Non-melanoma-skin cancer is an emerging clinical problem in the elderly, fair skinned population which predominantly affects patients aged older than 70 years. Its steady increase in incidence rates and morbidity is paralleled by related medical costs. Despite the fact that many elderly patients are in need of care and are living in nursing homes, specific data on the prevalence of skin cancer in home care and the institutional long-term care setting is currently lacking. A representative multicenter prevalence study was conducted in a random sample of ten institutional long-term care facilities in the federal state of Berlin, Germany. In total, n = 223 residents were included. Actinic keratoses, the precursor lesions of invasive cutaneous squamous cell carcinoma were the most common epithelial skin lesions (21.1%, 95% CI 16.2 to 26.9). Non-melanoma skin cancer was diagnosed in 16 residents (7.2%, 95% CI 4.5 to 11.3). None of the residents had a malignant melanoma. Only few bivariate associations were detected between non-melanoma skin cancer and demographic, biographic and functional characteristics. Male sex was significantly associated with actinic keratosis whereas female sex was associated with non-melanoma skin cancer. Smoking was associated with an increased occurrence of non-melanoma skin cancer. Regular dermatology check-ups in nursing homes would be needed but already now due to financial limitations, lack of time in daily clinical practice and limited number of practising dermatologists, it is not the current standard. With respect to the worldwide growing aging population new programs and decisions are required. Overall, primary health care professionals should play a more active role in early diagnosis of skin cancer in nursing home residents. Dermoscopy courses, web-based or smartphone-based applications and teledermatology may support health care professionals to provide elderly nursing home residents an early diagnosis of skin cancer.

Background: Body weight loss is a frequent complication after stroke, and its adverse effect on clinical outcome has been shown in several clinical trials. The purpose of this prospective longitudinal single-centre observational study was to investigate dynamical changes of body composition and body weight after ischemic stroke and an association with functional outcome. Methods: Sixty-seven consecutive patients (age 69 ± 11 years, body mass index 27.0 ± 4.1 kg/m2, 42% female patient, mean ± SD) with acute ischemic stroke with mild to moderate neurological deficit (National Institute of Health Stroke Scale median 4, ranged 0–12) were analysed in the acute phase (4 ± 2 days) and at 12 months (389 ± 26 days) follow-up. Body composition was examined by dual energy X-ray absorptiometry. Cachexia was defined according to the consensus definition by body weight loss ≥5% within 1 year and additional clinical signs. Lean tissue wasting was considered if a ratio of upper and lower limbs lean mass sum to squared height (kg/m2) was ≤5.45 kg/m2 for female patient and ≤7.25 kg/m2 for male patient. Results: According to the body weight changes after 12 months, 42 (63%) patients had weight gain or stable weight, 11 (16%) patients had moderate weight loss, and 14 (21%) patients became cachectic. A relative decline of 19% of fat tissue and 6.5% of lean tissue was observed in cachectic patients, while no changes of lean tissue were observed in non-cachectic patients after 12 months. The modified Rankin Scale was 48% higher (2.1 ± 1.6, P < 0.05), Barthel Index was 22% lower (71 ± 39, P < 0.01), and handgrip strength was 34% lower (21.9 ± 13.0, P < 0.05) in cachectic compared to non-cachectic patients after 12 months. The low physical performance if defined by Barthel Index <60 points was linked to the lean tissue wasting (OR 44.8, P < 0.01), presence of cachexia (OR 20.8, P < 0.01), and low body mass index <25 kg/m2 (OR 11.5, P < 0.05). After adjustment for cofounders, lean tissue wasting remained independently associated with the low physical performance at 12 months follow-up (OR 137.9, P < 0.05). Conclusions: In this cohort study, every fifth patient with ischemic stroke fulfilled the criteria of cachexia within 12 months after index event. The incidence of cachexia was 21%. Cachectic patients showed the lowest functional and physical capacity.

