Search

In order to guide a vehicle to the destination of a driving mission, various tasks shall be performed. These tasks include tactical and strategic planning of the driving mission and longitudinal and lateral vehicle motion control. Driver assistance systems support a human vehicle driver in performing these tasks. If faults occur in these systems, the vehicle driver is informed of the system limitations and shall take over the control of the vehicle. This fallback to a human driver is not an option in automated vehicles. If system limitations occur in these vehicles, a automated fallback level shall take over vehicle control. The automated driving system shall therefore be fail-safe. Fail-safe means that when faults occur, the automated driving system no longer has any function to perform a driving mission, but shall maintain the vehicle in a safe state and transition the vehicle into a Minimal Risk Condition (MRC). For this purpose, a situation-dependent MRC is selected. It is characterized by the global MRC concerning the length of the maneuver and the residual risk of the MRC itself. For the research project UNICARagil, the concept Safe Halt is proposed. This concept is intended to satisfy the requirements mentioned above. In the state of the art, an evaluation of this concept had not been included. This missing evaluation is performed in this thesis. The concept relies on pre-planned implicit emergency trajectories generated by a planning module. A unique concept feature is an independent environment perception system to ensure the Minimal Risk Maneuver (MRM) up to the MRC. Based on the pre-planned implicit emergency trajectory and the data of the independent environment perception system, Safe Halt plans trajectories up to the MRC. Thus, with this concept, even in the presence of failures to the environment perception system and to the strategic and tactical planning of an automated driving system, the safe state can be maintained, and the vehicle can be transitioned to a MRC. A methodology is presented to evaluate the concept of Safe Halt. For this purpose, the fault tolerance regimes of an automated vehicle are defined. Next, a reference implementation for Safe Halt is provided. For this, requirements for a Safe Halt in a generic automated driving system are identified first. These are supplemented by specific requirements from the application in the UNICARagil automated driving system. Finally, concepts and a synthesized reference solution are created for a Safe Halt in the UNICARagil ADS. The solution is verified with test criteria and test cases. A final evaluation of the Safe Halt concept shows a high effectiveness for the size of the subset of fault combinations of an automated driving system for which Safe Halt enables a fail-safe property. The requirements for Safe Halt are verified, and the specific requirements are met by the reference solution. The concept Safe Halt is thus suitable for an automated driving system to maintain a safe state. Validation of the concept in public road traffic is recommended.

The General Court has confirmed that a sign reproduced in a small size and in arguably a concealed location on the packaging of the product is unlikely to be noticed by the relevant consumer and, as a result, does not prove use of the mark.

T-668/19, Ardagh Metal Beverage Holdings GmbH & Co KG v EUIPO, EU:T:2021:420 (not available in English), 7 July 2021 The General Court clarifies its approach to sound marks and Article 7(1)(b) of the EU Trade Mark Regulation 2017/1001 (EUTMR).

OBJECTIVES: The programmed cell death-ligand 1 (PD-L1) 22C3 pharmDx assay is used as a companion diagnostic test to select head and neck squamous cell carcinoma (HNSCC) patients that may benefit from treatment with the checkpoint inhibitor pembrolizumab. Because the Dako platform is not universally available, we studied the performance of a 22C3 laboratory developed test (LDT) performed on a Ventana BenchMark Ultra compared to the 22C3 pharmDx assay.MATERIALS AND METHODS: Serial sections from tissue micro arrays (TMAs) containing tumour tissue from 97 HNSCC patients were stained with the 22C3 pharmDx assay and 22C3 LDT. All TMA cores were scored by three dedicated head and neck pathologists for PD-L1 expression.RESULTS: Substantial interobserver agreement was reported for both the standardized 22C3 pharmDx assay and the 22C3 LDT (respectively Fleiss' κ 0.62, 95% CI 0.57-0.67 and 0.63, 95% CI 0.58-0.68). Concordance between the assays was almost perfect on core and patient level (respectively Weighted κ 0.84, 95% CI 0.79-0.89 and 0.84, 95% CI 0.75-0.92). Intratumor heterogeneity between the cores per patient case was similar in both assays.CONCLUSION: After validation a 22C3 LDT is non-inferior to the standardized 22C3 pharmDx assay and can be safely used to select HNSCC patients for pembrolizumab treatment.

An unprecedented NiSn2 intermetallic with CoGe2-type crystal structure has been recovered (at ambient conditions) after high-pressure high-temperature treatment of a Ni33Sn67 precursor alloy at 10 GPa and 400 °C. The orthorhombic structure with Aeam space group symmetry is pseudotetragonal. Based on the evaluation of powder X-ray diffraction data, lattice parameters of a = b = 6.2818 Å and c = 11.8960 Å have been determined. Complicated line broadening and results of a further microstructure analysis, however, imply a defective character of the crystal structure. First-principles calculations with different model structures and a comparison with structural trends in the literature suggest that at the high-pressure high-temperature conditions a CuAl2-type crystal structure might be stable, which transforms to the recovered CoGe2-type crystal structure upon cooling or the release of pressure.

