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Sulfur mustard (SM) and its derivatives are potent genotoxic agents, which have been shown to trigger the activation of poly (ADP-ribose) polymerases (PARPs) and the depletion of their substrate, nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential molecule involved in numerous cellular pathways, including genome integrity and DNA repair, and thus, NAD+ supplementation might be beneficial for mitigating mustard-induced (geno)toxicity. In this study, the role of NAD+ depletion and elevation in the genotoxic stress response to SM derivatives, i.e., the monofunctional agent 2-chloroethyl-ethyl sulfide (CEES) and the crosslinking agent mechlorethamine (HN2), was investigated with the use of NAD+ booster nicotinamide riboside (NR) and NAD+ synthesis inhibitor FK866. The effects were analyzed in immortalized human keratinocytes (HaCaT) or monocyte-like cell line THP-1. In HaCaT cells, NR supplementation, increased NAD+ levels, and elevated PAR response, however, did not affect ATP levels or DNA damage repair, nor did it attenuate long- and short-term cytotoxicities. On the other hand, the depletion of cellular NAD+ via FK866 sensitized HaCaT cells to genotoxic stress, particularly CEES exposure, whereas NR supplementation, by increasing cellular NAD+ levels, rescued the sensitizing FK866 effect. Intriguingly, in THP-1 cells, the NR-induced elevation of cellular NAD+ levels did attenuate toxicity of the mustard compounds, especially upon CEES exposure. Together, our results reveal that NAD+ is an important molecule in the pathomechanism of SM derivatives, exhibiting compound-specificity. Moreover, the cell line-dependent protective effects of NR are indicative of system-specificity of the application of this NAD+ booster.
Mit Spannung wird die Entscheidung des BVerfG zu § 362 Nr. 5 StPO erwartet. Die Verfassungsbeschwerde des Beschuldigten, der vor Jahrzehnten vom Vorwurf des Mordes rechtskräftig freigesprochen worden war und der nun befürchten muss, auf der Grundlage des § 362 Nr. 5 StPO wegen derselben Tat verurteilt zu werden, hat die verfassungsrechtliche Überprüfung der Vorschrift veranlasst. Zuvor waren bereits in zahlreichen Texten von Rechtswissenschaftlern Argumente für und gegen die Regelung ausgetauscht worden. Verständlicherweise steht dabei Art. 103 Abs. 3 GG im Vordergrund. Wer § 362 Nr. 5 StPO ablehnt, begründet das in erster Linie mit einer Verletzung des ne-bis-in-idem-Grundsatzes. Nicht wenige Befürworter der erweiterten Wiederaufnahmemöglichkeit verweisen – gefühlsgeleitet − auf „materielle Gerechtigkeit“ sowie auf „schlechterdings unerträgliche Ergebnisse“. Unbefriedigend ist das für Menschen, die es weder ungerecht noch unerträglich finden, dass ein Tatverdächtiger nach rechtskräftigem Freispruch bis an sein Lebensende als „unschuldig“ gilt und zwar auch, wenn auf Grund neuer Beweismittel aus dem Freigesprochenen ein zu lebenslanger Freiheitsstrafe Verurteilter werden könnte. Dass das Festhalten am rechtskräftigen Freispruch richtig ist, dafür gibt es starke juristische Gründe. Auch für die Durchbrechung des Strafklageverbrauchs in den von § 362 Nr. 5 StPO erfassten Fällen gibt es gewiss beachtliche Gründe. Sie sind meines Erachtens jedoch nicht gewichtig genug. Im vorliegenden Text soll die verfassungsrechtliche Dimension außen vor bleiben. Eine neue Vorschrift, mit der das geltende Strafprozessrecht verändert wird, muss auch eine Prüfung am Maßstab des geltenden Strafprozessrechts durchlaufen, um akzeptiert werden zu können. § 362 Nr. 5 StPO fällt bei dieser Prüfung durch und sollte deshalb aufgehoben werden.
BtMG § 30 a Abs. 1
Der Anbau von Betäubungsmitteln in Form der Aufzucht umfasst sämtliche gärtnerischen oder landwirtschaftlichen Bemühungen, um Wachstum von in den Anlagen I bis III zum Betäubungsmittelgesetz genannten Pflanzen zu erreichen. Hierzu zählen namentlich das Bewässern, das Düngen und das Belichten
BGH, Urteil vom 6. September 2023 – 6 StR 107/23
Lanthanide based ceria nanomaterials are important practical materials due to the redox properties that are useful in the avenues pertaining to technology and life sciences. Sub 10 nm spherical and highly monodisperse Ce1−xYbxO2−y (0.04 ≤ x ≤ 0.22) nanoparticles were synthesized by thermal decomposition, annealed separately at 773 K and 1273 K for 2 hours and characterized. Elemental mapping for Yb3+ doped ceria nanoparticles shows homogeneous distribution of Yb3+ atoms in the ceria with low Yb3+ content annealed at 773 K and 1273 K for 2 hours. However, clusters are observed for 773 K annealed ceria samples with high concentration of Yb3+. These clusters are not detected in 1273 K annealed nanomaterials. Introducing small amounts of Yb3+ ions into the ceria lattice as spectroscopic probes can provide detailed information about the atomic structure and local environments allowing the monitoring of small structural changes, such as clustering. The emission spectra observed at room temperature and at 4 K have a manifold of bands that corresponds to the 2F5/2 → 2F7/2 transition of Yb3+ ions. Some small shifts are observed in the Stark splitting pattern depending on the sample and the annealing conditions. The deconvolution by PARAFAC analysis yielded luminescence decay kinetics as well as the associated luminescence spectra of three species for each of the low Yb3+ doped ceria samples annealed at 773 K and one species for the 1273 K annealed samples. However, the ceria samples with high concentration of Yb3+ annealed at the two temperatures showed only one species with lower decay times as compared to the low Yb3+ doped ceria samples.
Entscheidungen über die vorläufige Entziehung der Fahrerlaubnis nach § STPO § 111 a StPO rücken in der Regel nicht in das Licht der Öffentlichkeit. Sie müssen schon aus tatsächlichen oder rechtlichen Gründen eine Besonderheit darstellen, um über die Medien einem breiteren (Fach-)Publikum bekannt gemacht zu werden und auf diesem Weg ein großes Quantum Aufmerksamkeit auf sich zu ziehen. Dies gelang einem Beschluss des LG Oldenburg, über den Interessierte z. B. via „Juristischer Flurfunk“ oder „LTO“ im Dezember 2022 informiert worden sind. In der Begründung dieser Beschwerdeentscheidung bemerken die Richter beiläufig, dass ein E-Scooter von mehreren Benutzern gleichzeitig „in einer Art Mittäterschaft“ geführt werden könne. Der Verfasser des Beschlusses war sich wohl unsicher, ob die beiden E-Scooter-Fahrer in dem konkreten Fall wirklich Mittäter im Sinne des § STGB § 25 Abs. STGB § 25 Absatz 2 StGB waren oder nicht. Die Formulierung „Art Mittäterschaft“ klingt wie die Antwort „jein“ auf diese Frage. Sachverhalt und Entscheidung sind interessant und inspirieren zum Nachdenken darüber, ob und wie die Deliktstatbestände § STGB § 316 StGB und § STVG § 24 a StVG verwirklicht werden können, wenn nicht eine Person allein das Fahrzeug führt, sondern auf dessen Fortbewegung von mehreren Nutzern eingewirkt wird. Im Folgenden sollen über den aktuellen verfahrensgegenständlichen Sachverhalt hinaus weitere Varianten eines solchen Geschehens gewürdigt werden.
