficacy/test-anxiety linkage are needed.

Photothermal spectroscopy (PTS) is a promising sensing technique for the measurement of gases and aerosols. PTS systems using a Fabry–Pérot interferometer (FPI) are considered particularly promising owing to their robustness and potential for miniaturization. However, limited information is available on viable procedures for signal improvement through parameter tuning. In our work, we use an FPI-based PTS configuration, in which the excitation laser irradiates the target collinearly to the flowing gas. We demonstrate that the generated thermal wave, and thus the signal intensity, is significantly affected by the ratio between excitation modulation frequency and gas flow velocity towards another. We provide an analytical model that predicts the signal intensity with particular considerations of these two parameter settings and validate the findings experimentally. The results reveal the existence of an optimal working regime, depending on the modulation frequency and flow velocity.

The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization’s (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed ortho-C(sp2)-H-hydroxylation of a substituted 3′-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against Mycobacterium tuberculosis (Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of Mtb (Minimal Inhibitory Concentrations (MIC90) = 0.78 μm). In addition, we determined the chemical and metabolic stability as well as the pKa values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure–activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.

This work presents a method to determine the type of Lamb mode (antisymmetric or symmetric) that propagates through a lithium-ion pouch cell. To determine the type of mode and the group velocity at a specific frequency, two- and three-transducer setups were created. For these setups, it is important that all transducers have the same polarization direction. Two transducers are affixed to the center of the cell at a distance of several centimeters from each other so that the group velocity can be determined. Using cross-correlation, the group velocity of the emerging mode can be calculated. The measurement setup and the processing method was first validated with experiments on acrylic glass and aluminum plates. The measurements were supported with FEM simulations and a numerically calculated model. The output voltages of the receiving piezo-elements obtained in the FEM simulation are in agreement with the underlying theories. The phase shift, which results from the output voltage of the piezo-elements mounted one above the other on different sides of the plate, shows the type of mode. The results of the experimental determination of the Lamb mode that propagates through a lithium-ion pouch cell were validated with a numerically calculated multi-layer model and therefore validate this novel experimental approach.

Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5–50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity.

Inpatient gait analysis is an essential part of rehabilitation for foot amputees and includes the ground contact time (GCT) difference of both legs as an essential component. Doctors communicate improvement advice to patients regarding their gait pattern based on a few steps taken at the doctor’s visit. A wearable sensor system, called Suralis, consisting of an inertial measurement unit (IMU) and a pressure measuring sock, including algorithms calculating GCT, is presented. Two data acquisitions were conducted to implement and validate initial contact (IC) and toe-off (TO) event detection algorithms as the basis for the GCT difference determination for able-bodied and prosthesis wearers. The results of the algorithms show a median GCT error of −51.7 ms (IMU) and 14.7 ms (sensor sock) compared to the ground truth and thus represent a suitable possibility for wearable gait analysis. The wearable system presented, therefore, enables a continuous feedback system for patients and, above all, a remote diagnosis of spatio-temporal aspects of gait behaviour based on reliable data collected in everyday life.

A typical method for measuring the radial thermal conductivity of cylindrical objects is the pipe method. This method introduces a heating wire in combination with standard thermocouples and optical Fiber Bragg grating temperature sensors into the core of a cell. This experimental method can lead to high uncertainties due to the slightly varying setup for each measurement and the non-homogenous structure of the cell. Due to the lack of equipment on the market, researchers have to resort to such experimental methods. To verify the measurement uncertainties and to show the possible range of results, an additional method is introduced. In this second method the cell is disassembled, and the thermal conductivity of each cell component is calculated based on measurements with the laser flash method and differential scanning calorimetry. Those results are used to numerically calculate thermal conductivity and to parameterize a finite element model. With this model, the uncertainties and problems inherent in the pipe method for cylindrical cells were shown. The surprising result was that uncertainties of up to 25% arise, just from incorrect assumption about the sensor position. Furthermore, the change in radial thermal conductivity at different states of charge (SOC) was measured with fully functional cells using the pipe method.

The potential of gossypol and of its R-(−)-enantiomer (R-(−)-gossypol acetic acid, AT-101), has been evaluated for treatment of cancer as an independent agent and in combination with standard chemo-radiation-therapies, respectively. This review assesses the evidence for safety and clinical effectiveness of oral gossypol/AT-101 in treating various types of cancer. The databases PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov were examined. Phase I and II trials as well as single arm and randomized trials were included in this review. Results were screened to determine if they met inclusion criteria and then summarized using a narrative approach. A total of 17 trials involving 759 patients met the inclusion criteria. Overall, orally applied gossypol/AT-101 at low doses (30 mg daily or lower) was determined as well tolerable either as monotherapy or in combination with chemo-radiation. Adverse events should be strictly monitored and were successfully managed by dose-reduction or treating symptoms. There are four randomized trials, two performed in patients with advanced non-small cell lung cancer, one in subjects with head and neck cancer, and one in patients with metastatic castration-resistant prostate cancer. Thereby, standard chemotherapy (either docetaxel (two trials) or docetaxel plus cisplatin or docetaxel plus prednisone) was tested with and without AT-101. Within these trials, a potential benefit was observed in high-risk patients or in some patients with prolongation in progression-free survival or in overall survival. Strikingly, the most recent clinical trial combined low dose AT-101 with docetaxel, fluorouracil, and radiation, achieving complete responses in 11 of 13 patients with gastroesophageal carcinoma (median duration of 12 months) and a median progression-free survival of 52 months. The promising results shown in subsets of patients supports the need of further specification of AT-101 sensitive cancers as well as for the establishment of effective AT-101-based therapy. In addition, the lowest recommended dose of gossypol and its precise toxicity profile need to be confirmed in further studies. Randomized placebo-controlled trials should be performed to validate these data in large cohorts.