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Scalability is often mentioned in literature, but a stringent definition is missing. In particular, there is no general scalability assessment which clearly indicates whether a system scales or not or whether a system scales better than another. The key contribution of this article is the definition of a scalability index (SI) which quantifies if a system scales in comparison to another system, a hypothetical system, e.g., linear system, or the theoretically optimal system. The suggested SI generalizes different metrics from literature, which are specialized cases of our SI. The primary target of our scalability framework is, however, benchmarking of two systems, which does not require any reference system. The SI is demonstrated and evaluated for different use cases, that are (1) the performance of an IoT load balancer depending on the system load, (2) the availability of a communication system depending on the size and structure of the network, (3) scalability comparison of different location selection mechanisms in fog computing with respect to delays and energy consumption; (4) comparison of time-sensitive networking (TSN) mechanisms in terms of efficiency and utilization. Finally, we discuss how to use and how not to use the SI and give recommendations and guidelines in practice. To the best of our knowledge, this is the first work which provides a general SI for the comparison and benchmarking of systems, which is the primary target of our scalability analysis.
Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research
(2023)
A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.
Metaphors, Dead and Alive
(2023)
This paper examins how the medieval distinction between proper and improper signification can give a plausible explanation of both metaphorical use and the usual transformations a language can undergo. I will show how Thomas Aquinas distinguishes between ordinary ambiguous terms and metaphors, whereas William of Ockham and Walter Burley do not leave room for this distinction. I will argue that Ockham’s conception of transfer of sense through subsequent institution of words is best thought of as an explanation of how ordinary usage can contain ambiguities, whereas Burley’s conception of transfer of sense without new imposition is more plausible when it comes to explaining metaphors. If metaphorical use is lumped together with equivocation, the account of how they work cannot do full justice to either, an insight that we already find in Peter Abelard, if not in Boethius.
Aim: The climate and ecological crises are considered fundamental threats to human health. Healthcare workers in general and doctors in particular can contribute as change agents in mitigation and adaptation. Planetary health education (PHE) aims to harness this potential. This study explores perspectives among stakeholders involved in PHE at German medical schools on the characteristics of high-quality PHE and compares them to existing PHE frameworks.
Methods: In 2021, we conducted a qualitative interview study with stakeholders from German medical schools involved in PHE. Three different groups were eligible: faculty members, medical students actively involved in PHE, and study deans of medical schools. Recruitment was performed through national PHE networks and snowball sampling. Thematic qualitative text analysis according to Kuckartz was used for the analysis. Results were systematically compared to three existing PHE frameworks.
Results: A total of 20 participants (13 female) from 15 different medical schools were interviewed. Participants covered a wide range of professional backgrounds and experience in PHE education. The analysis revealed ten key themes: (1) Complexity and systems thinking, (2) inter- and transdisciplinarity, (3) ethical dimension, (4) responsibility of health professionals, (5) transformative competencies including practical skills, (6) space for reflection and resilience building, (7) special role of students, (8) need for curricular integration, (9) innovative and proven didactic methods, and (10) education as a driver of innovation. Six of our themes showed substantial overlap with existing PHE frameworks. Two of our themes were only mentioned in one of the frameworks, and two others were not explicitly mentioned. Few important elements of the frameworks did not emerge from our data.
Conclusions: In the light of increased attention regarding the connections of the climate and ecological crises and health, our results can be useful for anyone working toward the integration of planetary health into medical schools' and any health professions' curricula and should be considered when designing and implementing new educational activities.
Following the implementation of 2018’s laws on the rights of persons with disabilities (PWDs) in Egypt, students with disabilities (SWDs) have both legal and moral rights to meaningful learning opportunities and inclusive education. Despite that, SWDs still have very limited education resources which limit their career aspirations and quality of life. In this respect, education whether as part of formal education or lifelong learning is central to the museum’s mission. Museums, as part of non-formal education, are being acknowledged for their educative powers and investments in the development of quality formal, non-formal, and informal learning experiences. Further, phrases such as “inclusivity,” “accessibility,” and “diversity” were notably included in the newly approved museum definition by ICOM (2022) emphasizing museums’ obligations to embrace societal issues and shape a cultural attitude concerning disability rights, diversity, and equality together with overcoming exclusionary educational practices. The study seeks to investigate the existing resources and inclusive practices in Egyptian museums to achieve non-formal education for SWDs. Qualitative research approaches have been employed to answer a specific question: How can Egyptian museums work within their governing systems to support the learning of SWDs beyond their formal education system? The study aims to assess the potential of Egyptian museums in facilitating learning for SWDs. Further, it examines the capability of Egyptian museums in contributing to informal and non-formal learning for SWDs and striving for inclusive education inspired by the social model of disability that fosters inclusive educational programs and adopts a human rights-based approach. The results revealed that Egyptian museums contributed to the learning of SWDs, yet small-scale programs and individual efforts, but they are already engaged in active inclusive practices that address the learning of SWDs. The study suggests that they need to be acknowledged and supported by the government as state instruments and direct actors in advancing inclusive education and implementing appropriate pedagogies in favor of SWDs.
Alpine bumble bees are the most important pollinators in temperate mountain ecosystems. Although they are used to encounter small-scale successions of very different climates in the mountains, many species respond sensitively to climatic changes, reflected in spatial range shifts and declining populations worldwide. Cuticular hydrocarbons (CHCs) mediate climate adaptation in some insects. However, whether they predict the elevational niche of bumble bees or their responses to climatic changes remains poorly understood. Here, we used three different approaches to study the role of bumble bees’ CHCs in the context of climate adaptation: using a 1,300 m elevational gradient, we first investigated whether the overall composition of CHCs, and two potentially climate-associated chemical traits (proportion of saturated components, mean chain length) on the cuticle of six bumble bee species were linked to the species’ elevational niches. We then analyzed intraspecific variation in CHCs of Bombus pascuorum along the elevational gradient and tested whether these traits respond to temperature. Finally, we used a field translocation experiment to test whether CHCs of Bombus lucorum workers change, when translocated from the foothill of a cool and wet mountain region to (a) higher elevations, and (b) a warm and dry region. Overall, the six species showed distinctive, species-specific CHC profiles. We found inter- and intraspecific variation in the composition of CHCs and in chemical traits along the elevational gradient, but no link to the elevational distribution of species and individuals. According to our expectations, bumble bees translocated to a warm and dry region tended to express longer CHC chains than bumble bees translocated to cool and wet foothills, which could reflect an acclimatization to regional climate. However, chain lengths did not further decrease systematically along the elevational gradient, suggesting that other factors than temperature also shape chain lengths in CHC profiles. We conclude that in alpine bumble bees, CHC profiles and traits respond at best secondarily to the climate conditions tested in this study. While the functional role of species-specific CHC profiles in bumble bees remains elusive, limited plasticity in this trait could restrict species’ ability to adapt to climatic changes.