Notwehr gegen »Klimakleber«?
(2023)
Die verständliche Verärgerung über die Behinderung des fließenden Straßenverkehrs durch Menschen, die ihre Hände mit Sekundenkleber auf der Fahrbahn fixieren, hat Diskussionen über die (straf-)rechtliche Bewertung dieser Aktionen und möglicher Gegenmaßnahmen angeregt. Ein umstrittenes Thema ist die Selbsthilfe aufgehaltener Autofahrer, die sich freie Bahn dadurch verschaffen, dass sie die festgeklebten Menschen mit physischer Gewalt von der Fahrbahn entfernen, was erhebliche Verletzungen an den festgeklebten Händen zur Folge haben kann. Der Beitrag dreht sich um die bisher nur unvollständig erörterte Frage einer Rechtfertigung solcher Selbsthilfehandlungen gemäß § 32 StGB.
Der in diesem Beitrag vorgestellte Entwurf eines neu formulierten Notwehrrechts war Gegenstand und Grundlage einer lebhaften Diskussion, die im Rahmen einer Online-Tagung stattgefunden hat. Neben den Mitgliedern des Kriminalpolitischen Kreises, die zum Teil an der Erstellung des Gesetzesentwurfes mitgearbeitet hatten, waren weitere Experten und Interessierte beteiligt. Daraus resultierten wertvolle kritische Anmerkungen, die von der Arbeitsgruppe dankbar aufgenommen und umgesetzt wurden.
Dass unser geltendes Strafrecht eine „Verschlankung“ vertragen könnte, ist nun auch im Bundesjustizministerium bemerkt worden. Aus dem Besonderen Teil sollen Vorschriften entfernt werden, die aus unterschiedlichen Gründen nicht (mehr) benötigt werden. Als weitere Maßnahme der Entkriminalisierung steht möglicherweise die punktuelle Senkung von Strafrahmen auf der Agenda. Dies hat nicht nur eine Reduzierung des Sanktionsniveaus zur Folge, sondern kann dort, wo infolge der niedrigeren Strafrahmenuntergrenze aus Verbrechen Vergehen werden, Straflosigkeit bewirken. Das betrifft § 30 StGB, eine Vorschrift, die Anlass für die Überlegungen sein kann, nicht nur im Besonderen Teil, sondern auch im Allgemeinen Teil des StGB nach entbehrlichen Normen zu suchen. § 30 StGB ist aktuell anwendbar in Kombination mit den Tatbestandsvarianten des § 184b StGB, die Verbrechenscharakter haben. Welche strafrechtlichen Ergebnisse daraus resultieren können, ist in der Debatte um die Strafbarkeit von Kinderpornographie bislang nicht erörtert worden. Dasselbe gilt für den praktisch selten zur Anwendung kommenden § 16 Abs. 2 StGB, der neuerdings in Verbindung mit § 184b StGB und § 184c StGB in Erscheinung getreten ist. Aus der Betrachtung der Zusammenhänge dieser Vorschriften lassen sich einige Empfehlungen an die Gesetzgebung ableiten.
Mit Urteil vom 31. Oktober 2023 hat der 2. Senat des BVerfG die im Dezember 2021 durch „Gesetz zur Herstellung materieller Gerechtigkeit“ eingeführte Vorschrift § 362 Nr. 5 StPO für mit dem Grundgesetz unvereinbar und deshalb nichtig erklärt. Erwartungsgemäß waren die Reaktionen auf diese Entscheidung nicht nur zustimmende. Die vorliegende Anmerkung wendet sich nicht gegen das Ergebnis, setzt sich aber − auch kritisch − mit einigen Teilen der Entscheidungsbegründung sowie den Erwiderungen der beiden abweichend votierenden Senatsmitglieder auseinander.
The educational sector currently faces a massive digital transformation with various digital offerings entering the market. To provide some orientation in this transforming space, a national digital education platform (NDEP) is under development in Germany as part of a nationwide flagship project. On the one hand, in efficiently connecting the relevant stakeholders to each other and to value-adding education-related offerings, various benefits emerge. On the other hand, monopolising the educational sector and influencing the respective market through a state-controlled platform bears potential regulatory risks from misuse of power by the platform to malpractice by the users. Against this background, we aim to identify and systematise these potential drawbacks prior to the platform’s actual development and implementation. We pursue a qualitative, interpretivist approach for policy analysis, based on ten elite interviews and two workshops. Our results are threefold: (1) We capture the consolidated NDEP architecture; (2) We categorise the range of relevant functions and value propositions of the NDEP; (3) We derive 23 regulatory areas of conflict across the three building blocks that result from the potential ecosystem and function scope configurations of the NDEP. As a contribution to research, we shed new interdisciplinary light on the governance and infrastructure of public-private platforms that enable innovation and collaboration while integrating respective market segments. As a contribution to practice, we provide clear guidance for policy-makers in strategizing the development and governance of and through national digital platforms in education.
In this paper we consider surfaces which are critical points of the Willmore functional subject to constrained area.
In the case of small area we calculate the corrections to the intrinsic geometry induced by the ambient curvature.
These estimates together with the choice of an adapted geometric center of mass lead to refined position estimates in relation to the scalar curvature of the ambient manifold.
The Circular Economy (CE) - based on five principles (reduce, reuse, refurbish, repair, and recycle) - has received increased attention in both academia and practice in recent years. The transition to CE by public and private organizations can be seen as an entrepreneurial act encompassing their strategic policies, business models, structures, and processes. Little is known about the involvement of employees of organizations making this transition. Therefore, this study investigates the influence of organizations’ commitment to the five CE principles on their employees’ perceptions of the usefulness, ease of implementation, and acceptability of the principles. The method used is exploratory, a mixed-method approach combining PLS-SEM and fsQCA. This research contributes to the field by developing a unified theoretical perspective on the entrepreneurial context. It also highlights the impact of CE principles on organizations that are transitioning to more sustainable development.