Introduction: The specific uptake size index (SUSI) of striatal FP-CIT uptake is independent of spatial resolution in the SPECT image, in contrast to the specific binding ratio (SBR). This suggests that the SUSI is particularly appropriate for multi-site/multi-camera settings in which camera-specific effects increase inter-subject variability of spatial resolution. However, the SUSI is sensitive to inter-subject variability of striatum size. Furthermore, it might be more sensitive to errors of the estimate of non-displaceable FP-CIT binding. This study compared SUSI and SBR in the multi-site/multi-camera (MULTI) setting of a prospective multi-center study and in a mono-site/mono-camera (MONO) setting representative of clinical routine. Methods: The MULTI setting included patients with Parkinson’s disease (PD, n = 438) and healthy controls (n = 207) from the Parkinson Progression Marker Initiative. The MONO setting included 122 patients from routine clinical patient care in whom FP-CIT SPECT had been performed with the same double-head SPECT system according to the same acquisition and reconstruction protocol. Patients were categorized as “neurodegenerative” (n = 84) or “non-neurodegenerative” (n = 38) based on follow-up data. FP-CIT SPECTs were stereotactically normalized to MNI space. SUSI and SBR were computed for caudate, putamen, and whole striatum using unilateral ROIs predefined in MNI space. SUSI analysis was repeated in native patient space in the MONO setting. The area (AUC) under the ROC curve for identification of PD/“neurodegenerative” cases was used as performance measure. Results: In both settings, the highest AUC was achieved by the putamen (minimum over both hemispheres), independent of the semi-quantitative method (SUSI or SBR). The putaminal SUSI provided slightly better performance with ROI analysis in MNI space compared to patient space (AUC = 0.969 vs. 0.961, p = 0.129). The SUSI (computed in MNI space) performed slightly better than the SBR in the MULTI setting (AUC = 0.993 vs. 0.991, p = 0. 207) and slightly worse in the MONO setting (AUC = 0.969 vs. AUC = 0.976, p = 0.259). There was a trend toward larger AUC difference between SUSI and SBR in the MULTI setting compared to the MONO setting (p = 0.073). Variability of voxel intensity in the reference region was larger in misclassified cases compared to correctly classified cases for both SUSI and SBR (MULTI setting: p = 0.007 and p = 0.012, respectively). Conclusions: The SUSI is particularly useful in MULTI settings. SPECT images should be stereotactically normalized prior to SUSI analysis. The putaminal SUSI provides better diagnostic performance than the SUSI of the whole striatum. Errors of the estimate of non-displaceable count density in the reference region can cause misclassification by both SUSI and SBR, particularly in borderline cases. These cases might be identified by visual checking FP-CIT uptake in the reference region for particularly high variability.

Differences in gene regulation have been suggested to play essential roles in the evolution of phenotypic changes. Although DNA changes in cis-regulatory elements affect only the regulation of its corresponding gene, variations in gene regulatory factors (trans) can have a broader effect, because the expression of many target genes might be affected. Aiming to better understand how natural selection may have shaped the diversity of gene regulatory factors in human, we assembled a catalog of all proteins involved in controlling gene expression. We found that at least five DNA-binding transcription factor classes are enriched among genes located in candidate regions for selection, suggesting that they might be relevant for understanding regulatory mechanisms involved in human local adaptation. The class of KRAB-ZNFs, zinc-finger (ZNF) genes with a Krüppel-associated box, stands out by first, having the most genes located on candidate regions for positive selection. Second, displaying most nonsynonymous single nucleotide polymorphisms (SNPs) with high genetic differentiation between populations within these regions. Third, having 27 KRAB-ZNF gene clusters with high extended haplotype homozygosity. Our further characterization of nonsynonymous SNPs in ZNF genes located within candidate regions for selection, suggests regulatory modifications that might influence the expression of target genes at population level. Our detailed investigation of three candidate regions revealed possible explanations for how SNPs may influence the prevalence of schizophrenia, eye development, and fertility in humans, among other phenotypes. The genetic variation we characterized here may be responsible for subtle to rough regulatory changes that could be important for understanding human adaptation.

