Genetic code expansion in neurons for studying pathogenic mechanisms of Alzheimer disease

Every three seconds a new patient is diagnosed with Alzheimer disease (AD). The primary risk factor for this irreversible, progressive brain disorder is old age. It is a growing health concern, not only for the patients, but also for their relatives and society, because the number of affected people is expected to double every 20 years. New tools are necessary to expand the knowledge about the molecular mechanisms behind AD. The small neurotoxic amyloid β-peptide (Aβ) is produced by processing of the Amyloid Precursor Protein (APP) through a cascade of secretase cleavages. However, it is not fully understood in which subcellular location the processing takes place and how this is changed during the course of the disease. A major problem is the lack of methods labeling small peptides like Aβ in living cells. To investigate where the processing takes place, we developed a dual fluorescence labeling system. The C-terminal tail of APP is fluorescently labeled using a SNAP-tag, while the Aβ region of APP is fluorescently tagged with a turn-on dye at a non-canonical amino acid (ncAA). The ncAA is introduced at specific positions in APP using a genetic code expansion (GCE) strategy. Using this approach, APP can be fluorescently labeled at two sites in living HEK293T cells with minimal background. However, a key to understand the underlying molecular mechanisms in AD are appropriate model systems. Therefore, we produced Baculoviruses to transduce primary cortical neurons from mice with the GCE machinery and APP with a SNAPtag and an amber codon. We reduced background labeling caused by tetrazine dyes in the neurons by developing a two-step labeling protocol to block excessive ncAA. In parallel, we also established GCE in human induced pluripotent stem cells (hiPSCs) and differentiated them to neurons and brain organoids. The stable hiPSCs expressing the GCE machinery provide a unique platform to study and manipulate proteins in different cell types and development stages

An Outline of the Quaternary Stratigraphy of Austria

Es wird ein Überblick über die in Österreich verwendete Quartär-Stratigraphie gegeben. Die stratigraphische Gliederung der kartierbaren Sedimenteinheiten basiert teilweise auf Kriterien der Lithostratigraphie (lithologischer Eigenschaften) und jenen der Allostratigraphie (z.B. Diskonitinuitäten). Für das Altpleistozän (2.58–0.78 Ma) fehlen bis jetzt Spuren einer Vergletscherung. Die wenigen und isolierten Sedimentvorkommen belegen fluviatile Akkumulation und Lössablagerung in der Umgebung der Flüsse. Paläomagnetisch korrelierte Löss-Paläoboden – Sequenzen wie das Profil Stranzendorf mit der Gauss/Matuyama – Grenze bzw. Neogen/Quartär – Grenze dokumentieren in Übereinstimmung mit den globalen δ18O Werten etwas wärmere Bedingungen als im Mittelpleistozän (0.78–0.13 Ma). Vier Großvergletscherungen (Günz, Mindel, Riß und Würm) sind für Mittelpleistozän und Jungpleistozän belegt. Diese sind mit Sedimenten aus der Vorstoßphase überlagert von Grundmoräne, Endmoränen im Alpenvorland und damit verknüpfte Terrassenschüttungen sowie Lössakkumulation dokumentiert. Daraus ist die klimagesteuerte Sedimentation im Zusammenhang mit dem Vorstoß der Gletscher, der Ausbreitung des Permafrostes und der Frostschuttbildung bis ins Vorland erkennbar. Die jüngsten Großvergletscherungen Riß und Würm werden aufgrund geochronologischer Daten mit den Marinen Isotopenstufen (MIS) 6 und 2 korreliert. Für Günz und Mindel scheint eine Gleichzeitigkeit mit den Phasen massiver globaler Klimaverschlechterung während MIS 16 und MIS 12 plausibel. Dokumente für die schwächeren Glaziale wurden bisher nur in Lössprofilen (z.B. Krems Schießstätte) gefunden

AN EMPIRICAL AND MODELING ANALYSIS OF THE AREA-ELASTIC SURFACE IN A GYMNASIUM

The external load acting on an athlete during landing on area-elastic surfaces in gymnasiums is an important factor concerning overload injuries. Nevertheless, there is a lack of force measurements on this kind of surface. This study describes technical problems of these measurements and presents an easy method to calculate the most important characteristics of an area-elastic surface: spring and damping functions and accelerated mass. When using suitable non-linear spring and damping functions the simulations with the model of the surface lead to results, which agree very well with empirical measurements (r2 = .99,

Gerichtsstand in Verbraucherangelegenheiten im Österreichischen und Europäischen Zivilprozessrecht