General Court, T-193/18, Andreas Stihl v EUIPO, EU:T:2021:163, 24 March 2021 In its first judgment since the decision of the Court of Justice of the European Union (‘CJEU’) in the Red Bull case (C-124/18 P), the General Court has clarified its approach to colour marks and Article 4 of the EU Trade Mark Regulation 2017/1001 (‘EUTMR’).

Abstract Cu6Sn5 intermetallic occurs in the form of differently ordered phases η, η′ and η′′. In solder joints, this intermetallic can undergo changes in composition and the state of order without or while interacting with excess Cu and excess Sn in the system, potentially giving rise to detrimental changes in the mechanical properties of the solder. In order to study such processes in fundamental detail and to get more detailed information about the metastable and stable phase equilibria, model alloys consisting of Cu3Sn + Cu6Sn5 as well as Cu6Sn5 + Sn-rich melt were heat treated. Powder x-ray diffraction and scanning electron microscopy supplemented by electron backscatter diffraction were used to investigate the structural and microstructural changes. It was shown that Sn-poor η can increase its Sn content by Cu3Sn precipitation at grain boundaries or by uptake of Sn from the Sn-rich melt. From the kinetics of the former process at 513 K and the grain size of the η phase, we obtained an interdiffusion coefficient in η of (3 ± 1) × 10−16 m2 s−1. Comparison of this value with literature data implies that this value reflects pure volume (inter)diffusion, while Cu6Sn5 growth at low temperature is typically strongly influenced by grain-boundary diffusion. These investigations also confirm that η′′ forming below a composition-dependent transus temperature gradually enriches in Sn content, confirming that Sn-poor η′′ is metastable against decomposition into Cu3Sn and more Sn-rich η or (at lower temperatures) η′. Graphic Abstract

The Keck Planet Imager and Characterizer (KPIC) is a series of upgrades for the Keck II Adaptive Optics (AO) system and the NIRSPEC spectrograph to enable diffraction-limited, high-resolution ($R>30,000$) spectroscopy of exoplanets and low-mass companions in the K and L bands. Phase I consisted of single-mode fiber injection/extraction units (FIU/FEU) used in conjunction with an H-band pyramid wavefront sensor. Phase II, deployed and commissioned in 2022, adds a 1000-actuator deformable mirror, beam-shaping optics, a vortex coronagraph, and other upgrades to the FIU/FEU. The use of single-mode fibers provides a gain in stellar rejection, a substantial reduction in sky background, and an extremely stable line-spread function on the spectrograph. In this paper we present the results of extensive system-level laboratory testing and characterization showing the instrument's Phase II throughput, stability, repeatability, and other key performance metrics prior to delivery and during installation at Keck. We also demonstrate the capabilities of the various observing modes enabled by the new system modules using internal test light sources. Finally, we show preliminary results of on-sky tests performed in the first few months of Phase II commissioning along with the next steps for the instrument. Once commissioning of Phase II is complete, KPIC will continue to characterize exoplanets at an unprecedented spectral resolution, thereby growing its already successful track record of 23 detected exoplanets and brown dwarfs from Phase I. Using the new vortex fiber nulling (VFN) mode, Phase II will also be able to search for exoplanets at small angular separations less than 45 milliarcseconds which conventional coronagraphs cannot reach., 13 pages; 6 figures; to appear in Proceedings of the SPIE, Ground-based and Airborne Instrumentation for Astronomy IX, Vol. 12184

Fe–Mn–Al–Ni martensite distortion gives rise to complex backscattered Kikuchi diffraction patterns which cannot be interpreted by standard procedures. Analysis of these patterns reveals that they arise from nanoscale internal twinning and tetragonal distortion of the basically cubic close-packed martensite., Iron-based Fe–Mn–Al–Ni shape-memory alloys are of rather low materials cost and show remarkable pseudoelastic properties. To further understand the martensitic transformation giving rise to the pseudoelastic properties, different Fe–Mn–Al–Ni alloys have been heat treated at 1473 K and quenched in ice water. The martensite, which is formed from a body-centred cubic austenite, is commonly described as face-centered cubic (f.c.c.), even though there are also more complex, polytypical descriptions of martensite. The presently studied backscatter Kikuchi diffraction (BKD) patterns have been evaluated, showing a structure more complex than simple f.c.c. This structure can be described by nanoscale twins, diffracting simultaneously in the exciting volume. The twinned structure shows a tetragonal distortion, not uncommon for martensite in spite of the lack of interstitial elements. These features are evaluated by comparing the measured BKD patterns with dynamically simulated ones.