Rising numbers of patients with cardiovascular diseases and limited availability of donor hearts require new and improved therapy strategies. Human atrial appendage-derived cells (hAACs) are promising candidates for an allogeneic cell-based treatment. In this study, we evaluated their inductive and modulatory capacity regarding immune responses and underlying key mechanisms in vitro. For this, cryopreserved hAACs were either cultured in the presence of interferon-gamma (IFNγ) or left unstimulated. The expression of characteristic mesenchymal stromal cell markers (CD29, CD44, CD73, CD105, CD166) was revealed by flow cytometry that also highlighted a predominant negativity for CD90. A low immunogeneic phenotype in an inflammatory milieu was shown by lacking expression of co-stimulatory molecules and upregulation of the inhibitory ligands PD-L1 and PD-L2, despite de novo expression of HLA-DR. Co-cultures of hAACs with allogeneic peripheral blood mononuclear cells, proved their low immunogeneic state by absence of induced T cell proliferation and activation. Additionally, elevated levels of IL-1β, IL-33, and IL-10 were detectable in those cell culture supernatants. Furthermore, the immunomodulatory potential of hAACs was assessed in co-cultures with αCD3/αCD28-activated peripheral blood mononuclear cells. Here, a strong inhibition of T cell proliferation and reduction of pro-inflammatory cytokines (IFNγ, TNFα, TNFβ, IL-17A, IL-2) were observable after pre-stimulation of hAACs with IFNγ. Transwell experiments confirmed that mostly soluble factors are responsible for these suppressive effects. We were able to identify indolamin-2,3-dioxygenase (IDO) as a potential key player through a genome-wide gene expression analysis and could demonstrate its involvement in the observed immunological responses. While the application of blocking antibodies against both PD-1 ligands did not affect the immunomodulation by hAACs, 1-methyl-L-tryptophan as specific inhibitor of IDO was able to restore proliferation and to lower apoptosis of T cells. In conclusion, hAACs represent a cardiac-derived mesenchymal stromal-like cell type with a high potential for the application in an allogeneic setting, since they do not trigger T cell responses and even increase their immunomodulatory potential in inflammatory environments.

Human cytomegalovirus (HCMV) induces a uniquely high frequency of virus-specific effector/memory CD8+ T-cells, a phenomenon termed “memory inflation”. Thus, HCMV-based vaccines are particularly interesting in order to stimulate a sustained and strong cellular immune response against cancer. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high lethality and inevitable relapse. The current standard treatment does not significantly improve the desperate situation underlining the urgent need to develop novel approaches. Although HCMV is highly fastidious with regard to species and cell type, GBM cell lines are susceptible to HCMV. In order to generate HCMV-based therapeutic vaccine candidates, we deleted all HCMV-encoded proteins (immunoevasins) that interfere with MHC class I presentation. The aim being to use the viral vector as an adjuvant for presentation of endogenous tumor antigens, the presentation of high levels of vector-encoded neoantigens and finally the repurposing of bystander HCMV-specific CD8+ T cells to fight the tumor. As neoantigen, we exemplarily used the E6 and E7 proteins of human papillomavirus type 16 (HPV-16) as a non-transforming fusion protein (E6/E7) that covers all relevant antigenic peptides. Surprisingly, GBM cells infected with E6/E7-expressing HCMV-vectors failed to stimulate E6-specific T cells despite high level expression of E6/E7 protein. Further experiments revealed that MHC class I presentation of E6/E7 is impaired by the HCMV-vector although it lacks all known immunoevasins. We also generated HCMV-based vectors that express E6-derived peptide fused to HCMV proteins. GBM cells infected with these vectors efficiently stimulated E6-specific T cells. Thus, fusion of antigenic sequences to HCMV proteins is required for efficient presentation via MHC class I molecules during infection. Taken together, these results provide the preclinical basis for development of HCMV-based vaccines and also reveal a novel HCMV-encoded block of MHC class I presentation.