Purpose
This paper provides a systematization of the existing body of literature on both employee participation goals and the intervention formats in the context of organizational change. Furthermore, degrees of employee involvement that the intervention formats address are identified and related to the goals of employee participation. On this basis, determinants of employee involvement and participation in the context of digital transformation are unveiled.
Design/methodology/approach
Based on a systematic literature review the authors structure and relate employee participation goals and formats. Through a workshop with expert practitioners, the authors transfer and enhance these theoretical findings in the context of digital transformation. Experts rated the three most important goals and identified accompanying success factors, barriers and effects.
Findings
The results show that it is not necessarily the degree of involvement but a context-specific selection of measures, the quality of their implementation as well as the actual uptake of suggestions and activities developed by employees that contribute to employees accepting and participating in goal-directed transformations. Moreover, employees must have sufficient information and time for their participation in transformation processes.
Originality/value
This paper is based on a transformative approach, combining literature analysis to identify formats and goals of employee participation with experiential knowledge of digital transformation practitioners. In addition to relating intervention formats to goals pursued in organizational change processes, empirical and experiential perspectives are used to identify three very relevant goals and respective determinants in digital transformation processes.
Soziales Vertragsrecht
(2023)
The motion picture industry is subject to extensive business and management research conducted on a wide range of topics. Due to high research productivity, it is challenging to keep track of the abundance of publications. Against this background, we employ a bibliographic coupling analysis to gain a comprehensive understanding of current research topics. The following themes were defined: Key factors for success, word of mouth and social media, organizational and pedagogical dimensions, advertising—product placement and online marketing, tourism, the influence of data, the influence of culture, revenue maximization and purchase decisions, and the perception and identification of audiences. Based on the cluster analysis, we suggest the following future research opportunities: Exploring technological innovations, especially the influence of social media and streaming platforms in the film industry; the in-depth analysis of the use of artificial intelligence in film production, both in terms of its creative potential and ethical and legal challenges; the exploration of the representation of wokeness and minorities in films and their cultural and economic significance; and, finally, a detailed examination of the long-term effects of the COVID-19 pandemic and other crises on the film industry, especially in terms of changed consumption habits and structural adjustments.
Several lines of research have demonstrated spatial-numerical associations in both adults and children, which are thought to be based on a spatial representation of numerical information in the form of a mental number line. The acquisition of increasingly precise mental number line representations is assumed to support arithmetic learning in children. It is further suggested that sensorimotor experiences shape the development of number concepts and arithmetic learning, and that mental arithmetic can be characterized as “motion along a path” and might constitute shifts in attention along the mental number line. The present study investigated whether movements in physical space influence mental arithmetic in primary school children, and whether the expected effect depends on concurrency of body movements and mental arithmetic. After turning their body towards the left or right, 48 children aged 8 to 10 years solved simple subtraction and addition problems. Meanwhile, they either walked or stood still and looked towards the respective direction. We report a congruency effect between body orientation and operation type, i.e., higher performance for the combinations leftward orientation and subtraction and rightward orientation and addition. We found no significant difference between walking and looking conditions. The present results suggest that mental arithmetic in children is influenced by preceding sensorimotor cues and not necessarily by concurrent body movements.
HARE
(2023)
Sensor-based human activity recognition is becoming ever more prevalent. The increasing importance of distinguishing human movements, particularly in healthcare, coincides with the advent of increasingly compact sensors. A complex sequence of individual steps currently characterizes the activity recognition pipeline. It involves separate data collection, preparation, and processing steps, resulting in a heterogeneous and fragmented process. To address these challenges, we present a comprehensive framework, HARE, which seamlessly integrates all necessary steps. HARE offers synchronized data collection and labeling, integrated pose estimation for data anonymization, a multimodal classification approach, and a novel method for determining optimal sensor placement to enhance classification results. Additionally, our framework incorporates real-time activity recognition with on-device model adaptation capabilities. To validate the effectiveness of our framework, we conducted extensive evaluations using diverse datasets, including our own collected dataset focusing on nursing activities. Our results show that HARE’s multimodal and on-device trained model outperforms conventional single-modal and offline variants. Furthermore, our vision-based approach for optimal sensor placement yields comparable results to the trained model. Our work advances the field of sensor-based human activity recognition by introducing a comprehensive framework that streamlines data collection and classification while offering a novel method for determining optimal sensor placement.
The plasma membrane of mammalian cells links transmembrane receptors, various structural components, and membrane-binding proteins to subcellular processes, allowing inter- and intracellular communication. Therefore, membrane-binding proteins, together with structural components such as actin filaments, modulate the cell membrane in their flexibility, stiffness, and curvature. Investigating membrane components and curvature in cells remains challenging due to the diffraction limit in light microscopy. Preparation of 5–15-nm-thin plasma membrane sheets and subsequent inspection by metal replica transmission electron microscopy (TEM) reveal detailed information about the cellular membrane topology, including the structure and curvature. However, electron microscopy cannot identify proteins associated with specific plasma membrane domains. Here, we describe a novel adaptation of correlative super-resolution light microscopy and platinum replica TEM (CLEM-PREM), allowing the analysis of plasma membrane sheets with respect to their structural details, curvature, and associated protein composition. We suggest a number of shortcuts and troubleshooting solutions to contemporary PREM protocols. Thus, implementation of super-resolution stimulated emission depletion (STED) microscopy offers significant reduction in sample preparation time and reduced technical challenges for imaging and analysis. Additionally, highly technical challenges associated with replica preparation and transfer on a TEM grid can be overcome by scanning electron microscopy (SEM) imaging. The combination of STED microscopy and platinum replica SEM or TEM provides the highest spatial resolution of plasma membrane proteins and their underlying membrane and is, therefore, a suitable method to study cellular events like endocytosis, membrane trafficking, or membrane tension adaptations.
Introduction Climbing is an increasingly popular activity and imposes specific physiological demands on the human body, which results in unique injury presentations. Of particular concern are overuse injuries (non-traumatic injuries). These injuries tend to present in the upper body and might be preventable with adequate knowledge of risk factors which could inform about injury prevention strategies. Research in this area has recently emerged but has yet to be synthesized comprehensively. Therefore, the aim of this study was to conduct a systematic review of the potential risk factors and injury prevention strategies for overuse injuries in adult climbers.
Methods This systematic review was conducted in accordance with the PRISMA guidelines. Databases were searched systematically, and articles were deemed eligible based upon specific criteria. Research included was original and peer-reviewed, involving climbers, and published in English, German or Czech. Outcomes included overuse injury, and at least one or more variable indicating potential risk factors or injury prevention strategies. The methodological quality of the included studies was assessed with the Downs and Black Quality Index. Data were extracted from included studies and reported descriptively for population, climbing sport type, study design, injury definition and incidence/prevalence, risk factors, and injury prevention strategies.