Severe weather and climate change take a high toll on the most vulnerable population of Tajikistan. Every year, droughts, flooding or avalanches and non-optimal management practices cause food insecurity and affect the lives of exposed rural communities. Weather, Water and Climate Services (WWCS) that support agronomic decisions and early warning systems can greatly reduce socio-economic and environmental impacts on vulnerability and well-being. However, a lack of resources and local capacities have so far inhibited their development. In response to this urgent need, a consortium of Swiss federal institutions, the WMO and ICARDA, led by CARITAS Switzerland and with co-funding from the Swiss Agency for Development and Cooperation, support governmental and private sector partners in Tajikistan to develop WWCS. The project improves the observational database by deploying a large number of low-cost automated weather stations complemented by citizen observations in remote areas. These stations enable post-processing of forecasts and thereby the development of reliable services tailored to local user-needs. The underlying hardware and software developments follow a strict open-source policy and combine technical expertise in sensor development and statistical post-processing. The approach enables therefore replicability and scaling of the services at minimal costs. Comparative measurement studies show promising accuracy and stability of the data retrieval in comparison to more standard approaches. Post-processing of ECMWF ensemble predictions, which are now publicly available at a resolution of 0.4° (~40km), proved efficient to develop reliable air temperature forecasts. Pilot WWCS based on citizen observations have already helped to increase agricultural yield at a test site.

Court of Justice of the European Union, MINERAL MAGIC/MAGIC MINERALS BY JEROME ALEXANDER et al, C-809/18 P, EU: C:2020:902, 11/11/2020 The Court of Justice provides clear guidance on the test to be applied under Article 8(3) of the EU Trade Mark Regulation 2017/1001 (‘EUTMR).

Recently, III–V quantum dots (QDs) emerged as an environmentally friendly alternative to CdSe; however, they exhibit broader emission spectra and inferior photoluminescence quantum yield. Here, we ...

BackgroundPatients with Fabry disease (FD) on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in chronic kidney disease epidemiology collaboration-based estimated glomerular filtration rate (eGFR) and a worsened plasma lyso-Gb3 decrease. Hence, the most effective dose is still a matter of debate.MethodsIn this prospective observational study, we assessed end-organ damage and clinical symptoms in 78 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, which were assigned to continue this treatment (agalsidase-beta, regular-dose group, n=17); received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n=22); or were re-switched to agalsidase-beta after receiving agalsidase-alfa for 12 months (re-switch group, n=39) with a follow-up of 88±25 months.ResultsNo differences for clinical events were observed for all groups. Patients within the re-switch group started with the worst eGFR values at baseline (p=0.0217). Overall, eGFR values remained stable in the regular-dose group (p=0.1052) and decreased significantly in the re-switch and switch groups (pConclusionsOur data suggest that a re-switch to high dosage of agalsidase results in a better biochemical response, but not in a significant renal amelioration especially in classical males.

A current issue in electrical engineering is the enhancement of the quality of solder joints. This is mainly associated with the ongoing electrification of transportation as well as the miniaturization of (power) electronics. For the reliability of solder joints, intermetallic phases in the microstructure of the solder are of great importance. The formation of the intermetallic phases in the Cu-Sn solder system was investigated for different annealing temperatures between 472 K and 623 K using pure Cu as well as Cu-1at.%Ni and Cu-3at.%Ni substrate materials. These are relevant for lead frame materials in electronic components. The Cu and Cu-Ni alloys were in contact to galvanic plated Sn. This work is focused on the unexpected formation of the hexagonal ζ-(Cu,Ni)10Sn3phase at annealing temperatures of 523–623 K, which is far below the eutectoid decomposition temperature of binary ζ-Cu10Sn3of about 855 K. By using scanning electron microscopy, energy dispersive X-ray spectroscopy, electron backscatter diffraction and X-ray diffraction the presence of the ζ phase was confirmed and its structural properties were analyzed.

Purpose: This study analyzed the physiological response during Yo-Yo Intermittent Recovery Level 1 (YYIR1) test and re-test by in-field ergospirometry and time-series analyses of respiratory parame...

For direct imaging of exoplanets, Scalar Vortex Coronagraphs (SVCs) are an attractive alternative to the popularly used Vector Vortex Coronagraphs (VVCs). This is primarily because they are able to induce the same phase ramp regardless of the incoming light's polarization state. We tested a set of stepped SVC staircase masks in the Exoplanet Technology Laboratory (ET Lab) at Caltech on the High-Contrast Spectroscopy Testbed (HCST). Here we present some preliminary findings of their starlight suppression ability, achieving raw contrasts on the order of 1e-5 for 7 to 9 lambda/D. We also characterized their chromatic performance and performed wavefront control to achieve preliminary contrasts on the order of 1e-7 with EFC. These initial experimental results with SVCs have shown scalar vortex technology has a great potential for future exoplanet direct imaging missions., Comment: SPIE Optics + Photonics 2021

For automated driving, higher levels of automation pose new challenges in terms of safety. In this paper, we develop a generic behavior safety framework that maintains a safe vehicle state even in case of system failures. It is applicable to different configurations of automated driving system architectures. We verify the designed generic behavior safety framework by applying it to two different architectures from both projects PRORETA 5 and UNICARagil. The previously defined safety requirements are met with both applications, which indicates that the developed generic safety framework is also valid for other configurations of automated driving systems.