Xiphophorus fish exhibit a clear phenotypic polymorphism in puberty onset and reproductive strategies of males. In X. nigrensis and X. multilineatus, puberty onset is genetically determined and linked to a melanocortin 4 receptor (Mc4r) polymorphism of wild-type and mutant alleles on the sex chromosomes. We hypothesized that Mc4r mutant alleles act on wild-type alleles by a dominant negative effect through receptor dimerization, leading to differential intracellular signaling and effector gene activation. Depending on signaling strength, the onset of puberty either occurs early or is delayed. Here, we show by Förster Resonance Energy Transfer (FRET) that wild-type Xiphophorus Mc4r monomers can form homodimers, but also heterodimers with mutant receptors resulting in compromised signaling which explains the reduced Mc4r signaling in large males. Thus, hetero- vs. homo- dimerization seems to be the key molecular mechanism for the polymorphism in puberty onset and body size in male fish.
Introduction: Grasslands cover one third of the agricultural area in Germany and are mainly used for fodder production. However, grasslands fulfill many other ecosystem functions, like carbon storage, water filtration and the provision of habitats. In Germany, grasslands are mown and/or grazed multiple times during the year. The type and timing of management activities and the use intensity vary strongly, however co-determine grassland functions. Large-scale spatial information on grassland activities and use intensity in Germany is limited and not openly provided. In addition, the cause for patterns of varying mowing intensity are usually not known on a spatial scale as data on the incentives of farmers behind grassland management decisions is not available.
Methods: We applied an algorithm based on a thresholding approach utilizing Sentinel-2 time series to detect grassland mowing events to investigate mowing dynamics in Germany in 2018–2021. The detected mowing events were validated with an independent dataset based on the examination of public webcam images. We analyzed spatial and temporal patterns of the mowing dynamics and relationships to climatic, topographic, soil or socio-political conditions.
Results: We found that most intensively used grasslands can be found in southern/south-eastern Germany, followed by areas in northern Germany. This pattern stays the same among the investigated years, but we found variations on smaller scales. The mowing event detection shows higher accuracies in 2019 and 2020 (F1 = 0.64 and 0.63) compared to 2018 and 2021 (F1 = 0.52 and 0.50). We found a significant but weak (R2 of 0–0.13) relationship for a spatial correlation of mowing frequency and climate as well as topographic variables for the grassland areas in Germany. Further results indicate a clear value range of topographic and climatic conditions, characteristic for intensive grassland use. Extensive grassland use takes place everywhere in Germany and on the entire spectrum of topographic and climatic conditions in Germany. Natura 2000 grasslands are used less intensive but this pattern is not consistent among all sites.
Discussion: Our findings on mowing dynamics and relationships to abiotic and socio-political conditions in Germany reveal important aspects of grassland management, including incentives of farmers.
Background
Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking.
Methods
Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl.
Results
A total of 260 patients were enrolled (147 women (56.5%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0%) and PACS (21.9%) than in NFA (8.1%). Over time, 40/124 (32.3%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing’s syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9%; PACS, 24.0%; ACS, 39.0%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3% vs. 81.9% and 92.0%; p<0.05), diabetes (23.8% vs. 35.6% and 40.0%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95%-CI 0.89-13.29; ACS: HR 5.96, 95%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95%-CI 0.94-5.32; ACS: HR 2.60, 95%-CI 0.87-7.79; p=0.1). Twenty-five (12.6%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0% at diagnosis to 61.7% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group.
Conclusion
Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).
Providing adaptive, independence-preserving and theory-guided support to students in dealing with real-world problems in mathematics lessons is a major challenge for teachers in their professional practice. This paper examines this challenge in the context of simulations and mathematical modelling with digital tools: in addition to mathematical difficulties when autonomously working out individual solutions, students may also experience challenges when using digital tools. These challenges need to be closely examined and diagnosed, and might – if necessary – have to be overcome by intervention in such a way that the students can subsequently continue working independently. Thus, if a difficulty arises in the working process, two knowledge dimensions are necessary in order to provide adapted support to students. For teaching simulations and mathematical modelling with digital tools, more specifically, these knowledge dimensions are: pedagogical content knowledge about simulation and modelling processes supported by digital tools (this includes knowledge about phases and difficulties in the working process) and pedagogical content knowledge about interventions during the mentioned processes (focussing on characteristics of suitable interventions as well as their implementation and effects on the students’ working process). The two knowledge dimensions represent cognitive dispositions as the basis for the conceptualisation and operationalisation of a so-called adaptive intervention competence for teaching simulations and mathematical modelling with digital tools. In our article, we present a domain-specific process model and distinguish different types of teacher interventions. Then we describe the design and content of a university course at two German universities aiming to promote this domain-specific professional adaptive intervention competence, among others. In a study using a quasi-experimental pre-post design (N = 146), we confirm that the structure of cognitive dispositions of adaptive intervention competence for teaching simulations and mathematical modelling with digital tools can be described empirically by a two-dimensional model. In addition, the effectiveness of the course is examined and confirmed quantitatively. Finally, the results are discussed, especially against the background of the sample and the research design, and conclusions are derived for possibilities of promoting professional adaptive intervention competence in university courses.
Over the past years, scholars have explored eudaimonic video game experiences—profound entertainment responses that include meaningfulness, reflection, and others. In a comparatively short time, a plethora of explanations for the formation of such eudaimonic gaming experiences has been developed across multiple disciplines, making it difficult to keep track of the state of theory development. Hence, we present a theoretical overview of these explanations. We first provide a working definition of eudaimonic gaming experiences (i.e., experiences that reflect human virtues and encourage players to develop their potential as human beings fully) and outline four layers of video games—agency, narrative, sociality, and aesthetics—that form the basis for theorizing. Subsequently, we provide an overview of the theoretical approaches, categorizing them based on which of the four game layers their explanation mainly rests upon. Finally, we suggest the contingency of the different theoretical approaches for explaining eudaimonic experiences by describing how their usefulness varies as a function of interactivity. As different types of games offer players various levels of interactivity, our overview suggests which theories and which game layers should be considered when examining eudaimonic experiences for specific game types.
Fungal infections are a major global health burden where Candida albicans is among the most common fungal pathogen in humans and is a common cause of invasive candidiasis. Fungal phenotypes, such as those related to morphology, proliferation and virulence are mainly driven by gene expression, which is primarily regulated by kinase signaling cascades. Serine-arginine (SR) protein kinases are highly conserved among eukaryotes and are involved in major transcriptional processes in human and S. cerevisiae. Candida albicans harbors two SR protein kinases, while Sky2 is important for metabolic adaptation, Sky1 has similar functions as in S. cerevisiae. To investigate the role of these SR kinases for the regulation of transcriptional responses in C. albicans, we performed RNA sequencing of sky1Δ and sky2Δ and integrated a comprehensive phosphoproteome dataset of these mutants. Using a Systems Biology approach, we study transcriptional regulation in the context of kinase signaling networks. Transcriptomic enrichment analysis indicates that pathways involved in the regulation of gene expression are downregulated and mitochondrial processes are upregulated in sky1Δ. In sky2Δ, primarily metabolic processes are affected, especially for arginine, and we observed that arginine-induced hyphae formation is impaired in sky2Δ. In addition, our analysis identifies several transcription factors as potential drivers of the transcriptional response. Among these, a core set is shared between both kinase knockouts, but it appears to regulate different subsets of target genes. To elucidate these diverse regulatory patterns, we created network modules by integrating the data of site-specific protein phosphorylation and gene expression with kinase-substrate predictions and protein-protein interactions. These integrated signaling modules reveal shared parts but also highlight specific patterns characteristic for each kinase. Interestingly, the modules contain many proteins involved in fungal morphogenesis and stress response. Accordingly, experimental phenotyping shows a higher resistance to Hygromycin B for sky1Δ. Thus, our study demonstrates that a combination of computational approaches with integration of experimental data can offer a new systems biological perspective on the complex network of signaling and transcription. With that, the investigation of the interface between signaling and transcriptional regulation in C. albicans provides a deeper insight into how cellular mechanisms can shape the phenotype.