As a part of a larger interdisciplinary project on Shakespeare sonnets’ reception (Jacobs et al., 2017; Xue et al., 2017), the present study analyzed the eye movement behavior of participants reading three of the 154 sonnets as a function of seven lexical features extracted via Quantitative Narrative Analysis (QNA). Using a machine learning- based predictive modeling approach five ‘surface’ features (word length, orthographic neighborhood density, word frequency, orthographic dissimilarity and sonority score) were detected as important predictors of total reading time and fixation probability in poetry reading. The fact that one phonological feature, i.e., sonority score, also played a role is in line with current theorizing on poetry reading. Our approach opens new ways for future eye movement research on reading poetic texts and other complex literary materials (cf. Jacobs, 2015c).

MutationDistiller is a freely available online tool for user-driven analyses of Whole Exome Sequencing data. It offers a user-friendly interface aimed at clinicians and researchers, who are not necessarily bioinformaticians. MutationDistiller combines Mutation- Taster’s pathogenicity predictions with a phenotypebased approach. Phenotypic information is not limited to symptoms included in the Human Phenotype Ontology (HPO), but may also comprise clinical diagnoses and the suspected mode of inheritance. The search can be restricted to lists of candidate genes (e.g. virtual gene panels) and by tissue-specific gene expression. The inclusion of GeneOntology (GO) and metabolic pathways facilitates the discovery of hitherto unknown disease genes. In a novel approach, we trained MutationDistiller’s HPO-based prioritization on authentic genotype–phenotype sets obtained from ClinVar and found it to match or outcompete current prioritization tools in terms of accuracy. In the output, the program provides a list of potential disease mutations ordered by the likelihood of the affected genes to cause the phenotype. MutationDistiller provides links to gene-related information from various resources. It has been extensively tested by clinicians and their suggestions have been valued in many iterative cycles of revisions. The tool, a comprehensive documentation and examples are freely available at https://www.mutationdistiller.org/

Deep neural networks have led to state-of-the-art results in many medical imaging tasks including Alzheimer’s disease (AD) detection based on structural magnetic resonance imaging (MRI) data. However, the network decisions are often perceived as being highly non-transparent, making it difficult to apply these algorithms in clinical routine. In this study, we propose using layer-wise relevance propagation (LRP) to visualize convolutional neural network decisions for AD based on MRI data. Similarly to other visualization methods, LRP produces a heatmap in the input space indicating the importance/relevance of each voxel contributing to the final classification outcome. In contrast to susceptibility maps produced by guided backpropagation (“Which change in voxels would change the outcome most?”), the LRP method is able to directly highlight positive contributions to the network classification in the input space. In particular, we show that (1) the LRP method is very specific for individuals (“Why does this person have AD?”) with high inter-patient variability, (2) there is very little relevance for AD in healthy controls and (3) areas that exhibit a lot of relevance correlate well with what is known from literature. To quantify the latter, we compute size-corrected metrics of the summed relevance per brain area, e.g., relevance density or relevance gain. Although these metrics produce very individual “fingerprints” of relevance patterns for AD patients, a lot of importance is put on areas in the temporal lobe including the hippocampus. After discussing several limitations such as sensitivity toward the underlying model and computation parameters, we conclude that LRP might have a high potential to assist clinicians in explaining neural network decisions for diagnosing AD (and potentially other diseases) based on structural MRI data.

The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating MC4R variants are the most frequent cause of monogenic obesity. In general, obesity is a growing problem on a global scale and is of social, medical, and economic relevance. A significant goal is to develop optimized pharmacological tools targeting MC4R without adverse effects. To date, this has not been achieved because of inter alia non-selective ligands across the five functionally different MCR subtypes (MC1-5R). This motivates further investigation of (i) the three-dimensional MC4R structure, (ii) binding mechanisms of various ligands, and (iii) the molecular transfer process of signal transduction, with the aim of understanding how structural features are linked with functional-physiological aspects. Unfortunately, experimentally elucidated structural information is not yet available for theMC receptors, a group of class A G-protein coupled receptors (GPCRs). We, therefore, generated MC4R homology models and complexes with interacting partners to describe approximate structural properties associated with signaling mechanisms. In addition, molecular insights from pathogenic mutations were incorporated to discriminate more precisely their individual malfunction of the signal transfer mechanism.

Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia.

Symptoms of schizophrenia (SCZ) are likely to be generated by genetically mediated synaptic dysfunction, which contribute to large-scale functional neural dysconnectivity. Recent electrophysiological studies suggest that this dysconnectivity is present not only at a spatial level but also at a temporal level, operationalized as long-range temporal correlations (LRTCs). Previous research suggests that alpha and beta frequency bands have weaker temporal stability in people with SCZ. This study sought to replicate these findings with high-density electroencephalography (EEG), enabling a spatially more accurate analysis of LRTC differences, and to test associations with characteristic SCZ symptoms and cognitive deficits. A 128-channel EEG was used to record eyes-open resting state brain activity of 23 people with SCZ and 24 matched healthy controls (HCs). LRTCs were derived for alpha (8–12 Hz) and beta (13–25 Hz) frequency bands. As an exploratory analysis, LRTC was source projected using sLoreta. People with SCZ showed an area of significantly reduced beta-band LRTC compared with HCs over bilateral posterior regions. There were no between-group differences in alpha-band activity. Individual symptoms of SCZ were not related to LRTC values nor were cognitive deficits. The study confirms that people with SCZ have reduced temporal stability in the beta frequency band. The absence of group differences in the alpha band may be attributed to the fact that people had, in contrast to previous studies, their eyes open in the current study. Taken together, our study confirms the utility of LRTC as a marker of network instability in people with SCZ and provides a novel empirical perspective for future examinations of network dysfunction salience in SCZ research.

The presence of snow and ice at midlatitudes of Mars cannot be explained by current climatic conditions, as surface ice is unstable. However, a large variety of debris‐covered glaciers have been observed at both midlatitudes. Here, we report the presence of local, small‐scale, and debris‐covered stagnant ice deposits on the floor of a valley system in Terra Cimmeria. These deposits, termed valley fill deposits (VFD), have a distribution that is restricted to the host valley floor and to the extent of the ejecta blanket associated with Tarq impact crater. The VFD are characterized by convex‐upward morphology, various crevasses, sublimation pits, an average area of a few square kilometers, and occasional ejecta streaks on their surface. Our model age estimation points to two possible time frames for the Tarq impact event; thus, we suggest two formation scenarios for VFD: (I) distribution of ice due to impact into shallow ice during the Middle Amazonian and (II) post‐impact deposition of VFD due to precipitation. In both scenarios, ice preservation is most likely due to a lag of dust and debris deposited in the valley's topographic lows. Scenario I is more consistent with our geomorphological observation of the VFD being overlain by ejecta streaks. Our results highlight the importance of local geological events and conditions in the distribution and preservation of buried ice deposits on Mars and suggest that more small‐scale and debris‐covered ice deposits may exist in the midlatitudes than previously thought. These deposits are of high importance for future human exploration missions to Mars.

Analysis of 984 induced microearthquakes from The Geysers geothermal reservoir in California reveals that the retrieved moment tensors depend on the frequency band of the inverted waveforms. The observed dependence is more significant for the percentages of the double‐couple, compensated linear vector dipole, and isotropic (ISO) components than for the focal mechanisms. The average root‐mean‐square of the moment tensors obtained in different frequency bands is correlated with spectra of ambient noise. The percentages of double‐couple and ISO components tend to decrease and increase with the upper cutoff frequency (fu), respectively. This suggests that shear rupture radiates energy preferentially in a lower frequency band and tensile rupture in a higher frequency band. Events displaying a strong increase of the ISO with fu are confined within the same depth interval as the injection points. This might be related to the strong thermoelastic effects in the vicinity of injection points that promote opening of small cracks adjacent to the main fractures.