Maschinelle Systeme übernehmen einen immer größer werdenden Anteil der dynamischen Fahraufgabe automatisierter Fahrzeuge. Funktionale Degradationen können die Fähigkeiten dieser Systeme negativ beeinflussen, sodass sie die Fahraufgabe nicht weiter erfüllen können. In diesen Fällen wird bei höher automatisierten Systemen die Fahraufgabe von einer maschinellen Rückfallebene übernommen. Im Rahmen des Forschungsprojekts UNICARagil wird eine modulare und dienstbasierte funktionale Fahrzeugarchitektur entwickelt, für die in diesem Beitrag die Anforderungen und die Systemarchitektur einer geeigneten funktionalen Rückfallebene vorgestellt werden und der weitere Forschungsbedarf hinsichtlich der erforderlichen Fähigkeiten der Teilfunktionen, ihrer gegenseitigen Abhängigkeiten und der Absicherung der Teil- und Gesamtfunktionen erläutert wird.

In modernen Fahrzeugen werden vermehrt Fahrerassistenzsysteme zur Steigerung der Sicherheit und des Komforts eingesetzt. In Zukunft werden als Folge des technologischen Fortschritts die Anzahl und Komplexität dieser Systeme weiter zunehmen. Für das Testen und die Freigabe hochautomatisierter Fahrfunktionen besteht die Forderung, neue Qualitätsstandards und Methoden zu entwickeln. Zu diesem Zweck haben sich 17 Projektpartner aus der deutschen Automobilindustrie zu dem Verbundprojekt “Projekt zur Etablierung von generell akzeptierten Gütekriterien, Werkzeugen und Methoden sowie Szenarien und Situationen (PEGASUS) zusammengeschlossen. Das Ziel des Projekts ist die Entwicklung eines einheitlichen Vorgehens im Bereich Test und Erprobung. Darüber hinaus wird europaweit im “ENABLE-S3“-Projekt an bereichsübergreifenden virtuellen Plattformen für die Validierung und Verifizierung hochautomatisierter Funktionen geforscht. Der Gültigkeitsbereich dieser Plattformen erstreckt sich von der Luftfahrt, über die Automobilindustrie, die Landwirtschaft, das Gesundheitswesen bis zur Schifffahrt und die Bahnindustrie. Das Fachgebiet Fahrzeugtechnik Darmstadt (FZD) ist an beiden Projekten beteiligt. Für das PEGASUS-Projekt werden Validierungsmethoden von Simulationsmodellen für aktive Sensoren entwickelt. Im Zuge dessen wird das Modell eines Radarsensors erarbeitet, das eine hohe Modellgüte aufweist. Für die Verwendung der simulierten Radarsignale in nachgelagerten Fahrerassistenzsystemen ist die Detektion und zeitliche Verfolgung von statischen und dynamischen Objekten innerhalb der Signale erforderlich. Dies gelingt mithilfe sogenannter Tracking-Algorithmen. Zurzeit steht dem Fachgebiet FZD kein solcher Algorithmus zur Verfügung. In dieser Thesis wird daher die Analyse und Entwicklung eines Tracking-Algorithmus beschrieben. Für die Implementierung wird zunächst eine Analyse des aktuellen Stands der Entwicklungen von Tracking-Verfahren durchgeführt. Im Anschluss wird ein Open Source Tracking-Algorithmus implementiert, der eine Identifizierung und Untersuchung seiner Schlüsselparameter zulässt. Für die Verwendung des Tracking-Algorithmus mit Signalen eines realen Radarsensors wird eine Schnittstelle zwischen beiden Bausteinen definiert. Um einen belastbaren Vergleich der Leistungsfähigkeit verschiedener Tracking-Algorithmen zu erhalten, wird eine Analyse bekannter Kriterien und Metriken durchgeführt. Mithilfe dieser Methoden werden die Einflüsse von Variationen der Schlüsselparameter auf die Qualität der Tracking-Ergebnisse untersucht. Gleichzeit werden Konzepte zur Erstellung von Testfällen für Tracking-Algorithmen dargelegt. Zusammen mit den Metriken wird damit eine Bewertungsgrundlage für die Qualität von Tracking-Ergebnissen präsentiert. Die Untersuchungen des implementierten Algorithmus zeigen, dass dieser die geforderten Funktionen eines Tracking-Verfahrens erfüllt. Durch die Auswertung der Tracking-Ergebnisse bei Variation der Schlüsselparameter werden die Einflüsse einzelner Parameter auf die Tracking-Qualität deutlich. Während dieser Analyse zeigt sich, dass die gewählten Metriken und Testfälle eine systematische Untersuchung der Tracking-Ergebnisse zulassen. Sie sind folglich auch für zukünftige Einschätzungen der Tracking-Qualität weiterer Algorithmen einsetzbar.