Stress experiences of healthcare assistants in family practice at the onset of the COVID-19 pandemic
(2023)
Background: At the beginning of the pandemic in 2020, healthcare assistants in general practices were confronted with numerous new challenges. The aim of the study was to investigate the stress factors of healthcare assistants in March/April 2020 as well as in the further course of the pandemic in 2020.
Methods: From August to December 2020, 6,300 randomly selected healthcare assistants in four German states were invited to participate in the study. We performed a mixed methods design using semi-structured telephone interviews and a cross-sectional survey with quantitative and open questions. The feeling of psychological burden was assessed on a 6-point likert-scale. We defined stress factors and categorized them in patient, non-patient and organizational stress factors. The results of the three data sets were compared within a triangulation protocol.
Results: One thousand two hundred seventy-four surveys were analyzed and 28 interviews with 34 healthcare assistants were conducted. Of the participants, 29.5% reported experiences of a very high or high feeling of psychological burden in March/April 2020. Worries about the patients’ health and an uncertainty around the new disease were among the patient-related stress factors. Non-patient-related stress factors were problems with the compatibility of work and family, and the fear of infecting relatives with COVID-19. Organizational efforts and dissatisfaction with governmental pandemic management were reported as organizational stress factors. Support from the employer and team cohesion were considered as important resources.
Discussion: It is necessary to reduce stress among healthcare assistants by improving their working conditions and to strengthen their resilience to ensure primary healthcare delivery in future health crises.
Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior.
Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts.
Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.”
Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept.
The execution of voluntary movements is primarily governed by the cerebral hemisphere contralateral to the moving limb. Previous research indicates that the ipsilateral motor network, comprising the primary motor cortex (M1), supplementary motor area (SMA), and premotor cortex (PM), plays a crucial role in the planning and execution of limb movements. However, the precise functions of this network and its interplay in different task contexts have yet to be fully understood. Twenty healthy right-handed participants (10 females, mean age 26.1 ± 4.6 years) underwent functional MRI scans while performing biceps brachii representations such as bilateral, unilateral flexion, and bilateral flexion-extension. Ipsilateral motor evoked potentials (iMEPs) were obtained from the identical set of participants in a prior study using transcranial magnetic stimulation (TMS) targeting M1 while employing the same motor tasks. The voxel time series was extracted based on the region of interest (M1, SMA, ventral PM and dorsal PM). Directed functinal connectivity was derived from the extracted time series using time-resolved partial directed coherence. We found increased connectivity from left-PMv to both sides M1, as well as right-PMv to both sides SMA, in unilateral flexion compared to bilateral flexion. Connectivity from left M1 to left-PMv, and left-SMA to right-PMd, also increased in both unilateral flexion and bilateral flexion-extension compared to bilateral flexion. However, connectivity between PMv and right-M1 to left-PMd decreased during bilateral flexion-extension compared to unilateral flexion. Additionally, during bilateral flexion-extension, the connectivity from right-M1 to right-SMA had a negative relationship with the area ratio of iMEP in the dominant side. Our results provide corroborating evidence for prior research suggesting that the ipsilateral motor network is implicated in the voluntary movements and underscores its involvement in cognitive processes such as movement planning and coordination. Moreover, ipsilateral connectivity from M1 to SMA on the dominant side can modulate the degree of ipsilateral M1 activation during bilateral antagonistic contraction.
The signals that coordinate and control movement in vertebrates are transmitted from motoneurons (MNs) to their target muscle cells at neuromuscular junctions (NMJs). Human NMJs display unique structural and physiological features, which make them vulnerable to pathological processes. NMJs are an early target in the pathology of motoneuron diseases (MND). Synaptic dysfunction and synapse elimination precede MN loss suggesting that the NMJ is the starting point of the pathophysiological cascade leading to MN death. Therefore, the study of human MNs in health and disease requires cell culture systems that enable the connection to their target muscle cells for NMJ formation. Here, we present a human neuromuscular co-culture system consisting of induced pluripotent stem cell (iPSC)-derived MNs and 3D skeletal muscle tissue derived from myoblasts. We used self-microfabricated silicone dishes combined with Velcro hooks to support the formation of 3D muscle tissue in a defined extracellular matrix, which enhances NMJ function and maturity. Using a combination of immunohistochemistry, calcium imaging, and pharmacological stimulations, we characterized and confirmed the function of the 3D muscle tissue and the 3D neuromuscular co-cultures. Finally, we applied this system as an in vitro model to study the pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and found a decrease in neuromuscular coupling and muscle contraction in co-cultures with MNs harboring ALS-linked SOD1 mutation. In summary, the human 3D neuromuscular cell culture system presented here recapitulates aspects of human physiology in a controlled in vitro setting and is suitable for modeling of MND.
Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97%) and could detect mutations in the majority (79%) of tested T-cell lymphoma samples.
Highlights
• The integrated stress response leads to a general ATF4-dependent activation of NRF2
• ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization
• An elevation of NRF2 transcript levels fosters this effect
• NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply
Summary
The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.
Salivary gland tumors (SGTs) are a relevant, highly diverse subgroup of head and neck tumors whose entity determination can be difficult. Confocal Raman imaging in combination with multivariate data analysis may possibly support their correct classification. For the analysis of the translational potential of Raman imaging in SGT determination, a multi-stage evaluation process is necessary. By measuring a sample set of Warthin tumor, pleomorphic adenoma and non-tumor salivary gland tissue, Raman data were obtained and a thorough Raman band analysis was performed. This evaluation revealed highly overlapping Raman patterns with only minor spectral differences. Consequently, a principal component analysis (PCA) was calculated and further combined with a discriminant analysis (DA) to enable the best possible distinction. The PCA-DA model was characterized by accuracy, sensitivity, selectivity and precision values above 90% and validated by predicting model-unknown Raman spectra, of which 93% were classified correctly. Thus, we state our PCA-DA to be suitable for parotid tumor and non-salivary salivary gland tissue discrimination and prediction. For evaluation of the translational potential, further validation steps are necessary.
During the COVID-19 pandemic, social distancing restricted psycho-oncological care. Therefore, this secondary analysis examines the changes in anxiety, fear of progression, fatigue, and depression in cancer patients after a video-based eHealth intervention. We used a prospective observational design with 155 cancer patients with mixed tumor entities. Data were assessed before and after the intervention and at a three-month follow-up using self-reported questionnaires (GAD-7, FOP-Q-SF, PHQ-8, and EORTC QLQ-FA12). The eight videos included psychoeducation, Acceptance and Commitment Therapy elements, and yoga and qigong exercises. The results showed that three months after finishing the video-based intervention, participants showed significantly reduced fear of progression (d = −0.23), depression (d = −0.27), and fatigue (d = −0.24) compared to the baseline. However, there was no change in anxiety (d = −0.09). Findings indicated marginal improvements in mental distress when using video-based intervention for cancer patients for up to three months, but long-term effectiveness must be confirmed using a controlled design.