An efficient water oxidation system is a prerequisite for developing solar energy conversion devices. Using advanced time-resolved spectroscopy, we study the initial catalytic relevant electron transfer events in the light-driven water oxidation system utilizing [Ru(bpy)3]2+ (bpy = 2,2′-bipyridine) as a light harvester, persulfate as a sacrificial electron acceptor, and a high-valent iron clathrochelate complex as a catalyst. Upon irradiation by visible light, the excited state of the ruthenium dye is quenched by persulfate to afford a [Ru(bpy)3]3+/SO4˙− pair, showing a cage escape yield up to 75%. This is followed by the subsequent fast hole transfer from [Ru(bpy)3]3+ to the FeIV catalyst to give the long-lived FeV intermediate in aqueous solution. In the presence of excess photosensitizer, this process exhibits pseudo-first order kinetics with respect to the catalyst with a rate constant of 3.2(1) × 1010 s−1. Consequently, efficient hole scavenging activity of the high-valent iron complex is proposed to explain its high catalytic performance for water oxidation.

Two computational studies provide different sentiment analyses for text segments (e.g., “fearful” passages) and figures (e.g., “Voldemort”) from the Harry Potter books (Rowling, 1997, 1998, 1999, 2000, 2003, 2005, 2007) based on a novel simple tool called SentiArt. The tool uses vector space models together with theory-guided, empirically validated label lists to compute the valence of each word in a text by locating its position in a 2d emotion potential space spanned by the words of the vector space model. After testing the tool's accuracy with empirical data from a neurocognitive poetics study, it was applied to compute emotional figure and personality profiles (inspired by the so-called “big five” personality theory) for main characters from the book series. The results of comparative analyses using different machine-learning classifiers (e.g., AdaBoost, Neural Net) show that SentiArt performs very well in predicting the emotion potential of text passages. It also produces plausible predictions regarding the emotional and personality profile of fiction characters which are correctly identified on the basis of eight character features, and it achieves a good cross-validation accuracy in classifying 100 figures into “good” vs. “bad” ones. The results are discussed with regard to potential applications of SentiArt in digital literary, applied reading and neurocognitive poetics studies such as the quantification of the hybrid hero potential of figures.

This study presents a comprehensive analysis of processes determining heat waves across different climates in Europe for the period 1979–2016. Heat waves are defined using a percentile‐based index and the main processes quantified along trajectories are adiabatic compression by subsidence and local and remote diabatic processes in the upper and lower troposphere. This Lagrangian analysis is complemented by an Eulerian calculation of horizontal temperature advection. During typical summers in Europe, one or two heat waves occur, with an average duration of five days. Whereas high near‐surface temperatures over Scandinavia are accompanied by omega‐like blocking structures at 500 hPa, heat waves over the Mediterranean are connected to comparably flat ridges. Tracing air masses backwards from the heat waves, we identify three trajectory clusters with coherent thermodynamic characteristics, vertical motions, and geographic origins. In all regions, horizontal temperature advection is almost negligible. In two of the three clusters, subsidence in the free atmosphere is very important in establishing high temperatures near the surface, while the air masses in the third cluster are warmed primarily due to diabatic heating near the surface. Large interregional differences occur between the British Isles and western Russia. Over the latter region, near‐surface transport and diabatic heating appear to be very important in determining the intensity of the heat waves, whereas subsidence and adiabatic warming are of first‐order importance for the British Isles. Although the large‐scale pattern is quasistationary during heat wave days, new air masses are entrained steadily into the lower troposphere during the life cycle of a heat wave. Overall, the results of the present study provide a guideline as to which processes and diagnostics weather and climate studies should focus on to understand the severity of heat waves.