Background and Objectives: Abdominal trauma among severely injured patients with an injury severity score (ISS) of 16 and above can lead to potentially life-threatening injuries that might need immediate surgical intervention. Traumatic injuries to the diaphragm (TID) are a challenging condition often accompanied by other injuries in the thoracoabdominal region. Materials and Methods: We retrospectively analyzed the occurrence and clinical course of TID among severely injured patients treated at our center between 2008 and 2019 and compared them to other groups of severely injured patients without TID. Results: Thirty-five patients with TID and a median ISS of 41 were treated in the period mentioned above. They were predominantly middle-aged men and mostly victims of blunt trauma as a consequence of motor vehicle accidents. A total of 70.6% had left-sided TID, and in 69.6%, the size of defect was larger than 10 cm. The diagnosis was made with computed tomography (CT) in 68.6% of the cases, while in 25.8%, it was made intraoperatively or delayed by a false-negative initial CT scan, and in 5.7%, an intraoperative diagnosis was made without preoperative CT imaging. Surgical repair was mostly conducted via laparotomy, performing a direct closure with continuous suture. A comparison to 191 patients that required laparotomy for abdominal injuries other than TID revealed significantly higher rates of concomitant injuries to several abdominal organs among patients suffering from TID. Compared to all other severely injured patients treated in the same period (n = 1377), patients suffering from TID had a significantly higher median ISS and a longer mean duration of hospital stay. Conclusions: Our findings show that TID can be seen as an indicator of particularly severe thoracoabdominal trauma that requires increased attention from the treatment team so as not to miss relevant concomitant injuries that require immediate intervention.

Diffraction and reflection from the optical edges is the dominant source of stray light from a starshade. However, recent progress in optical edge design has led to much reduced predictions in this source. Secondary sources now also play a role; these sources arise from two or more reflections from the starshade structure. These multiple reflections allow light to reach the telescope from parts of the structure that are shaded from direct sunlight. Here we analyze the secondary sources for the starshade model developed as part of the S5 technology development and show the effects of optical edge mechanical design variants and mitigations.

Accurate measurement of exoplanetary masses is a critical step in addressing key aspects of NASA’s science vision. Astrometry can detect and measure masses of planets orbiting the target star. However, the signal for earth-analogs is in the sub-microarcsecond regime, well beyond our instrumentation. In this paper, we study part of an astrometry error budget for the HabEx Workhorse Camera and we propose a calibration approach to reach earth-analog sensitivity.

General Court of the European Union, Case T-573/18 FORM EINES SCHNÜRSENKELS (3D), EU:T:2020:32, 5 February 2020

Court of Justice of the European Union, EUIPO v Wajos GmbH, C-783/18 P, EU:C:2019:1073, 12 December 2019 By a judgment rendered on 12 December 2019, the Court of Justice of the European Union dismissed the appeal filed by the European Union Intellectual Property Office (EUIPO) against a judgment of the General Court allowing the registration of a bottle taking the shape of an amphora.

Fabry disease (FD) is a lysosomal storage disease, treatable by enzyme replacement therapy (ERT) that substitutes deficient α-galactosidase A (AGAL). The formation of neutralising anti-drug antibodies (ADA) inhibiting AGAL activity during infusion is associated with disease progression in affected male patients. In this study we analysed if ADAs also inhibit endothelial enzyme uptake as well as intracellular enzyme activity. Therefore, fluorescence-labelled AGAL in combination with ADA-positive sera from FD patients (n = 8) was used to analyse enzyme uptake in endothelial and FD-specific cells. Furthermore, immune adsorption and a comprehensive ADA epitope mapping were performed. Pre-incubation of AGAL with ADAs significantly inhibited intracellular enzyme activity, which was rescued by immune adsorption (both P < .01). ADAs from some patients also inhibited enzyme uptake. ADA epitope mapping identified an epitope at position 121 to 140 aa potentially responsible for uptake inhibition for these patients. Further analyses revealed the presence of stable AGAL/ADA-immune complexes at pH 4.5 and decreased intracellular enzyme activity in endothelial cells (P < .001). Finally, the pre-incubation of AGAL with ADAs resulted in a reduced depletion of intracellular globotriaosylceramide in patient-derived AGAL-deficient cells, demonstrating a direct negative impact of ADAs on intracellular clearance. Neutralising ADAs may not only inhibit infused AGAL activity, but according to their epitopes can also inhibit endothelial AGAL uptake. Indeed, internalised AGAL/ADA-complexes may not dissociate, underlining the importance of novel therapeutic approaches for ADA reduction and prevention to increase therapy efficiency in affected patients.