During the COVID-19 pandemic, the novel coronavirus had an impact not only on public health but also on the mental health of the population. Public sentiment on mental health and depression is often captured only in small, survey-based studies, while work based on Twitter data often only looks at the period during the pandemic and does not make comparisons with the pre-pandemic situation. We collected tweets that included the hashtags #MentalHealth and #Depression from before and during the pandemic (8.5 months each). We used LDA (Latent Dirichlet Allocation) for topic modeling and LIWC, VADER, and NRC for sentiment analysis. We used three machine-learning classifiers to seek evidence regarding an automatically detectable change in tweets before vs. during the pandemic: (1) based on TF-IDF values, (2) based on the values from the sentiment libraries, (3) based on tweet content (deep-learning BERT classifier). Topic modeling revealed that Twitter users who explicitly used the hashtags #Depression and especially #MentalHealth did so to raise awareness. We observed an overall positive sentiment, and in tough times such as during the COVID-19 pandemic, tweets with #MentalHealth were often associated with gratitude. Among the three classification approaches, the BERT classifier showed the best performance, with an accuracy of 81% for #MentalHealth and 79% for #Depression. Although the data may have come from users familiar with mental health, these findings can help gauge public sentiment on the topic. The combination of (1) sentiment analysis, (2) topic modeling, and (3) tweet classification with machine learning proved useful in gaining comprehensive insight into public sentiment and could be applied to other data sources and topics.
This retrospective study aims to provide an intra-individual comparison of aortic CT angiographies (CTAs) using first-generation photon-counting-detector CT (PCD-CT) and third-generation energy-integrating-detector CT (EID-CT). High-pitch CTAs were performed with both scanners and equal contrast-agent protocols. EID-CT employed automatic tube voltage selection (90/100 kVp) with reference tube current of 434/350 mAs, whereas multi-energy PCD-CT scans were generated with fixed tube voltage (120 kVp), image quality level of 64, and reconstructed as 55 keV monoenergetic images. For image quality assessment, contrast-to-noise ratios (CNRs) were calculated, and subjective evaluation (overall quality, luminal contrast, vessel sharpness, blooming, and beam hardening) was performed independently by three radiologists. Fifty-seven patients (12 women, 45 men) were included with a median interval between examinations of 12.7 months (interquartile range 11.1 months). Using manufacturer-recommended scan protocols resulted in a substantially lower radiation dose in PCD-CT (size-specific dose estimate: 4.88 ± 0.48 versus 6.28 ± 0.50 mGy, p < 0.001), while CNR was approximately 50% higher (41.11 ± 8.68 versus 27.05 ± 6.73, p < 0.001). Overall image quality and luminal contrast were deemed superior in PCD-CT (p < 0.001). Notably, EID-CT allowed for comparable vessel sharpness (p = 0.439) and less pronounced blooming and beam hardening (p < 0.001). Inter-rater agreement was good to excellent (0.58–0.87). Concluding, aortic PCD-CTAs facilitate increased image quality with significantly lower radiation dose compared to EID-CTAs
Anxious depression represents a subtype of major depressive disorder and is associated with increased suicidality, severity, chronicity and lower treatment response. Only a few studies have investigated the differences between anxious depressed (aMDD) and non-anxious depressed (naMDD) patients regarding treatment dosage, serum-concentration and drug-specific treatment response. In our naturalistic and prospective study, we investigated whether the effectiveness of therapy including antidepressants (SSRI, SNRI, NaSSA, tricyclics and combinations) in aMDD patients differs significantly from that in naMDD patients. In a sample of 346 patients, we calculated the anxiety somatization factor (ASF) and defined treatment response as a reduction (≥50%) in the Hamilton Depression Rating Scale (HDRS)-21 score after 7 weeks of pharmacological treatment. We did not observe an association between therapy response and the baseline ASF-scores, or differences in therapy outcomes between aMDD and naMDD patients. However, non-responders had higher ASF-scores, and at week 7 aMDD patients displayed a worse therapy outcome than naMDD patients. In subgroup analyses for different antidepressant drugs, venlafaxine-treated aMDD patients showed a significantly worse outcome at week 7. Future prospective, randomized-controlled studies should address the question of a worse therapy outcome in aMDD patients for different psychopharmaceuticals individually.
Dimethyl fumarate attenuates lymphocyte infiltration and reduces infarct size in experimental stroke
(2023)
Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood–brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.
DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix into the active site pocket in the protein. Alkyltransferases then directly and irreversibly transfer the alkyl group from the base to the active site cysteine residue. In contrast, alkyltransferase-like proteins recruit nucleotide excision repair components for O\(^6\)-alkylguanine elimination. One or more of these proteins are found in all kingdoms of life, and where this has been determined, their overall DNA repair mechanism is strictly conserved between organisms. Nevertheless, between species, subtle as well as more extensive differences that affect target lesion preferences and/or introduce additional protein functions have evolved. Examining these differences and their functional consequences is intricately entwined with understanding the details of their DNA repair mechanism(s) and their biological roles. In this review, we will present and discuss various aspects of the current status of knowledge on this intriguing protein family.
Highlights
• Synthesis of a new tracer molecule.
• Robust and easy screening method for a broad range of compound activities.
• FP assay validation considering limited use of starting material, DMSO tolerance, variation in incubation time and temperature.
• Possibility of extension to HTP assay.
Abstract
The macrophage infectivity potentiator (Mip) protein belongs to the immunophilin superfamily. This class of enzymes catalyzes the interconversion between the cis and trans configuration of proline-containing peptide bonds. Mip has been shown to be important for the virulence of a wide range of pathogenic microorganisms, including the Gram-negative bacterium Burkholderia pseudomallei. Small molecules derived from the natural product rapamycin, lacking its immunosuppression-inducing moiety, inhibit Mip's peptidyl-prolyl cis-trans isomerase (PPIase) activity and lead to a reduction in pathogen load in vitro. Here, a fluorescence polarization assay (FPA) to enable the screening and effective development of BpMip inhibitors was established. A fluorescent probe was prepared, derived from previous pipecolic scaffold Mip inhibitors labeled with fluorescein. This probe showed moderate affinity for BpMip and enabled a highly robust FPA suitable for screening large compound libraries with medium- to high-throughput (Z factor ∼ 0.89) to identify potent new inhibitors. The FPA results are consistent with data from the protease-coupled PPIase assay. Analysis of the temperature dependence of the probe's binding highlighted that BpMip's ligand binding is driven by enthalpic rather than entropic effects. This has considerable consequences for the use of low-temperature kinetic assays.
We study the influence of nodal structures in two-dimensional quantum mechanical densities on wave packet entanglement. This is motivated by our recent study [Entropy, 25, 970 (2023)], which showed that the mutual information derived from the momentum-space probability density of a coupled two-particle system exhibits an unusual time dependence, which is not encountered if the position-space density is employed in the calculation. In studying a model density, here, we identify cases where the mutual information increases with the number of nodes in the wave function and approaches a finite value, whereas in this limit, the linear correlation vanishes. The results of the analytical model are then applied to interpret the correlation measures for coupled electron-nuclear dynamics, which are treated by numerically solving the time-dependent Schrödinger equation.