Results Out of 1,183 records, a total of 34 studies were included in the final analysis. Higher climbing intensity, bouldering, reduced grip/finger strength, use of a “crimp” grip, and previous injury were associated with an increased risk of overuse injury. Additionally, a strength training intervention prevented shoulder and elbow injuries. BMI/body weight, warm up/cool downs, stretching, taping and hydration were not associated with risk of overuse injury. The evidence for the risk factors of training volume, age/years of climbing experience, and sex was conflicting.
Discussion This review presents several risk factors which appear to increase the risk of overuse injury in climbers. Strength and conditioning, load management, and climbing technique could be targeted in injury prevention programs, to enhance the health and wellbeing of climbing athletes. Further research is required to investigate the conflicting findings reported across included studies, and to investigate the effectiveness of injury prevention programs.
Systematic Review Registrationhttps://www.crd.york.ac.uk/, PROSPERO (CRD42023404031).
The deficiency of a (bio)chemical reaction network can be conceptually interpreted as a measure of its ability to support exotic dynamical behavior and/or multistationarity. The classical definition of deficiency relates to the capacity of a network to permit variations of the complex formation rate vector at steady state, irrespective of the network kinetics. However, the deficiency is by definition completely insensitive to the fine details of the directionality of reactions as well as bounds on reaction fluxes. While the classical definition of deficiency can be readily applied in the analysis of unconstrained, weakly reversible networks, it only provides an upper bound in the cases where relevant constraints on reaction fluxes are imposed. Here we propose the concept of effective deficiency, which provides a more accurate assessment of the network’s capacity to permit steady state variations at the complex level for constrained networks of any reversibility patterns. The effective deficiency relies on the concept of nonstoichiometric balanced complexes, which we have already shown to be present in real-world biochemical networks operating under flux constraints. Our results demonstrate that the effective deficiency of real-world biochemical networks is smaller than the classical deficiency, indicating the effects of reaction directionality and flux bounds on the variation of the complex formation rate vector at steady state.
Introduction Flux phenotypes from different organisms and growth conditions allow better understanding of differential metabolic networks functions. Fluxes of metabolic reactions represent the integrated outcome of transcription, translation, and post-translational modifications, and directly affect growth and fitness. However, fluxes of intracellular metabolic reactions cannot be directly measured, but are estimated via metabolic flux analysis (MFA) that integrates data on isotope labeling patterns of metabolites with metabolic models. While the application of metabolomics technologies in photosynthetic organisms have resulted in unprecedented data from 13CO2-labeling experiments, the bottleneck in flux estimation remains the application of isotopically nonstationary MFA (INST-MFA). INST-MFA entails fitting a (large) system of coupled ordinary differential equations, with metabolite pools and reaction fluxes as parameters. Here, we focus on the Calvin-Benson cycle (CBC) as a key pathway for carbon fixation in photosynthesizing organisms and ask if approaches other than classical INST-MFA can provide reliable estimation of fluxes for reactions comprising this pathway.
Methods First, we show that flux estimation with the labeling patterns of all CBC intermediates can be formulated as a single constrained regression problem, avoiding the need for repeated simulation of time-resolved labeling patterns.
Results We then compare the flux estimates of the simulation-free constrained regression approach with those obtained from the classical INST-MFA based on labeling patterns of metabolites from the microalgae Chlamydomonas reinhardtii, Chlorella sorokiniana and Chlorella ohadii under different growth conditions.
Discussion Our findings indicate that, in data-rich scenarios, simulation-free regression-based approaches provide a suitable alternative for flux estimation from classical INST-MFA since we observe a high qualitative agreement (rs=0.89) to predictions obtained from INCA, a state-of-the-art tool for INST-MFA.
Caenorhabditis elegans (C. elegans) is gaining recognition and importance as an organismic model for toxicity testing in line with the 3Rs principle (replace, reduce, refine). In this study, we explored the use of C. elegans to examine the toxicities of alkylating sulphur mustard analogues, specifically the monofunctional agent 2-chloroethyl-ethyl sulphide (CEES) and the bifunctional, crosslinking agent mechlorethamine (HN2). We exposed wild-type worms at different life cycle stages (from larvae L1 to adulthood day 10) to CEES or HN2 and scored their viability 24 h later. The susceptibility of C. elegans to CEES and HN2 paralleled that of human cells, with HN2 exhibiting higher toxicity than CEES, reflected in LC50 values in the high µM to low mM range. Importantly, the effects were dependent on the worms’ developmental stage as well as organismic age: the highest susceptibility was observed in L1, whereas the lowest was observed in L4 worms. In adult worms, susceptibility to alkylating agents increased with advanced age, especially to HN2. To examine reproductive effects, L4 worms were exposed to CEES and HN2, and both the offspring and the percentage of unhatched eggs were assessed. Moreover, germline apoptosis was assessed by using ced-1p::GFP (MD701) worms. In contrast to concentrations that elicited low toxicities to L4 worms, CEES and HN2 were highly toxic to germline cells, manifesting as increased germline apoptosis as well as reduced offspring number and percentage of eggs hatched. Again, HN2 exhibited stronger effects than CEES. Compound specificity was also evident in toxicities to dopaminergic neurons–HN2 exposure affected expression of dopamine transporter DAT-1 (strain BY200) at lower concentrations than CEES, suggesting a higher neurotoxic effect. Mechanistically, nicotinamide adenine dinucleotide (NAD+) has been linked to mustard agent toxicities. Therefore, the NAD+-dependent system was investigated in the response to CEES and HN2 treatment. Overall NAD+ levels in worm extracts were revealed to be largely resistant to mustard exposure except for high concentrations, which lowered the NAD+ levels in L4 worms 24 h post-treatment. Interestingly, however, mutant worms lacking components of NAD+-dependent pathways involved in genome maintenance, namely pme-2, parg-2, and sirt-2.1 showed a higher and compound-specific susceptibility, indicating an active role of NAD+ in genotoxic stress response. In conclusion, the present results demonstrate that C. elegans represents an attractive model to study the toxicology of alkylating agents, which supports its use in mechanistic as well as intervention studies with major strength in the possibility to analyze toxicities at different life cycle stages.
Our subject is a new catalogue of radar-based heavy rainfall events (CatRaRE) over Germany and how it relates to the concurrent atmospheric circulation. We classify daily ERA5 fields of convective indices according to CatRaRE, using an array of 13 statistical methods, consisting of 4 conventional (“shallow”) and 9 more recent deep machine learning (DL) algorithms; the classifiers are then applied to corresponding fields of
simulated present and future atmospheres from the Coordinated Regional Climate Downscaling Experiment (CORDEX) project. The inherent uncertainty of the DL results from the stochastic nature of their optimization is addressed by employing an ensemble approach using 20 runs for each network. The shallow random forest method performs best with an equitable threat score (ETS) around 0.52, followed by the DL networks ALL-CNN and ResNet with an ETS near 0.48. Their success can be understood as a result of conceptual simplicity and parametric parsimony, which obviously best fits the relatively simple classification task. It is found that, on summer days, CatRaRE convective atmospheres over Germany occur with a probability of about 0.5. This probability is projected to increase, regardless of method, both in ERA5-reanalyzed and CORDEX-simulated atmospheres: for the historical period we find a centennial increase of about 0.2 and for the future period one of slightly below 0.1.