ZrO2-reinforced high alloy steels have a strong tendency for pore formation during thermal joining and are therefore considered as non-weldable. However, present investigations have shown that it is possible to join particle-reinforced steels by a dissimilar electron beam braze-welding with a beam offset. The joints were characterised by light optical microscopy (OM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) methods, such as electron backscatter diffraction (EBSD), energy dispersive X-ray spectroscopy (EDS) and selected area electron diffraction (SAED). The mechanical properties and the deformation behaviour of the welded material were studied in tensile tests. The quality and type of the joints depend on the dilution of the weld. The welds with a level of dilution between 2 and 10% are free of defects and show an epitaxial growth onto the base material which yields superior mechanical properties compared to the welds without dilution. The welds produced by electron beam brazing exhibited the formation of oxide films which prevented an epitaxial growth of the solidified material. Therefore, a significant impact on the results of the tensile tests was noticed.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to variants in the coding sequence of desmosomal genes. The potential contribution of non-coding desmoglein-2 (DSG2) variants for development of ARVC is undescribed. We sequenced 1450 base pairs upstream of ATG in the DSG2 gene in 65 unrelated patients diagnosed with ARVC (10 borderline cases). Identified variants was evaluated by cosegregation and allele population frequency analysis, in silico tools, immunohistological investigations of myocardial biopsies, gene reporter assays, electrophoretic mobility shift assays (EMSA), and chromatin immunoprecipitation. The genetic analysis identified one novel, rare heterozygous DSG2 upstream variant (-317G A) in a genetically unexplained ARVC patient. The variant segregated with signs of disease, was absent in publicly available databases, and affected a predicted binding site for activating protein-1 (AP-1). Immunohistochemical analysis of a myocardial biopsy from the -317G A patient showed a marked reduction in DSG2 protein levels compared to healthy controls. Luciferase reporter gene assays showed promoter activity of the identified DSG2 upstream region and a general reduction in transcriptional activity in the presence of the minor DSG2_A allele (p .01). Moreover, the DSG2_A allele reduced DSG2 activation by TGF-beta1 and a protein kinase C pathway activator (PMA; all p .001 vs. DSG2_G). EMSAs showed altered transcription factor binding in presence of the DSG2_A allele. Chromatin immunoprecipitation assays in wild type epithelial cells identified AP-1 components c-FOS and c-JUN at the -317 locus. In conclusion, the non-coding DSG2 promoter variant -317G A reduces DSG2 transcription in vitro and reduced myocardial DSG2 protein levels were observed in vivo. Our data support a contribution of non-coding DSG2 variants to the pathogenesis of ARVC.

Circulatory microRNAs (c-miRNAs) are regulated in response to physical activity and may exert anti-atherosclerotic effects. Since the vascular endothelium is an abundant source of c-miRNAs, we aimed to identify novel vasculoprotective exercise-induced c-miRNAs by the combined analysis of published endothelial miRNA array data followed by in vivo and in vitro validation. We identified 8 different array-based publications reporting 185 endothelial shear stress-regulated miRNAs of which 13 were identified in ≥3 independent reports. Nine miRNAs had already been associated with physical activity. Of the remaining novel miRNAs, miR-98-3p and miR-125-5p were selected for further analysis due to reported vasculoprotective effects. Analysis in two different 4-week high-intensity interval training (HIIT) groups (group 1 [n=27]: 4x30 s, group 2 [n=25]: 8x15 s; all-out running) suggested significantly elevated miR-98 and miR-125a-5p levels in response to acute exercise at baseline and at follow-up. Endothelial in vitro shear stress experiments revealed increased miR-125a-5p and miR-98-3p levels in medium of human umbilical vein endothelial cells at 30 dyn/cm2 after 20 and 60 min, respectively. Our results suggest that miR-98-3p and miR-125a-5p can be rapidly secreted by endothelial cells, which might be the source of increased c-miR-98-3p and -125a-5p levels in response to HIIT. Both miRNAs attenuate endothelial inflammation and may mediate vasculoprotective effects of physical exercise including HIIT.