We demonstrate monolithic high contrast gratings (MHCG) based on GaSb/AlAs0.08Sb0.92 epitaxial structures with sub-wavelength gratings enabling high reflection of unpolarized mid-infrared radiation at the wavelength range from 2.5 to 5 µm. We study the reflectivity wavelength dependence of MHCGs with ridge widths ranging from 220 to 984 nm and fixed 2.6 µm grating period and demonstrate that peak reflectivity of above 0.7 can be shifted from 3.0 to 4.3 µm for ridge widths from 220 to 984 nm, respectively. Maximum reflectivity of up to 0.9 at 4 µm can be achieved. The experiments are in good agreement with numerical simulations, confirming high process flexibility in terms of peak reflectivity and wavelength selection. MHCGs have hitherto been regarded as mirrors enabling high reflection of selected light polarization. With this work, we show that thoughtfully designed MHCG yields high reflectivity for both orthogonal polarizations simultaneously. Our experiment demonstrates that MHCGs are promising candidates to replace conventional mirrors like distributed Bragg reflectors to realize resonator based optical and optoelectronic devices such as resonant cavity enhanced light emitting diodes and resonant cavity enhanced photodetectors in the mid-infrared spectral region, for which epitaxial growth of distributed Bragg reflectors is challenging.
The pathophysiology of tremor in Parkinson’s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um\(^2\), p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic–rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.
Small bacterial regulatory RNAs (sRNAs) have been implicated in the regulation of numerous metabolic pathways. In most of these studies, sRNA-dependent regulation of mRNAs or proteins of enzymes in metabolic pathways has been predicted to affect the metabolism of these bacteria. However, only in a very few cases has the role in metabolism been demonstrated. Here, we performed a combined transcriptome and metabolome analysis to define the regulon of the sibling sRNAs NgncR_162 and NgncR_163 (NgncR_162/163) and their impact on the metabolism of Neisseria gonorrhoeae. These sRNAs have been reported to control genes of the citric acid and methylcitric acid cycles by posttranscriptional negative regulation. By transcriptome analysis, we now expand the NgncR_162/163 regulon by several new members and provide evidence that the sibling sRNAs act as both negative and positive regulators of target gene expression. Newly identified NgncR_162/163 targets are mostly involved in transport processes, especially in the uptake of glycine, phenylalanine, and branched-chain amino acids. NgncR_162/163 also play key roles in the control of serine-glycine metabolism and, hence, probably affect biosyntheses of nucleotides, vitamins, and other amino acids via the supply of one-carbon (C\(_1\)) units. Indeed, these roles were confirmed by metabolomics and metabolic flux analysis, which revealed a bipartite metabolic network with glucose degradation for the supply of anabolic pathways and the usage of amino acids via the citric acid cycle for energy metabolism. Thus, by combined deep RNA sequencing (RNA-seq) and metabolomics, we significantly extended the regulon of NgncR_162/163 and demonstrated the role of NgncR_162/163 in the regulation of central metabolic pathways of the gonococcus.
Wind energy is a key option in global dialogues about climate change mitigation. Here, we combined observations from surface wind stations, reanalysis datasets, and state‐of‐the‐art regional climate models from the Coordinated Regional Climate Downscaling Experiment (CORDEX Africa) to study the current and future wind energy potential in Zambia. We found that winds are dominated by southeasterlies and are rarely strong with an average speed of 2.8 m·s\(^{−1}\). When we converted the observed surface wind speed to a turbine hub height of 100 m, we found a ~38% increase in mean wind speed for the period 1981–2000. Further, both simulated and observed wind speed data show statistically significant increments across much of the country. The only areas that divert from this upward trend of wind speeds are the low land terrains of the Eastern Province bordering Malawi. Examining projections of wind power density (WPD), we found that although wind speed is increasing, it is still generally too weak to support large‐scale wind power generation. We found a meagre projected annual average WPD of 46.6 W·m\(^{−2}\). The highest WPDs of ~80 W·m\(^{−2}\) are projected in the northern and central parts of the country while the lowest are to be expected along the Luangwa valley in agreement with wind speed simulations. On average, Zambia is expected to experience minor WPD increments of 0.004 W·m\(^{−2}\) per year from 2031 to 2050. We conclude that small‐scale wind turbines that accommodate cut‐in wind speeds of 3.8 m·s\(^{−1}\) are the most suitable for power generation in Zambia. Further, given the limitations of small wind turbines, they are best suited for rural and suburban areas of the country where obstructions are few, thus making them ideal for complementing the government of the Republic of Zambia's rural electrification efforts.
Polymeric Janus Fibers
(2023)
Janus fibers are a class of composite materials comprising mechanical and chemical to biological functionality. Combining different materials and functionalities in one micro- or even nanoscale fiber enables otherwise unreachable synergistic physicochemical effects with unprecedented opportunities for technical or biomedical applications. Here, recent developments of processing technologies and applications of polymeric Janus fibers will be reviewed. Various examples in the fields of textiles, catalysis, sensors as well as medical applications, like drug delivery systems, tissue engineering and antimicrobial materials, are presented to illuminate the outstanding potential of such high-end functional materials for novel applications in the upcoming future.
Given the growing interest of corporate stakeholders in Metaverse applications, there is a need to understand accessibility of these technologies for marginalized populations such as people living with dementia to ensure inclusive design of Metaverse applications. We assessed the accessibility of extended reality technology for people living with mild cognitive impairment and dementia to develop accessibility guidelines for these technologies. We used four strategies to synthesize evidence for barriers and facilitators of accessibility: (1) Findings from a non-systematic literature review, (2) guidelines from well-researched technology, (3) exploration of selected mixed reality technologies, and (4) observations from four sessions and video data of people living with dementia using mixed reality technologies. We utilized template analysis to develop codes and themes towards accessibility guidelines. Future work can validate our preliminary findings by applying them on video recordings or testing them in experiments.
The fast and accurate yield estimates with the increasing availability and variety of global satellite products and the rapid development of new algorithms remain a goal for precision agriculture and food security. However, the consistency and reliability of suitable methodologies that provide accurate crop yield outcomes still need to be explored. The study investigates the coupling of crop modeling and machine learning (ML) to improve the yield prediction of winter wheat (WW) and oil seed rape (OSR) and provides examples for the Free State of Bavaria (70,550 km2), Germany, in 2019. The main objectives are to find whether a coupling approach [Light Use Efficiency (LUE) + Random Forest (RF)] would result in better and more accurate yield predictions compared to results provided with other models not using the LUE. Four different RF models [RF1 (input: Normalized Difference Vegetation Index (NDVI)), RF2 (input: climate variables), RF3 (input: NDVI + climate variables), RF4 (input: LUE generated biomass + climate variables)], and one semi-empiric LUE model were designed with different input requirements to find the best predictors of crop monitoring. The results indicate that the individual use of the NDVI (in RF1) and the climate variables (in RF2) could not be the most accurate, reliable, and precise solution for crop monitoring; however, their combined use (in RF3) resulted in higher accuracies. Notably, the study suggested the coupling of the LUE model variables to the RF4 model can reduce the relative root mean square error (RRMSE) from −8% (WW) and −1.6% (OSR) and increase the R
2 by 14.3% (for both WW and OSR), compared to results just relying on LUE. Moreover, the research compares models yield outputs by inputting three different spatial inputs: Sentinel-2(S)-MOD13Q1 (10 m), Landsat (L)-MOD13Q1 (30 m), and MOD13Q1 (MODIS) (250 m). The S-MOD13Q1 data has relatively improved the performance of models with higher mean R
2 [0.80 (WW), 0.69 (OSR)], and lower RRMSE (%) (9.18, 10.21) compared to L-MOD13Q1 (30 m) and MOD13Q1 (250 m). Satellite-based crop biomass, solar radiation, and temperature are found to be the most influential variables in the yield prediction of both crops.