Introduction This study examined the effects of an 8-week backward running (BR) vs. forward running (FR) training programmes on measures of physical fitness in young female handball players.
Methods Twenty-nine players participated in this study. Participants were randomly assigned to a FR training group, BR training group, and a control group.
Results and discussion Within-group analysis indicated significant, small-to-large improvements in all performance tests (effect size [g] = 0.36 to 1.80), except 5-m forward sprint-time in the BR group and 5- and 10-m forward sprint-time in the FR group. However, the CG significantly decreased forward sprint performance over 10-m and 20-m (g = 0.28 to 0.50) with no changes in the other fitness parameters. No significant differences in the amount of change scores between the BR and FR groups were noted. Both training interventions have led to similar improvements in measures of muscle power, change of direction (CoD) speed, sprint speed either forward or backward, and repeated sprint ability (RSA) in young female handball players, though BR training may have a small advantage over FR training for 10-m forward sprint time and CoD speed, while FR training may provide small improvements over BR training for RSAbest. Practitioners are advised to consider either FR or BR training to improve various measures of physical fitness in young female handball players.
Introduction Early linguistic background, and in particular, access to language, lays the foundation of future reading skills in deaf and hard-of-hearing signers. The current study aims to estimate the impact of two factors – early access to sign and/or spoken language – on reading fluency in deaf and hard-of-hearing adult Russian Sign Language speakers.
Methods In the eye-tracking experiment, 26 deaf and 14 hard-of-hearing native Russian Sign Language speakers read 144 sentences from the Russian Sentence Corpus. Analysis of global eye-movement trajectories (scanpaths) was used to identify clusters of typical reading trajectories. The role of early access to sign and spoken language as well as vocabulary size as predictors of the more fluent reading pattern was tested.
Results Hard-of-hearing signers with early access to sign language read more fluently than those who were exposed to sign language later in life or deaf signers without access to speech sounds. No association between early access to spoken language and reading fluency was found.
Discussion Our results suggest a unique advantage for the hard-of-hearing individuals from having early access to both sign and spoken language and support the existing claims that early exposure to sign language is beneficial not only for deaf but also for hard-of-hearing children.
We review an approach for reconstructing oscillatory networks’ undirected and directed connectivity from data. The technique relies on inferring the phase dynamics model. The central assumption is that we observe the outputs of all network nodes. We distinguish between two cases. In the first one, the observed signals represent smooth oscillations, while in the second one, the data are pulse-like and can be viewed as point processes. For the first case, we discuss estimating the true phase from a scalar signal, exploiting the protophase-to-phase transformation. With the phases at hand, pairwise and triplet synchronization indices can characterize the undirected connectivity. Next, we demonstrate how to infer the general form of the coupling functions for two or three oscillators and how to use these functions to quantify the directional links. We proceed with a different treatment of networks with more than three nodes. We discuss the difference between the structural and effective phase connectivity that emerges due to high-order terms in the coupling functions. For the second case of point-process data, we use the instants of spikes to infer the phase dynamics model in the Winfree form directly. This way, we obtain the network’s coupling matrix in the first approximation in the coupling strength.
Introduction Vagally mediated heart rate variability is an index of autonomic nervous system activity that is associated with a large variety of outcome variables including psychopathology and self-regulation. While practicing heart rate variability biofeedback over several weeks has been reliably associated with a number of positive outcomes, its acute effects are not well known. As the strongest association with vagally mediated heart rate variability has been found particularly within the attention-related subdomain of self-regulation, we investigated the acute effect of heart rate variability biofeedback on attentional control using the revised Attention Network Test.
Methods Fifty-six participants were tested in two sessions. In one session each participant received a heart rate variability biofeedback intervention, and in the other session a control intervention of paced breathing at a normal ventilation rate. After the biofeedback or control intervention, participants completed the Attention Network Test using the Orienting Score as a measure of attentional control.
Results Mixed models revealed that higher resting baseline vagally mediated heart rate variability was associated with better performance in attentional control, which suggests more efficient direction of attention to target stimuli. There was no significant main effect of the intervention on attentional control. However, an interaction effect indicated better performance in attentional control after biofeedback in individuals who reported higher current stress levels.
Discussion The results point to acute beneficial effects of heart rate variability biofeedback on cognitive performance in highly stressed individuals. Although promising, the results need to be replicated in larger or more targeted samples in order to reach stronger conclusions about the effects.
BACKGROUND: Patients with diabetes exhibit an increased prevalence for emotional disorders compared with healthy humans, partially due to a shared pathogenesis including hormone resistance and inflammation, which is also linked to intestinal dysbiosis. The preventive intake of probiotic lactobacilli has been shown to improve dysbiosis along with mood and metabolism. Yet, a potential role of Lactobacillus rhamnosus (Lacticaseibacillus rhamnosus 0030) (LR) in improving emotional behavior in established obesity and the underlying mechanisms are unknown.
METHODS: Female and male C57BL/6N mice were fed a low-fat diet (10% kcal from fat) or high-fat diet (HFD) (45% kcal from fat) for 6 weeks, followed by daily oral gavage of vehicle or 1 3 10 8 colony-forming units of LR, and assessment of anxiety- and depressive-like behavior. Cecal microbiota composition was analyzed using 16S ribosomal RNA sequencing, plasma and cerebrospinal fluid were collected for metabolomic analysis, and gene expression of different brain areas was assessed using reverse transcriptase quantitative polymerase chain reaction.
RESULTS: We observed that 12 weeks of HFD feeding induced hyperinsulinemia, which was attenuated by LR application only in female mice. On the contrary, HFD-fed male mice exhibited increased anxiety- and depressive-like behavior, where the latter was specifically attenuated by LR application, which was independent of metabolic changes. Furthermore, LR application restored the HFD-induced decrease of tyrosine hydroxylase, along with normalizing cholecystokinin gene expression in dopaminergic brain regions; both tyrosine hydroxylase and cholecystokinin are involved in signaling pathways impacting emotional disorders.
CONCLUSIONS: Our data show that LR attenuates depressive-like behavior after established obesity, with changes in the dopaminergic system in male mice, and mitigates hyperinsulinemia in obese female mice.