Large bioacoustic archives of wild animals are an important source to identify reappearing communication patterns, which can then be related to recurring behavioral patterns to advance the current understanding of intra-specific communication of non-human animals. A main challenge remains that most large-scale bioacoustic archives contain only a small percentage of animal vocalizations and a large amount of environmental noise, which makes it extremely difficult to manually retrieve sufficient vocalizations for further analysis – particularly important for species with advanced social systems and complex vocalizations. In this study deep neural networks were trained on 11,509 killer whale (Orcinus orca) signals and 34,848 noise segments. The resulting toolkit ORCA-SPOT was tested on a large-scale bioacoustic repository – the Orchive – comprising roughly 19,000 hours of killer whale underwater recordings. An automated segmentation of the entire Orchive recordings (about 2.2 years) took approximately 8 days. It achieved a time-based precision or positive-predictive-value (PPV) of 93.2% and an area-under-the-curve (AUC) of 0.9523. This approach enables an automated annotation procedure of large bioacoustics databases to extract killer whale sounds, which are essential for subsequent identification of significant communication patterns. The code will be publicly available in October 2019 to support the application of deep learning to bioaoucstic research. ORCA-SPOT can be adapted to other animal species.

A sustainable economy fulfills societal needs in a fundamentally different way to the current economic system. Improvements to the efficiency of existing technologies or practices appear insufficient for achieving sustainable development within the planetary boundaries. Disruptive, systemic and transformational changes appear necessary in order to replace existing technologies and practices to establish a sustainable economy. Such innovations often start out in niches; however, the scaling up and the ultimate replacement of current socio-technical systems requires governance to allow for the coordination of actors, the reorganization of socio-technical systems and the mobilization and allocation of resources. As governmental institutions are part of the current (non-sustainable) systems and thereby fail to provide coherent, integrated and transformative governance, we explore whether institutional innovation from non-state actors can step in to provide governance of transformation processes. Based on explorative qualitative case studies of networks in the food sector, city planning and reporting tools, we analyze the potential of bottom-up institutional innovations to coordinate actors in transformation processes.

Staphylococcus aureus is a major human pathogen and has to cope with reactive oxygen and chlorine species (ROS, RCS) during infections. The low molecular weight thiol bacillithiol (BSH) is an important defense mechanism of S. aureus for detoxification of ROS and HOCl stress to maintain the reduced state of the cytoplasm. Under HOCl stress, BSH forms mixed disulfides with proteins, termed as S-bacillithiolations, which are reduced by bacilliredoxins (BrxA and BrxB). The NADPH-dependent flavin disulfide reductase YpdA is phylogenetically associated with the BSH synthesis and BrxA/B enzymes and was recently suggested to function as BSSB reductase (Mikheyeva et al., 2019). Here, we investigated the role of the complete bacilliredoxin BrxAB/BSH/YpdA pathway in S. aureus COL under oxidative stress and macrophage infection conditions in vivo and in biochemical assays in vitro. Using HPLC thiol metabolomics, a strongly enhanced BSSB level and a decreased BSH/BSSB ratio were measured in the S. aureus COL ypdA deletion mutant under control and NaOCl stress. Monitoring the oxidation degree (OxD) of the Brx-roGFP2 biosensor revealed that YpdA is required for regeneration of the reduced BSH redox potential (EBSH) upon recovery from oxidative stress. In addition, the ypdA mutant was impaired in H2O2 detoxification as measured with the novel H2O2-specific Tpx-roGFP2 biosensor. Phenotype analyses further showed that BrxA and YpdA are required for survival under NaOCl and H2O2 stress in vitro and inside murine J-774A.1 macrophages in infection assays in vivo. Finally, NADPH-coupled electron transfer assays provide evidence for the function of YpdA in BSSB reduction, which depends on the conserved Cys14 residue. YpdA acts together with BrxA and BSH in de-bacillithiolation of S-bacillithiolated GapDH. In conclusion, our results point to a major role of the BrxA/BSH/YpdA pathway in BSH redox homeostasis in S. aureus during recovery from oxidative stress and under infections.