In Österreich werden Geschäfte zwischen einem Verbraucher und einem Unternehmer durch das KSchG (Konsumentenschutzgesetz) materiellrechtlich geschützt. Der zuständigkeitsrechtliche Schutz durch § 14 KSchG umfasst sämtliche Rechtsgeschäfte eines Verbrauchers. Die örtliche Zuständigkeit bestimmt sich aber nach dem allgemeinen Zuständigkeitssystem der JN (Jurisdiktionsnorm) und es werden zum Schutz des Verbrauchers nur Prorogationsverbote (Verbote zum Abschluss von Gerichtsstandsvereinbarungen) vorgesehen. In den meisten Fällen liegt der Gerichtsstand für Klagen gegen den Verbraucher bei dessen allgemeinem Gerichtsstand. Bei Klagen gegen den Unternehmer kann hingegen der Gerichtsstand auch weit entfernt sein. Bei der EuGVVO (Europäische Gerichtsstands- und Vollstreckungsverordnung) werden nicht alle Verbrauchergeschäfte zuständigkeitsrechtlich geschützt. Bei Teilzahlungskäufen und Darlehensverträgen ist der Schutz der Art 15 ff EuGVVO immer anzuwenden. Alle übrigen Rechtsgeschäfte sind nur dann geschützt, wenn der Vertragspartner des Verbrauchers im Wohnsitzstaat des Verbrauchers tätig geworden ist. Die Art 15 ff EuGVVO sehen einen Verbrauchergerichtsstand vor. Sowohl für Klagen des Unternehmers gegen den Verbraucher als auch für Klagen des Verbrauchers gegen den Unternehmer befindet sich der Gerichtsstand am Wohnsitz des Verbrauchers. Zur Verbesserung des Verbraucherschutzes in Österreich wird vom Verfasser ein Gesetzesvorschlag gemacht, der auch für Klagen des Verbrauchers gegen den Unternehmer einen Gerichtsstand am allgemeinen Gerichtsstand des Verbrauchers vorsieht. Für den europäischen Bereich wird vom Verfasser ein Gesetzesvorschlag gemacht, der eine Heilung einer Unzuständigkeit zu Lasten des Verbrauchers ohne entsprechende Belehrung des Verbrauchers ausschließt

Structure and Tectonics of the erosional convergent margin off Antofagasta, North Chile (23°30'S)

Subduction erosion has dominated the evolution of the north Chile convergent continental margin since at least the Mesozoic. We investigate the structure of the Antofagasta (23°S) sector of this margin along a transect using coincident wide-angle and near-vertical seismic profiling and gravity data. A 2-D velocity field of the overriding and subducting plates was obtained using joint refraction and reflection travel time tomography. A velocity-derived density distribution was used to model marine gravity data and substantiate the velocity model. The gravity and velocity models imply that the overriding plate is mainly made of arc-type igneous basement. The upper plate is constructed of two main rock bodies separated by a subhorizontal layer defined by a velocity inversion, the top coincident with a reflection in near-vertical seismic images. The seismic boundary is interpreted as a detachment separating an upper extended domain with large-scale normal faulting from a lower domain apparently undergoing a different type of deformation. Velocity-derived porosity indicates that the front of the margin is probably fluid-saturated and disaggregated by fracturation as a consequence of frontal subduction erosion. Fluids carried into the subduction channel within slope debris filling underthrusting grabens reduce basal friction and probably induce hydrofracturing and basal erosion along the underside of the overriding plate. At depths greater than ∼20 km, porosity and density values imply that most fluids have been exhausted and the lower part of the upper plate is structurally coherent and little fractured. The change in physical properties leads to increased mechanical coupling along the plate boundary and occurs at the updip limit of the distribution of aftershocks of the 1995 Antofagasta earthquake (M w = 8.0) defining the seismogenic zone

Comparing Different Performance Factors of Conventional VS Immersive Service Prototypes

Service prototyping is an innovative iterative process envisioned to enhance the service development process while refining the anticipated service experience. Immersive technologies, such as: Virtual Reality (VR), Augmented Reality (AR), and Mixed Reality (MR), in service prototyping have the potential to enhancing the co-creation of service ideas. It is intended to transform intangible service aspects into an experience, even before the service exists. However, there is a lack of research studies comparing different forms of service prototype. Such studies would help to find out the most appropriate Service Prototype (SP) form for exploring, communicating and evaluating new service ideas. Several SP experiment sessions were conducted in France and Germany within an academic context in 2018 to compare different performance factors of conventional Service Prototypes (CSP) versus Immersive Service Prototypes (ISP). The participants have to disassemble and then reassemble a simple three-part mechanical element with the aid of four different SP forms. This paper presents the results of the experiment sessions, involving 38 participants, conducted at Furtwangen University campus in Germany. These results reveal that participants preferred ISP forms rather than CSP forms. However, it also confirms that there are still some difficulties in applying and using VR or AR devices.This complete empirical study has been carried out successively at the Furtwangen University and then at ENSAM Laval and Angers Campuses. Authors wish to acknowledge their gratitude and appreciation to ENSAM and Furtwangen University, as well as all experiment participants that contributed to this study