DUO-GAIT
(2023)
In recent years, there has been a growing interest in developing and evaluating gait analysis algorithms based on inertial measurement unit (IMU) data, which has important implications, including sports, assessment of diseases, and rehabilitation. Multi-tasking and physical fatigue are two relevant aspects of daily life gait monitoring, but there is a lack of publicly available datasets to support the development and testing of methods using a mobile IMU setup. We present a dataset consisting of 6-minute walks under single- (only walking) and dual-task (walking while performing a cognitive task) conditions in unfatigued and fatigued states from sixteen healthy adults. Especially, nine IMUs were placed on the head, chest, lower back, wrists, legs, and feet to record under each of the above-mentioned conditions. The dataset also includes a rich set of spatio-temporal gait parameters that capture the aspects of pace, symmetry, and variability, as well as additional study-related information to support further analysis. This dataset can serve as a foundation for future research on gait monitoring in free-living environments.
Introduction LingoTalk is a German speech-language app designed to enhance lexical retrieval in individuals with aphasia. It incorporates automatic speech recognition (ASR) to provide therapist-independent feedback. The execution and effectiveness of a self-administered intervention with LingoTalk was explored in a case series study.
Methods Three individuals with chronic aphasia participated in a highly individualized, supervised self-administered intervention lasting 3 weeks. The LingoTalk app closely monitored the frequency, intensity and progress of the intervention. Treatment efficacy was assessed using a multiple baseline design, examining both item-specific treatment effects and generalization to untreated items, an untreated task, and spontaneous speech.
Results All participants successfully completed the intervention with LingoTalk, although one participant was not able to use the ASR feature. None of the participants fully adhered to the treatment protocol. All participants demonstrated significant and sustained improvement in the naming of practiced items, although there was limited evidence of generalization. Additionally, there was a slight reduction in word-finding difficulties during spontaneous speech.
Discussion This small-scale study indicates that self-administered intervention with LingoTalk can improve oral naming of treated items. Thus, it has the potential to complement face-to-face speech-language therapy, such as within in a “flipped speech room” approach. The choice of feedback mode is discussed. Transparent progress monitoring of the intervention appears to positively influence patients' motivation.
Linguistic structure modulates attention in reading: evidence from negative concord in Italian
(2023)
We report the reading performance of an Italian speaker with egocentric Neglect Dyslexia on sentences with Negative Concord structures, which contain a linguistic cue to the presence of a preceding negative marker and compare it to sentences with no such cue. As predicted, the frequency of reading the whole sentence, including the initial negative marker non, was higher in Negative Concord structures than in sentences which also started with non, but crucially, lacked the medially positioned linguistic cue to the presence of non.
These data support the claim that the presence of linguistic cues to sentence structure modulates attention during reading in Neglect Dyslexia.
This study explored the effects of an 8-week repeated backward running training (RBRT) programme on measures of physical fitness in youth male soccer players. Youth male soccer players were randomly allocated into a RBRT group (n = 20; 13.95 +/- 0.22y) or a control group (CG; n = 16; 14.86 +/- 0.29y). The CG continued normal soccer training, while the RBRT group replaced some soccer drills with RBRT twice per week. Within-group analysis revealed that RBRT improved all performance variables ( increment -9.99% to 14.50%; effect size [ES] = -1.79 to 1.29; p <= 0.001). Meanwhile, trivial-to-moderate detrimental effects on sprinting and change of direction (CoD) speed ( increment 1.55% to 10.40%; p <= 0.05) were noted in the CG. The number of individuals improving performance above the smallest worthwhile change ranged from 65-100% across all performance variables in the RBRT group, whereas<50% in the CG reached that threshold. The between-group analysis indicated that the RBRT group improved performance on all performance tasks more than the CG (ES = -2.23 to 1.10; p <= 0.05). These findings demonstrate that substituting part of a standard soccer training regimen with RBRT can enhance youth soccer players' sprinting, CoD, jumping, and RSA performance.
The European Union is highly dependent on soybean imports from overseas to meet its protein demands. Individual Member States have been quick to declare self-sufficiency targets for plant-based proteins, but detailed strategies are still lacking. Rising global temperatures have painted an image of a bright future for soybean production in Europe, but emerging climatic risks such as drought have so far not been included in any of those outlooks.
Here, we present simulations of future soybean production and the most prominent risk factors across Europe using an ensemble of climate and soybean growth models. Projections suggest a substantial increase in potential soybean production area and productivity in Central Europe, while southern European production would become increasingly dependent on supplementary irrigation. Average productivity would rise by 8.3% (RCP 4.5) to 8.7% (RCP 8.5) as a result of improved growing conditions (plant physiology benefiting from rising temperature and CO2 levels) and farmers adapting to them by using cultivars with longer phenological cycles. Suitable production area would rise by 31.4% (RCP 4.5) to 37.7% (RCP 8.5) by the mid-century, contributing considerably more than productivity increase to the production potential for closing the protein gap in Europe.
While wet conditions at harvest and incidental cold spells are the current key challenges for extending soybean production, the models and climate data analysis anticipate that drought and heat will become the dominant limitations in the future. Breeding for heat-tolerant and water-efficient genotypes is needed to further improve soybean adaptation to changing climatic conditions.
Art. 1 Abs. 2 Buchst. b der RL 93/83/EWG des Rates vom 27. September 1993 zur Koordinierung bestimmter urheber- und leistungsschutzrechtlicher Vorschriften betreffend Satellitenrundfunk und Kabelweiterverbreitung ist dahin auszulegen, dass ein Satellitenbouquet-Anbieter, der verpflichtet ist, für eine Handlung in Form der öffentlichen Wiedergabe über Satellit, an der er mitwirkt, die Zustimmung der Inhaber der betreffenden Urheberrechte und verwandten Schutzrechte einzuholen, diese Zustimmung – entsprechend der dem betreffenden Sendeunternehmen erteilten Zustimmung – nur in dem Mitgliedstaat einholen muss, in dem die programmtragenden Signale in die zum Satelliten führende Kommunikationskette eingegeben werden.
Entrepreneurship education research has a strong “output” focus on impact studies but pays much less attention to the “inside” or process perspective of the way entrepreneurship education occurs. In particular, the scattered previous entrepreneurship curriculum research has not managed to provide a current and comprehensive overview of the curricular elements that constitute entrepreneurship education. To overcome this shortcoming, we aim to identify the teaching objectives, teaching contents, teaching methods, and assessment methods discussed in entrepreneurship curriculum research. To this end, we conducted a systematic literature review on the four entrepreneurship curriculum dimensions and collected all mentioned curriculum items. We used a two-stage coding procedure to find the genuinely entrepreneurship-specific items. Among numerous items (also from business management and other subjects), we found 26 objectives, 34 contents, 11 teaching methods, and 7 assessment methods that were entrepreneurship-specific. Most of these items were addressed by only a few scholarly papers.