Hochintensives Intervalltraining (HIIT) kann die korperliche Leistungsfahigkeit sowohl bei gesunden Menschen als auch bei Patienten mit lebensstilinduzierten Erkrankungen effektiv verbessern. Ziel der Studie war zu prufen, ob (I) die individuelle Leistungsfahigkeit und (II) eine HIIT-Intervention Auswirkungen auf optische Koharenztomographie Angiographie(OCTA)-Messungen am Augenhintergrund von jungen gesunden Erwachsenen haben. Es absolvierten 65 gesunde Probanden einen standardisierten stufenformigen Lauftest, um die individuelle Fitness zu erheben. Bestimmt wurde diese als Geschwindigkeit an der individuellen anaeroben Laktatschwelle und maximalen Laufgeschwindigkeit. Anschliesend folgte ein 4‑wochiges HIIT mit 2 Trainingseinheiten pro Woche. OCTA-Aufnahmen zur Messung der foveal avaskularen Zone (FAZ) sowie der Flussdichten in verschiedenen Segmentierungen an Makula und Sehnerv wurden in korperlicher Ruhe vor und nach HIIT durchgefuhrt. Es zeigte sich eine inverse Korrelation zwischen individueller Fitness und FAZ-Grose. Weitere Korrelationen zwischen individueller Fitness und anderen gemessenen OCTA-Parametern ergaben sich nicht. Als Antwort auf das HIIT verringerten sich die mittlere FAZ-Grose im tiefen retinalen Plexus und die makulare Flussdichte im superfiziellen retinalen Plexus um 14,00 ± 13,02 % bzw. um 1,26 ± 3,20 %. Die Flussdichte der peripapillaren „nerve head layer“ zeigte einen Anstieg von 1,94 ± 2,39 %. Alle anderen Parameter zeigten keine signifikanten Unterschiede zwischen den Messungen vor und nach HIIT. Es zeigten sich Unterschiede in OCTA-Messungen der FAZ in Abhangigkeit von der individuellen Leistungsfahigkeit. Durch HIIT lassen sich signifikante Veranderungen in einigen OCTA-Parametern induzieren. Daher scheint die OCTA eine vielversprechende Modalitat im Bereich der Sportmedizin zu sein.

BackgroundPatients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically in vivo as expected. Here, we aimed to establish a patient-specific and mutation-specific cell model to evaluate the amenability to chaperone therapy in FD.MethodsSince current tests to determine amenability are limited to heterologous mutation expression in HEK293T cells with endogenous AGAL activity, we generated CRISPR/Cas9-mediated AGAL-deficient HEK293T cells as a basis for mutant overexpression. Furthermore, primary urinary cells from patients were isolated and immortalised as a patient-specific cell model system to evaluate the amenability to chaperone therapy.ResultsUnder treatment (>13 months), carriers of p.N215S (n=6) showed a significant reduction of plasma lyso-Gb3 (pA cells.ConclusionWe conclude that repeated AGAL activity measurements in patients’ white blood cells are mandatory to assess the in vivo amenability to migalastat. Plasma lyso-Gb3 might be an appropriate tool to measure the biochemical response to migalastat. Patients with low AGAL activities and increasing lyso-Gb3 levels despite in vitro amenability might not benefit sufficiently from chaperone treatment.

The blood-brain barrier (BBB) represents one of the biggest hurdles for CNS related drug delivery, preventing permeation of most molecules, and therefore poses a major challenge for researchers in finding effective treatments for CNS diseases. The low permeability of molecules through the BBB is linked on one hand to the extreme tightness by tight junction (TJ) formation limiting the paracellular transport, and on the other hand to the presence of ATP-driven efflux pumps which actively transport unwanted compounds out of the brain. In this study we evaluated the applicability of the immortalized human cell line hCMEC/D3 for ABC transporter studies, focusing on the most expressed ABC transporters at the human BBB: P-glycoprotein (PGP, ABCB1), multidrug resistance protein 4 (MRP4, ABCC4) and breast cancer resistance protein (BCRP, ABCG2). Therefore, a two-step screening method was applied, consisting of a regular uptake assay (96-well format) and bidirectional transport studies, using a transwell system as in vitro simulation of the human BBB. In conclusion, the hCMEC/D3 based in vitro BBB model is well suited to screen drug candidates for ABC transporter interactions on the basis of a regular uptake assay, but in terms of transcellular permeability studies the cell line is limited by a lack of sufficient junctional tightness.

Starshade in formation flight with a space telescope is a rapidly maturing technology that would enable imaging and spectral characterization of small planets orbiting nearby stars in the not-too-distant future. While performance models of starshade-assisted exoplanet imaging have been developed and used to design future missions, their results have not been verified from the analyses of synthetic images. Following a rich history of using community data challenges to evaluate image-processing capabilities in astronomy and exoplanet fields, the Starshade Technology Development to TRL5 (S5), a focused technology development activity managed by the NASA Exoplanet Exploration Program, is organizing and implementing a starshade exoplanet data challenge. The purpose of the data challenge is to validate the flow down of requirements from science to key instrument performance parameters and to quantify the required accuracy of noisy background calibration with synthetic images. This data challenge distinguishes itself from past efforts in the exoplanet field in that (1) it focuses on the detection and spectral characterization of small planets in the habitable zones of nearby stars, and (2) it develops synthetic images that simultaneously include multiple background noise terms—some observations specific to starshade—including residual starlight, solar glint, exozodiacal light, detector noise, as well as variability resulting from starshade’s motion and telescope jitter. We provide an overview of the design and rationale of the data challenge. Working with data challenge participants, we expect to achieve improved understanding of the noise budget and background calibration in starshade-assisted exoplanet observations in the context of both starshade rendezvous with Roman and Habitable Exoplanet Observatory. This activity will thus help NASA prioritize further technology developments and prepare the science community for analyzing starshade exoplanet observations.