The Child PTSD Symptom Scale: Psychometric properties among earthquake survivors

From PubMed via Jisc Publications RouterEvidence for a single underlying factor structure of posttraumatic stress disorder (PTSD) in children remains elusive. We assessed the underlying factor structure of the Child PTSD Symptom Scale through exploratory (EFA) and confirmatory factor analyses (CFA) in 570 survivors of the 2015 Gorkha earthquake in Nepal. The EFA suggests that the three-factor DSM-IV model fit these data best. The CFA suggests that while the DSM-IV model adequately fit these data, the four-factor King model fit them better. There was no evidence of differential item functioning by age or gender, and internal consistency of the scale was high. PTSD (overall or by factor) was not correlated with functional impairment. Inconsistent psychometric results across contexts and methodologies suggest that our current theoretical conceptualizations and empirical models of posttraumatic stress are lacking. Future studies must both document the instrument properties to assure internal validity and cross-study comparisons and, bolstered by increased psychometric data and analyses, rework theoretical models of PTSD with improved cross-cultural validity.The research was funded by World Vision International (ended 2015), an elrha R2HC award from the Wellcome Trust and DFID (ended 2016), and additional funding from the National Institute of Mental Health (T32MH096724 and R01MH110872). The funding sources had no role in the analysis or interpretation of this study. Dr. Sabrina Hermosilla received funding from the National Institute of Mental Health (T32MH096724 and R01MH110872) to complete analytic and dissemination-related activities on this manuscript.pubpu

Osteochondritis Dissecans of the Knee Associated With Mechanical Overload

Background: Osteochondritis dissecans (OCD) of the knee is a rare but potentially incapacitating disorder in which subchondral bone detaches, leading to an osteochondral fragment that can become unstable and progress into a loose body. The exact cause is unknown, although several biological and mechanical factors have been described. Purpose: To provide insight into epidemiological data of a large cohort of patients affected by OCD of the knee and to identify potential factors contributing to the cause of this disorder. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 236 patients (259 knees) affected by OCD were included in our Knee Registry (2005-2022) and retrospectively analyzed. Patient characteristics were extracted from the medical records. Location and International Cartilage Regeneration & Joint Preservation Society grade (1-4) of OCD were assessed using magnetic resonance imaging. If available, a full-leg standing radiograph was used to assess alignment. Additionally, a statistical scoring system for instability risk was created. Results: A total of 263 OCD lesions were identified in 259 knees, 66.2% on the medial femoral condyle (MFC), 26.6% on the lateral femoral condyle (LFC), 3.8% on the trochlea, 2.7% on the patella, and 0.8% on the lateral tibia plateau. Male patients made up 57.6% of the sample, which had a mean age of 21.8 years. A very high percentage of patients (77.1%; n = 182) practiced sports, of whom 67.6% (n = 123) were engaged in high-impact sports. The location of the OCD lesions and the leg alignment (n = 110) were significantly correlated: MFC lesions were associated with more varus than valgus alignment (47.5% vs 11.3%) and patients with LFC lesions had more valgus than varus alignment (46.7% vs 20.0%; P =.002). Based on age, smoking, sports activity, and preceding trauma, a multivariable scoring system (0-11 points) was created. An increased risk of lesion instability was associated with an increased score: 29.0% at 0 points and 97.0% at 11 points. Conclusion: This study provides detailed epidemiological data for 236 patients affected by OCD of the knee. Older age, smoking, inactivity, and preceding trauma were predictive for instability of OCD lesions. There was an association between OCD of the MFC and varus malalignment and between OCD of the LFC and valgus malalignment. This finding, in combination with the high percentage of patients practicing high-impact sports, suggests an important role for mechanical overload in the pathogenesis of OCD

ZZ-boson polarization as a model-discrimination analyzer

Determining the spin of any new particle is critical in identifying the true theory among various extensions of the Standard Model (SM). The degree of $Z$-boson polarization in any two-body decay process $A\to B Z$ is sensitive to the spin assignments of two new particles $A$ and $B$. Considering all possible spin-0, 1/2 and 1 combinations in a renormalizable field theory, we demonstrate that $Z$-boson polarization can indeed play a role of a decisive and universal analyzer in distinguishing the different spin assignments.Comment: 10 pages, 3 figures, 1 tabl

Systematic review of cure and recurrence rates following minimally invasive parathyroidectomy

Background The majority of patients with primary hyperparathyroidism (PHPT) have a single overactive adenoma. Advances in preoperative imaging and surgical adjuncts have given rise to minimally invasive parathyroidectomy (MIP), with lower complication rates in comparison with bilateral neck exploration. Misdiagnosis and undertreatment of multiglandular disease, leading to potentially higher recurrence rates, remains a concern. This study evaluated risks of long‐term (1 year or more) recurrence following ‘targeted’ MIP in PHPT. Methods Multiple databases were searched for studies published between January 2004 and March 2017, looking at long‐term outcomes (1 year or more) following targeted MIP for PHPT. English‐language studies, with at least 50 patients and a mean follow‐up of 1 year, were included. Results A total of 5282 patients from 14 studies were included. Overall mean recurrence and cure rates were 1·6 (range 0–3·5) and 96·9 (95·5–100) per cent respectively. Mean follow‐up was 33·5 (1–145) months. When intraoperative parathyroid hormone (PTH) measurements were not done, cure rates were higher (99·3 per cent versus 98·1 per cent with use of intraoperative PTH measurement; P < 0·001) and recurrence rates lower (0·2 versus 1·5 per cent respectively; P < 0·001). Conclusion Targeted MIP for a presumed single overactive adenoma was associated with very low recurrence rates, without the need for intraoperative PTH measurement when preoperative imaging studies were concordant. Targeted MIP should be encouraged