Die Öffentlichkeitsarbeit des Council of Jews from Germany in deutsch-jüdischen Nachkriegsperiodika
(2023)
Immer Ärger mit dem Pkw
(2023)
The Gutenberg-Richter (GR) and the Omori-Utsu (OU) law describe the earthquakes' energy release and temporal clustering and are thus of great importance for seismic hazard assessment. Motivated by experimental results, which indicate stress-dependent parameters, we consider a combined global data set of 127 main shock-aftershock sequences and perform a systematic study of the relationship between main shock-induced stress changes and associated seismicity patterns. For this purpose, we calculate space-dependent Coulomb Stress (& UDelta;CFS) and alternative receiver-independent stress metrics in the surrounding of the main shocks. Our results indicate a clear positive correlation between the GR b-value and the induced stress, contrasting expectations from laboratory experiments and suggesting a crucial role of structural heterogeneity and strength variations. Furthermore, we demonstrate that the aftershock productivity increases nonlinearly with stress, while the OU parameters c and p systematically decrease for increasing stress changes. Our partly unexpected findings can have an important impact on future estimations of the aftershock hazard.
Providing students with efficient instruction tailored to their individual characteristics in the cognitive and affective domains is an important goal in research on computer-based learning. This is especially important when seeking to enhance students' learning experience, such as by counteracting boredom, a detrimental emotion for learning. However, studies comparing instructional strategies triggered by either cognitive or emotional characteristics are surprisingly scarce. In addition, little research has examined the impact of these types of instructional strategies on performance and boredom trajectories within a lesson. In the present study, we compared the effectiveness of an intelligent tutoring system that adapted variable levels of hint details to a combination of students' dynamic, self-reported emotions and task performance (i.e., the experimental condition) to a traditional hint delivery approach consisting of a progressive, incremental supply of details following students' failures (i.e., the control condition). Linear mixed models of time-related changes in task performance and the intensity of boredom over two 1-h sessions showed that students (N = 104) in the two conditions exhibited equivalent progression in task performance and similar trajectories in boredom intensity. However, a consideration of students' achievement levels in the analyses (i.e., their final performance on the task) revealed that higher achievers in the experimental condition showed a reduction in boredom during the first session, suggesting possible benefits of using emotional information to increase the contingency of the hint delivery strategy and improve students’ learning experience.
Purpose
This study investigates the communication behavior of public health organizations on Twitter during the COVID-19 vaccination campaign in Brazil. It contributes to the understanding of the organizational framing of health communication by showcasing several instances of framing devices that borrow from (Brazilian) internet culture. The investigation of this case extends the knowledge by providing a rich description of the organizational framing of health communication to combat misinformation in a politically charged environment.
Design/methodology/approach
The authors collected a Twitter dataset of 77,527 tweets and analyzed a purposeful subsample of 536 tweets that contained information provided by Brazilian public health organizations about COVID-19 vaccination campaigns. The data analysis was carried out quantitatively and qualitatively by combining social media analytics techniques and frame analysis.
Findings
The analysis showed that Brazilian health organizations used several framing devices that have been identified by previous literature such as hashtags, links, emojis or images. However, the analysis also unearthed hitherto unknown visual framing devices for misinformation prevention and debunking that borrow from internet culture such as “infographics,” “pop culture references” and “internet-native symbolism.”
Research limitations/implications
First, the identification of framing devices relating to internet culture add to our understanding of the so far little addressed framing of misinformation combat messages. The case of Brazilian health organizations provides a novel perspective to knowledge by offering a notion of internet-native symbols (e.g. humor, memes) and popular culture references for misinformation combat, including misinformation prevention. Second, this study introduces a frontier of political contextualization to misinformation research that does not relate to the partisanship of the spreaders but that relates to the political dilemmas of public organizations with a commitment to provide accurate information to citizens.
Practical implications
The findings inform decision-makers and public health organizations about framing devices that are tailored to internet-native audiences and can guide strategies to carry out information campaigns in misinformation-laden social media environments.
Social implications
The findings of this case study expose the often-overlooked cultural peculiarities of framing information campaigns on social media. The report of this study from a country in the Global South helps to contrast several assumptions and strategies that are prevalent in (health) discourses in Western societies and scholarship.
Originality/value
This study uncovers unconventional and barely addressed framing devices of health organizations operating in Brazil, which provides a novel perspective to the body of research on misinformation. It contributes to existing knowledge about frame analysis and broadens the understanding of frame devices borrowing from internet culture. It is a call for a frontier in misinformation research that deals with internet culture as part of organizational strategies for successful misinformation combat.
This study focuses on three key aspects: (a) crude throat swab samples in a viral transport medium (VTM) as templates for RT-LAMP reactions; (b) a biotinylated DNA probe with enhanced specificity for LFA readouts; and (c) a digital semi-quantification of LFA readouts. Throat swab samples from SARS-CoV-2 positive and negative patients were used in their crude (no cleaning or pre-treatment) forms for the RT-LAMP reaction. The samples were heat-inactivated but not treated for any kind of nucleic acid extraction or purification. The RT-LAMP (20 min processing time) product was read out by an LFA approach using two labels: FITC and biotin. FITC was enzymatically incorporated into the RT-LAMP amplicon with the LF-LAMP primer, and biotin was introduced using biotinylated DNA probes, specifically for the amplicon region after RT-LAMP amplification. This assay setup with biotinylated DNA probe-based LFA readouts of the RT-LAMP amplicon was 98.11% sensitive and 96.15% specific. The LFA result was further analysed by a smartphone-based IVD device, wherein the T-line intensity was recorded. The LFA T-line intensity was then correlated with the qRT-PCR Ct value of the positive swab samples. A digital semi-quantification of RT-LAMP-LFA was reported with a correlation coefficient of R2 = 0.702. The overall RT-LAMP-LFA assay time was recorded to be 35 min with a LoD of three RNA copies/µL (Ct-33). With these three advancements, the nucleic acid testing-point of care technique (NAT-POCT) is exemplified as a versatile biosensor platform with great potential and applicability for the detection of pathogens without the need for sample storage, transportation, or pre-processing.
The physiological dependence of animals on dietary intake of vitamins, amino acids, and fatty acids is ubiquitous. Sharp differences in the availability of these vital dietary biomolecules among different resources mean that consumers must adopt a range of strategies to meet their physiological needs. We review the emerging work on omega-3 long-chain polyunsaturated fatty acids, focusing predominantly on predator-prey interactions, to illustrate that trade-off between capacities to consume resources rich in vital biomolecules and internal synthesis capacity drives differences in phenotype and fitness of consumers. This can then feedback to impact ecosystem functioning. We outline how focus on vital dietary biomolecules in eco-eco-devo dynamics can improve our understanding of anthropogenic changes across multiple levels of biological organization.