Atmospheric circulation is a key driver of climate variability, and the representation of atmospheric circulation modes in regional climate models (RCMs) can enhance the credibility of regional climate projections. This study examines the representation of large‐scale atmospheric circulation modes in Coupled Model Inter‐comparison Project phase 5 RCMs once driven by ERA‐Interim, and by two general circulation models (GCMs). The study region is Western Europe and the circulation modes are classified using the Promax rotated T‐mode principal component analysis. The results indicate that the RCMs can replicate the classified atmospheric modes as obtained from ERA5 reanalysis, though with biases dependent on the data providing the lateral boundary condition and the choice of RCM. When the boundary condition is provided by ERA‐Interim that is more consistent with observations, the simulated map types and the associating time series match well with their counterparts from ERA5. Further, on average, the multi‐model ensemble mean of the analysed RCMs, driven by ERA‐Interim, indicated a slight improvement in the representation of the modes obtained from ERA5. Conversely, when the RCMs are driven by the GCMs that are models without assimilation of observational data, the representation of the atmospheric modes, as obtained from ERA5, is relatively less accurate compared to when the RCMs are driven by ERA‐Interim. This suggests that the biases stem from the GCMs. On average, the representation of the modes was not improved in the multi‐model ensemble mean of the five analysed RCMs driven by either of the GCMs. However, when the best‐performed RCMs were selected on average the ensemble mean indicated a slight improvement. Moreover, the presence of the North Atlantic Oscillation (NAO) in the simulated modes depends also on the lateral boundary conditions. The relationship between the modes and the NAO was replicated only when the RCMs were driven by reanalysis. The results indicate that the forcing model is the main factor in reproducing the atmospheric circulation.
A series of novel imide‐functionalized C\(_{64}\) nanographenes is investigated as acceptor components in organic solar cells (OSCs) in combination with donor polymer PM6. These electron‐poor molecules either prevail as a monomer or self‐assemble into dimers in the OSC active layer depending on the chosen imide substituents. This allows for the controlled stacking of electron‐poor and electron‐rich π–scaffolds to establish a novel class of non‐fullerene acceptor materials to tailor the bulk‐heterojunction morphology of the OSCs. The best performance is observed for derivatives that are able to self‐assemble into dimers, reaching power conversion efficiencies of up to 7.1%.
Aim
Global warming is assumed to restructure mountain insect communities in space and time. Theory and observations along climate gradients predict that insect abundance and richness, especially of small‐bodied species, will increase with increasing temperature. However, the specific responses of single species to rising temperatures, such as spatial range shifts, also alter communities, calling for intensive monitoring of real‐world communities over time.
Location
German Alps and pre‐alpine forests in south‐east Germany.
Methods
We empirically examined the temporal and spatial change in wild bee communities and its drivers along two largely well‐protected elevational gradients (alpine grassland vs. pre‐alpine forest), each sampled twice within the last decade.
Results
We detected clear abundance‐based upward shifts in bee communities, particularly in cold‐adapted bumble bee species, demonstrating the speed with which mobile organisms can respond to climatic changes. Mean annual temperature was identified as the main driver of species richness in both regions. Accordingly, and in large overlap with expectations under climate warming, we detected an increase in bee richness and abundance, and an increase in small‐bodied species in low‐ and mid‐elevations along the grassland gradient. Community responses in the pre‐alpine forest gradient were only partly consistent with community responses in alpine grasslands.
Main Conclusion
In well‐protected temperate mountain regions, small‐bodied bees may initially profit from warming temperatures, by getting more abundant and diverse. Less severe warming, and differences in habitat openness along the forested gradient, however, might moderate species responses. Our study further highlights the utility of standardized abundance data for revealing rapid changes in bee communities over only one decade.
Among the parent borirane, benzoborirene and ortho‐dicarbadodecaborane‐fused borirane, the latter possesses the highest ring strain and the highest Lewis acidity according to our density functional theory (DFT) studies. The synthesis of this class of compounds is thus considerably challenging. The existing examples require either a strong π‐donating group or an extra ligand for B‐coordination, which nevertheless suppresses or completely turns off the Lewis acidity. The title compound, which possesses both features, not only allows the 1,2‐insertion of P=O, C=O or C≡N to proceed under milder conditions, but also enables the heretofore unknown dearomative 1,4‐insertion of Ar−(C=O)− into a B−C bond. The fusion of strained molecular systems to an o‐carborane cage shows great promise for boosting both the ring strain and acidity.
The Seville Strategy spurred a signifi cant paradigm shift in UNESCO’s MAB Programme, re-conceptualising the research programme as a modern tool for the dual mandate of nature conservation and sustainable development. However, many biosphere reserves failed to comply with the new regulations and in 2013 the ‘Exit Strategy’ was announced to improve the quality of the global network.
This study presents a global assessment of the implementation of the quality enhancement strategies, highlighting signifi cant differences worldwide through 20 country-specifi c case studies. It concludes that the strategies have been fundamental in improving the credibility and coherence of the MAB Programme. Challenges in the implementation were not unique to individual countries but were common to all Member States with pre-Seville sites, and in many states the process has led to a rejuvenation of national biosphere reserve networks.
Der Lebensmittelonlinehandel in Deutschland gewann, verstärkt durch die Covid-19-Pandemie, an Umsatzanteilen im Lebensmitteleinzelhandel. Hierdurch wurden neue Anforderungen an Arbeit und Beschäftigung in Deutschland geschaffen. Insbesondere in urbanen Räumen hat die Lebensmittelzustellung durch neu entstandene Betriebsformen zugenommen. So entstehen durch das Versprechen der Betriebe, Lebensmittel in kurzen Zeiträumen zu liefern, verschiedene Logistikstandorte und u.a. urbane Fahrradlieferdienste. Während Medien und Gewerkschaften bereits vor der Entstehung prekärer Arbeitsbedingungen warnen, sind die genauen Auswirkungen des Lebensmittelonlinehandels auf die Entwicklung neuer Arbeitsstandorte und die dort stattfindende Beschäftigung nur unzureichend bekannt. Diese Arbeit untersucht den Lebensmittelonlinehandel anhand seiner Betriebsformen, Standorte und Arbeitsprozesse sowie deren Auswirkungen auf Beschäftigte in Deutschland. Den konzeptionellen Hintergrund bilden Arbeiten der geographischen Handelsforschung sowie Debatten zu Arbeitsplatzqualität und Beschäftigung. Für die Analyse sind Primärdaten und Sekundärdaten erhoben worden. Es zeigt sich, dass teilweise komplexe Betriebsformen entstehen, bei denen sich die Arbeit und Arbeitsorte verändern. Zudem entstehen neue Herausforderungen für die Beschäftigten (u.a. physische und psychische Belastung), welche in dieser Arbeit identifiziert werden.