Optical coherence tomography angiography (OCT-A) represents the most recent modality in retinal imaging for non-invasive and depth-selective visualization of blood flow in retinal vessels. With regard to quantitative OCTA measurements for early detection of subclinical alterations, it is of great interest, which intra- and extra-ocular factors affect the results of OCTA measurements. Here, we performed OCTA imaging of the central retina in 65 eyes of 65 young healthy female and male participants and evaluated individual physical fitness levels by standard lactate diagnostic using an incremental maximal performance running test. The main finding was that OCTA measurements of the foveal avascular zone (FAZ) area were associated with physical fitness. Using multivariate regression analysis, we found that running speed at the individual lactate threshold, a marker strongly associated with aerobic performance capacity, significantly contributed to differences in FAZ area (β = 0.111, p = 0.032). The data indicates that smaller FAZ areas are likely observed in individuals with higher aerobic exercise capacity. Our findings are also of interest with respect to the potential use of retinal OCTA imaging to detect exercise-induced microvascular adaptations in future studies.

Open abdominal wounds with intestinal fistula formation are challenging complications in abdominal surgery. Special fistula devices (SFD) used along with negative pressure wound therapy with instillation and dwell time (NPWTi-d), may improve management of these wounds, increasing NPWT dressing durability and helping decrease dressing leakage.A 57-year-old, obese (body mass index: 55 kg/m²) female with a long history of Crohn disease and multiple intestinal resections, presented with an incarcerated parastomal hernia, abscess formation, and septic shock. After the hernia was repositioned and the infection controlled, a bovine mesh-augmented hernia repair was performed. Skin rotation flaps for wound closure became necrotic and led to an infected, open abdominal wound measuring about 60 cm x 50 cm with formation of 2 additional small bowel fistulas alongside the ostomy and a massive bacterial and fungal superinfection. After surgical debridement, NPWTi-d with 10 minutes soaking time with isotonic saline solution followed by 2 to 4 hours negative pressure therapy with -125 mm Hg combined with SFDs was initiated; once the infection was controlled approximately 3 weeks after initiation, treatment was switched to traditional NPWT with -125 mm Hg continuous negative pressure and SFDs. Dressings were changed on demand. During the whole treatment period, local infection was brought under control, the wound was clean, and thick granulation tissue formed (even on exposed parts of the mesh). The dressing stability provided a high level of patient comfort.By providing expedient wound cleaning, decontamination, local infection control, and patient comfort, as well as helping generate granulation tissue even on biological mesh, NPWTi-d used with SFDs represents a viable tool for the management of challenging fistulizing abdominal wounds.

High-contrast imaging enabled by a starshade in formation flight with a space telescope can provide a near-term pathway to search for and characterize temperate and small planets of nearby stars. NASA's Starshade Technology Development Activity to TRL5 (S5) is rapidly maturing the required technologies to the point at which starshades could be integrated into potential future missions. Here we reappraise the noise budget of starshade-enabled exoplanet imaging to incorporate the experimentally demonstrated optical performance of the starshade and its optical edge. Our analyses of stray light sources - including the leakage through micrometeoroid damage and the reflection of bright celestial bodies - indicate that sunlight scattered by the optical edge (i.e., the solar glint) is by far the dominant stray light. With telescope and observation parameters that approximately correspond to Starshade Rendezvous with Roman and HabEx, we find that the dominating noise source would be exozodiacal light for characterizing a temperate and Earth-sized planet around Sun-like and earlier stars and the solar glint for later-type stars. Further reducing the brightness of solar glint by a factor of 10 with a coating would prevent it from becoming the dominant noise for both Roman and HabEx. With an instrument contrast of 1E-10, the residual starlight is not a dominant noise; and increasing the contrast level by a factor 10 would not lead to any appreciable change in the expected science performance. If unbiased calibration of the background to the photon-noise limit can be achieved, Starshade Rendezvous with Roman could provide nearly photon-limited spectroscopy of temperate and Earth-sized planets of F, G, and K stars, Accepted for publication in the Journal of Astronomical Telescopes, Instruments, and Systems (JATIS)

The perimeter of a sunflower-like starshade has hundreds of meters of sharp edges that are directly exposed to sunlight. The sunlight diffracts and reflects from the edge resulting in a dual-lobed glint pattern that can be brighter than an exoplanet. We present estimates of the glint brightness distribution for the Starshade Rendezvous Mission and the HabEx Starshade Mission concepts based on measurements of flight-like, environmentally tested, uncoated metallic edges using custom-built scatterometers. A companion paper addresses the performance for edges coated with a thin anti-reflection coating.