The study addresses the question, if observed changes in terms of Arctic-midlatitude linkages during winter are driven by Arctic Sea ice decline alone or if the increase of global sea surface temperatures plays an additional role. We compare atmosphere-only model experiments with ECHAM6 to ERA-Interim Reanalysis data. The model sensitivity experiment is implemented as a set of four combinations of sea ice and sea surface temperature boundary conditions. Atmospheric circulation regimes are determined and evaluated in terms of their cyclone and blocking characteristics and changes in frequency during winter. As a prerequisite, ECHAM6 reproduces general features of circulation regimes very well. Tropospheric changes induced by the change of boundary conditions are revealed and further impacts on the large-scale circulation up into the stratosphere are investigated. In early winter, the observed increase of atmospheric blocking in the region between Scandinavia and the Urals are primarily related to the changes in sea surface temperatures. During late winter, we f nd a weakened polar stratospheric vortex in the reanalysis that further impacts the troposphere. In the model sensitivity study a climatologically weakened polar vortex occurs only if sea ice is reduced and sea surface temperatures are increased together. This response is delayed compared to the reanalysis. The tropospheric response during late winter is inconclusive in the model, which is potentially related to the weak and delayed response in the stratosphere. The model experiments do not reproduce the connection between early and late winter as interpreted from the reanalysis. Potentially explaining this mismatch, we identify a discrepancy of ECHAM6 to reproduce the weakening of the stratospheric polar vortex through blocking induced upward propagation of planetary waves.
This paper deals with the long-term behavior of positive operator semigroups on spaces of bounded functions and of signed measures, which have applications to parabolic equations with unbounded coefficients and to stochas-tic analysis. The main results are a Tauberian type theorem characterizing the convergence to equilibrium of strongly Feller semigroups and a generalization of a classical convergence theorem of Doob. None of these results requires any kind of time regularity of the semigroup.
In real-world scene perception, human observers generate sequences of fixations to move image patches into the high-acuity center of the visual field. Models of visual attention developed over the last 25 years aim to predict two-dimensional probabilities of gaze positions for a given image via saliency maps. Recently, progress has been made on models for the generation of scan paths under the constraints of saliency as well as attentional and oculomotor restrictions. Experimental research demonstrated that task constraints can have a strong impact on viewing behavior. Here, we propose a scan-path model for both fixation positions and fixation durations, which include influences of task instructions and interindividual differences. Based on an eye-movement experiment with four different task conditions, we estimated model parameters for each individual observer and task condition using a fully Bayesian dynamical modeling framework using a joint spatial-temporal likelihood approach with sequential estimation. Resulting parameter values demonstrate that model properties such as the attentional span are adjusted to task requirements. Posterior predictive checks indicate that our dynamical model can reproduce task differences in scan-path statistics across individual observers.
We consider a system of noninteracting particles on a line with initial positions distributed uniformly with density ? on the negative half-line. We consider two different models: (i) Each particle performs independent Brownian motion with stochastic resetting to its initial position with rate r and (ii) each particle performs run -and-tumble motion, and with rate r its position gets reset to its initial value and simultaneously its velocity gets randomized. We study the effects of resetting on the distribution P(Q, t) of the integrated particle current Q up to time t through the origin (from left to right). We study both the annealed and the quenched current distributions and in both cases, we find that resetting induces a stationary limiting distribution of the current at long times. However, we show that the approach to the stationary state of the current distribution in the annealed and the quenched cases are drastically different for both models. In the annealed case, the whole distribution P-an(Q, t) approaches its stationary limit uniformly for all Q. In contrast, the quenched distribution P-qu(Q, t) attains its stationary form for Q < Q(crit)(t), while it remains time dependent for Q > Q(crit)(t). We show that Q(crit)(t) increases linearly with t for large t. On the scale where Q <; Q(crit)(t), we show that P-qu(Q, t) has an unusual large deviation form with a rate function that has a third-order phase transition at the critical point. We have computed the associated rate functions analytically for both models. Using an importance sampling method that allows to probe probabilities as tiny as 10-14000, we were able to compute numerically this nonanalytic rate function for the resetting Brownian dynamics and found excellent agreement with our analytical prediction.
The capillary-venous pathology cerebral cavernous malformation (CCM) is caused by loss of CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and in-operable regions of the central nervous system. Previous pharmacological suppression screens in disease models of CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This finding raised a need to investigate the involvement of retinoic acid in CCM and test whether it has a curative effect in preclinical mouse models. Here, we show that components of the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models of CCM. We complemented this analysis by pharmacologically modifying retinoic acid levels in zebrafish and human endothelial cell models of CCM, and in acute and chronic mouse models of CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrafish showed positive effects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development of vascular lesions in adult chronic murine models of CCM were drug regiment-sensitive, possibly due to adverse developmental effects of this hormone. A treatment with high doses of retinoic acid even worsened CCM lesions in an adult chronic murine model of CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modification of retinoic acid levels can alleviate CCM phenotypes.
Fetal alcohol-spectrum disorder (FASD) is underdiagnosed and often misdiagnosed as attention-deficit/hyperactivity disorder (ADHD). Here, we develop a screening tool for FASD in youth with ADHD symptoms. To develop the prediction model, medical record data from a German University outpatient unit are assessed including 275 patients aged 0-19 years old with FASD with or without ADHD and 170 patients with ADHD without FASD aged 0-19 years old. We train 6 machine learning models based on 13 selected variables and evaluate their performance. Random forest models yield the best prediction models with a cross-validated AUC of 0.92 (95% confidence interval [0.84, 0.99]). Follow-up analyses indicate that a random forest model with 6 variables - body length and head circumference at birth, IQ, socially intrusive behaviour, poor memory and sleep disturbance - yields equivalent predictive accuracy. We implement the prediction model in a web-based app called FASDetect - a user-friendly, clinically scalable FASD risk calculator that is freely available at https://fasdetect.dhc-lab.hpi.de.
Purpose
Due to the increasing application of genome analysis and interpretation in medical disciplines, professionals require adequate education. Here, we present the implementation of personal genotyping as an educational tool in two genomics courses targeting Digital Health students at the Hasso Plattner Institute (HPI) and medical students at the Technical University of Munich (TUM).
Methods
We compared and evaluated the courses and the students ' perceptions on the course setup using questionnaires.
Results
During the course, students changed their attitudes towards genotyping (HPI: 79% [15 of 19], TUM: 47% [25 of 53]). Predominantly, students became more critical of personal genotyping (HPI: 73% [11 of 15], TUM: 72% [18 of 25]) and most students stated that genetic analyses should not be allowed without genetic counseling (HPI: 79% [15 of 19], TUM: 70% [37 of 53]). Students found the personal genotyping component useful (HPI: 89% [17 of 19], TUM: 92% [49 of 53]) and recommended its inclusion in future courses (HPI: 95% [18 of 19], TUM: 98% [52 of 53]).
Conclusion
Students perceived the personal genotyping component as valuable in the described genomics courses. The implementation described here can serve as an example for future courses in Europe.