Durch die Einfügung des § 35a VwVfG ist das Verständnis bezüglich der Vollautomatisierung gewisser Prozesse nicht mehr gesetzesfremd. Die Schwierigkeit der Transformation rechtlicher Entscheidungsregime in ein vollautomatisiertes, algorithmisches Entscheidungssystem besteht in der notwendigen Abbildung der juristischen Sprache, der Logik und Schlussfolgerung. Das zugrundeliegende Entscheidungsregime des jeweiligen Sachrechts muss in eine formale Sprache übersetzt werden, die objektiv, abstrakt und eindeutig formuliert sein muss. Bei den notwendig zu formalisierenden Rechtsbegriffen der so geeigneten Entscheidungsregime hat sich eine Verengung der begrifflichen und inhaltlichen Voraussetzungen in einer Form vollzogen, die eine logische Durchdringung der Tatbestandsmerkmale mittels logikbasierter Repräsentationssprache ermöglichen und eine Überleitung in ein begriffliches Datenmodell lückenlos erfolgen kann. Die Auslegungsbedürftigkeit und Kontextvarianz als Struktur des Rechtssystems tritt in derartig gelagerten Fällen nahezu vollständig zurück, was zur Folge hat, dass das Risiko einer „fehlerhaften“ Entscheidung des Systems aufgrund einer nicht erwünschten Klassifizierung nicht vorliegt. Die Umsetzung dieser Entscheidungsstrukturen erfolgt durch regelbasierte Systeme. Diese sind starr und arbeiten in streng vorgegebenen Grenzen. Für die Automatisierung rechtlich relevanter Vorgänge ist deren Wert immens, da alleine regelbasierte Systeme in der Lage sind, vollautomatisiert Entscheidungen zu treffen und sich hierbei im Rahmen vertretbarer Risikoübernahmen des Staates bewegen. Durch die technische Möglichkeit des Einsatzes vollautomatisiert ablaufender, regelbasiert arbeitender Entscheidungssysteme ist nicht nur eine zu berücksichtigende Verfahrensgestaltungsalternative, sondern eine Verfahrensermessensreduktion auf Null in Hinblick auf formallogisch aufgebaute gesetzliche Konditionalprogramme entstanden. Dies resultiert aus dem Umstand, dass diese Verfahrensgestaltung rechtmäßiges Entscheiden geradezu perpetuiert und gleichsam sämtliche das Verfahrensermessen leitende Handlungsdirektiven weitaus optimaler zur Geltung zu bringen vermag als die analoge Bearbeitung durch Amtswaltende.
The phase space for the standard model of the basic four forces for n quanta includes all possible ensemble combinations of their quantum states m, a total of n**m states. Neighbor states reach according to transition possibilities (S-matrix) with emergent time from entropic ensemble gradients.
We replace the “big bang” by a condensation event (interacting qubits become decoherent) and inflation by a crystallization event – the crystal unit cell guarantees same symmetries everywhere. Interacting qubits solidify and form a rapidly growing domain where the n**m states become separated ensemble states, rising long-range forces stop ultimately further growth. After that very early events, standard cosmology with the hot fireball model takes over. Our theory agrees well with lack of inflation traces in cosmic background measurements, large-scale structure of voids and filaments, supercluster formation, galaxy formation, dominance of matter and life-friendliness.
We prove qubit interactions to be 1,2,4 or 8 dimensional (agrees with E8 symmetry of our universe). Repulsive forces at ultrashort distances result from quantization, long-range forces limit crystal growth. Crystals come and go in the qubit ocean. This selects for the ability to lay seeds for new crystals, for self-organization and life-friendliness.
We give energy estimates for free qubits vs bound qubits, misplacements in the qubit crystal and entropy increase during qubit decoherence / crystal formation. Scalar fields for color interaction and gravity derive from the permeating qubit-interaction field. Hence, vacuum energy gets low only inside the qubit crystal. Condensed mathematics may advantageously model free / bound qubits in phase space.
Mittels einer klinischen Studie wurden die Furchtgeneralisierung und Aufmerksamkeitslenkung von 44 gesunden Kindern und Jugendlichen im Alter von 9-17 Jahren untersucht. Eine Übergeneralisierung konditionierter Furcht sowie veränderte Aufmerksamkeitsprozesse werden in zahlreichen Arbeiten mit der Entstehung und Aufrechterhaltung von Angsterkrankungen in Verbindung gebracht. Der Hauptteil der Forschung beschränkte sich bislang auf die Untersuchung von erwachsenen Probanden. Da Angsterkrankungen jedoch häufig bereits im Kindes- und Jugendalter entstehen und sich in der Erforschung psychiatrischer Erkrankungen zunehmend eine dimensionale Betrachtungsweise durchsetzt, bestand das Ziel der Studie darin, etwaige Alterseffekte und den Einfluss der Ängstlichkeit auf die genannten Phänomene bei gesunden Probanden zu untersuchen. Darüber hinaus wurde ein potentiell präventiver Ansatz erforscht. Im Ergebnis zeigten sich in den Gruppenvergleichen keine relevanten Differenzen. Interessanterweise deutete sich in der Gruppe der älteren Probanden entgegen der Erwartung eine verstärkte Furchtgeneralisierung an, die womöglich mit einer veränderten Beziehung zu Furcht und Risiko in der Adoleszenz zusammenhängt. Aus den Befunden ergibt sich die Notwendigkeit weiterer, prospektiver Arbeiten, um unser Verständnis der Ätiologie von Angsterkrankungen zu verbessern. Weiterhin ist noch offen, inwiefern es sich bei der Übergeneralisierung und einer veränderten Aufmerksamkeitslenkung um Risikofaktoren für die Entwicklung von Angsterkrankungen oder vielmehr um Epiphänomene handelt, die erst mit Ausbruch der Erkrankung auftreten. Der Einsatz von Methoden der virtuellen Realität erscheint besonders geeignet, diese Prozesse zukünftig noch besser zu erforschen.
Studien weisen darauf hin, dass viele berufstätige Lehrkräfte, jedoch auch bereits ein gewisser Anteil der Lehramtsstudierenden, stimmliche Auffälligkeiten haben. Fachvertreter:innen stellen auf Basis dieser Erkenntnislage Forderungen nach stimmpräventiven Maßnahmen im Rahmen des Studiums. Solche Angebote sollen angehende Lehrkräfte auf die Stimmbelastung im Beruf vorbereiten und möglichen Beschwerden und Erkrankungen vorbeugen. Mit der Arbeit wird das Ziel verfolgt stimmpräventive Maßnahmen, die im Rahmen des Projekts STARKE-STIMME-macht-SCHULE am Lehrstuhl für Sprachheilpädagogik an der Universität Würzburg angeboten werden, einer wissenschaftlichen Evaluation zu unterziehen. Dazu wurden ehemalige Studierende des Lehramts Sprachheilpädagogik (N = 49) zu ihrem stimmlichen Befinden mittels Voice Handicap Index (VHI) befragt. Neben den Entwicklungen in dieser Gruppe selbst erfolgten Vergleiche mit Kontrollgruppen: Studierende anderer Fachrichtungen (N = 184) und sonderpädagogische Lehrkräfte ohne Prävention (N = 38). Dabei zeigt sich, dass die VHI-Werte der studentischen Interventionsgruppe und die der Interventionsgruppe Lehrkräfte keine bedeutsamen Unterschiede aufweisen. Vergleiche zwischen beiden Gruppen an Lehrkräften verdeutlichen zwar, dass vorhandene Stimmprobleme gleich häufig auftreten, jedoch ergibt die nähere Analyse Hinweise auf stärker empfundene Einschränkungen in der Kontrollgruppe, z. B. hinsichtlich zwei oder mehr wöchentlich empfundener Symptomen. Die Ergebnisse zeigen zudem auf, dass die Interventionsgruppe mehr Verhaltensweisen für die Gesunderhaltung der Stimme umsetzt im Vergleich zu den Lehrkräften, die keine Stimmprävention erfahren haben. Somit deuten Aspekte wie eine ausbleibende Verschlechterung der stimmlichen Verfassung mit Eintritt in die Berufstätigkeit, das regelmäßige Anwenden stimmpräventiver Maßnahmen und eine wirksame Früherkennung die Wirksamkeit der präventiven Maßnahmen im Rahmen des Projekts STARKE-STIMME-macht-SCHULE an.
The discovery, heterologous expression, and characterization of channelrhodopsin-2 (ChR2) – a light-sensitive cation channel found in the green alga Chlamydomonas reinhardtii – led to the success of optogenetics as a powerful technology, first in neuroscience. ChR2 was employed to induce action potentials by blue light in genetically modified nerve cells. In optogenetics, exogenous photoreceptors are expressed in cells to manipulate cellular activity. These photoreceptors were in the beginning mainly microbial opsins. During nearly two decades, many microbial opsins and their mutants were explored for their application in neuroscience. Until now, however, the application of optogenetics to plant studies is limited to very few reports. Several optogenetic strategies for plant research were demonstrated, in which most attempts are based on non-opsin optogenetic tools. Opsins need retinal (vitamin A) as a cofactor to generate the functional protein, the rhodopsin. As most animals have eyes that contain animal rhodopsins, they also have the enzyme - a 15, 15'-Dioxygenase - for retinal production from food-supplied provitamin A (beta-carotene). However, higher plants lack a similar enzyme, making it difficult to express functional rhodopsins successfully in plants. But plant chloroplasts contain plenty of beta-carotene. I introduced a gene, coding for a 15, 15'-Dioxygenase with a chloroplast target peptide, to tobacco plants. This enzyme converts a molecule of β-carotene into two of all-trans-retinal. After expressing this enzyme in plants, the concentration of all-trans-retinal was increased greatly. The increased retinal concentration led to increased expression of several microbial opsins, tested in model higher plants. Unfortunately, most opsins were observed intracellularly and not in the plasma membrane. To improve their localization in the plasma membrane, some reported signal peptides were fused to the N- or C-terminal end of opsins. Finally, I helped to identify three microbial opsins -- GtACR1 (a light-gated anion channel), ChR2 (a light-gated cation channel), PPR (a light-gated proton pump) which express and work well in the plasma membrane of plants. The transgene plants were grown under red light to prevent activation of the expressed opsins. Upon illumination with blue or green light, the activation of these opsins then induced the expected change of the membrane potential, dramatically changing the phenotype of plants with activated rhodopsins.
This study is the first which shows the potential of microbial opsins for optogenetic research in higher plants, using the ubq10 promoter for ubiquitous expression. I expect this to be just the beginning, as many different opsins and tissue-specific promoters for selective expression now can be tested for their usefulness. It is further to be expected that the here established method will help investigators to exploit more optogenetic tools and explore the secrets, kept in the plant kingdom.
In dieser Arbeit wurden Bewohner/-innen der Würzburger Gemeinschaftsunterkünfte für Geflüchtete auf das Vorliegen einer Schistosomiasis gescreent. Lag eine behandlungsdürftige Infektion vor, wurden die Teilnehmenden mit Praziquantel behandelt, um im nachfolgenden Verlauf freiwillig an der Erstellung einer Schistosomen-DNA-Kinetik mitzuwirken. Eine Besonderheit der Studie lag dabei in der fehlenden Möglichkeit einer Reinfektion, da sich die Betroffenen während des Follow-ups in einem Endemie-freien Gebiet aufhielten. Für das Screening kamen ein CCA-Urin-Schnelltest sowie ein ICT zum Einsatz. Die Diagnosesicherung wurde durch die Mikroskopie oder die qPCR angestrebt. Es zeigte sich, dass die Kombination von CCA-Test und ICT einen positiven prädiktiven Wert von 80 % für das tatsächliche Vorliegen einer Schistosomen-Infektion liefert. Die Schistosomiasis-Prävalenz der hier untersuchten, in einem Nicht-Endemiegebiet lebenden Risikopopulation, wurde auf 3,9 % bestimmt und ist im Vergleich zu bisherigen Veröffentlichungen als niedrig anzusehen. Dabei ist zu beachten, dass die Prävalenz zum Teil deutlich überschätzt werden kann, sofern der CCA-Urin-Schnelltest als alleiniges Diagnosekriterium eingesetzt wird (PrävalenzCCA = 27,6 %). Die Erstellung der DNA-Kinetik mittels qPCR zeigte, dass die Behandlung mit Praziquantel einen nach 3 Tagen messbaren, signifikanten (p < 0,05) Anstieg der DNA-Konzentration im Serum zur Folge hatte, welcher im weiteren Verlauf kontinuierlich abfiel. Im Mittel wurde nach 48 Tagen der Schwellenwert der DNA-Konzentration unterschritten, der ohne vorausgegangene Behandlung als positiv und therapiebedürftig gewertet worden wäre. Durch Inter- und Extrapolation der gewonnen Daten, konnte eine Funktion errechnet werden, die den zeitlichen Verlauf des Zerfalls der Schistosomen-DNA beschreibt und somit zur Ermittlung weiterer Therapie- und Kontrollmöglichkeit der Schistosomiasis beitragen kann.
Die Prävalenz von Infektionen mit Neisseria gonorrhoeae (NG) bei HIV-positiven Patientinnen und Patienten einer auf HIV-Infektionen spezialisierten Klinik in Mwanza im Nordwesten Tansani- as erwies sich mit 0,4% bei Männern und 3,9% bei Frauen als relativ niedrig. In dieser aktuellen Studie gab es unter Verwendung molekularer Antibiotikaresistenz(AMR)-Tests keine Hinweise auf eine Resistenz gegen Cephalosporine der dritten Generation. Weitere Kontrollen und Entwicklungen von NG- und AMR-Tests müssen implementiert werden. Molekulare Diagnoseverfahren auf der Basis von Urinproben als diagnostisches Material zum Nachweis von NG weisen wesentliche Vorteile für das Screening auf. Die Durchführung eines Urinstreifentests hatte keinen positiven Vorhersagewert bezüglich einer Infektion mit NG oder einer AMR. Künftige Untersuchungen sind anzuregen, um einerseits eine exaktere Angabe der Prävalenzraten und Risikofaktoren von Infektionen mit NG sowie deren Resistenzlage zu ermöglichen und andererseits eine effizientere Versorgung bzw. Behandlung der Gonorrhoe gewährleisten zu können.