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Insect pollinators provide crucial ecosystem services yet face increasing environmental pressures. The challenges posed by novel and reemerging pathogens on bee health means we need to improve our understanding of the immune system, an important barrier to infections and disease. Despite the importance of solitary bees, which are ecologically relevant, our understanding of the genomic basis and molecular mechanisms underlying their immune potential, and how intrinsic and extrinsic factors may influence it is limited. To improve our understanding of the genomic architecture underlying immunity of a key solitary bee pollinator, we characterized putative immune genes of the red mason bee, Osmia bicornis. In addition, we used publicly available RNA-seq datasets to determine how sexes differ in immune gene expression and splicing but also how pesticide exposure may affect immune gene expression in females. Through comparative genomics, we reveal an evolutionarily conserved set of more than 500 putative immune-related genes. We found genome-wide patterns of sex-biased gene expression, with greater enrichment of immune-related processes among genes with higher constitutive expression in males than females. Our results also suggest an up-regulation of immune-related genes in response to exposure to two common neonicotinoids, thiacloprid and imidacloprid. Collectively, our study provides important insights into the gene repertoire, regulation and expression differences in the sexes of O. bicornis, as well as providing additional support for how neonicotinoids can affect immune gene expression, which may affect the capacity of solitary bees to respond to pathogenic threats.

Diabetes, obesity and metabolism 23(12), 2814-2818 (2021). doi:10.1111/dom.14517, Published by Wiley-Blackwell, Oxford [u.a.]

Quantifying the morphology of organisms remains fundamental in ecology given the form-function relationship. Morphology is quantifiable in traits, landmarks, and outlines, and the choice of approach may influence ecological conclusions to an unknown extent. Here, we apply these three approaches to 111 individual coral reef fish of 40 species common in Micronesia. We investigate the major dimensions of morphological variability among individuals, families, and predefined feeding functional groups. We find that although the approaches are complementary, they coincide in capturing elongation as the main dimension of variability. Furthermore, the choice of approach led to different interpretations regarding the degree of morphological differentiation among taxonomic and feeding functional groups. We also use each morphology dataset to compute community-scale morphological diversity on Palauan reefs and investigate how the choice of dataset affects the detection of differences among sites and wave exposure levels. The exact ranking of sites from highest to lowest morphological diversity was sensitive to the approach used, but not the broad spatial pattern of morphological diversity. Conclusions regarding the effect of wave exposure on morphological diversity were robust to the approach used. Biodiversity hotspots (e.g., areas of exceptionally high diversity and/or endemism) are considered important conservation targets but their location may depend on the biodiversity metric used. In the same vein, our results caution against labelling particular sites as morphological diversity hotspots when metrics consider only a single aspect of morphology.

Cumulative human pressures and climate change can induce nonlinear discontinuous dynamics in ecosystems, known as regime shifts. Regime shifts typically imply hysteresis, a lacking or delayed system response when pressures are reverted, which can frustrate restoration efforts. Here, we investigate whether the northern Adriatic Sea fish and macroinvertebrate community, as depicted by commercial fishery landings, has undergone regime shifts over the last 40 years, and the reversibility of such changes. We use a stochastic cusp model to show that, under the interactive effect of fishing pressure and water warming, the community reorganized through discontinuous changes. We found that part of the community has now reached a new stable state, implying that a recovery towards previous baselines might be impossible. Interestingly, total landings remained constant across decades, masking the low resilience of the community. Our study reveals the importance of carefully assessing regime shifts and resilience in marine ecosystems under cumulative pressures and advocates for their inclusion into management.

After several reforms of the Common Agricultural Policy and gradual liberalisation, direct payments that serve to stabilise farm incomes remain highly pertinent for EU farmers in that they continue to contribute a high share of total farm income. This was also reflected in our survey of German farmers’ perspectives on direct payments, which showed the importance that these payments play in their financial situation. However, several economists have pointed to the lack of justification for poorly targeted direct payments in achieving societal goals, namely the delivery of valued public goods. In particular, the surveyed German farmers also recognised societal disapproval of the direct payment scheme. However, without direct payments, an accelerated structural change in German agriculture is very likely, leading to larger, less diversified farms and more intensive farming; which contrasts with the expectations of the German society for the agriculture sector. As German tax payers contribute substantially to financing the CAP, societal approval in terms of animal welfare and environmental services should receive greater priority in the direct payment scheme. The latter could be achieved by a well‐aimed targeting of direct payments, providing compensation for farmers producing agri‐environmental public goods and/or clearly contributing to improved animal welfare. Apres plusieurs reformes de la politique agricole commune et une liberalisation progressive, les paiements directs qui servent a stabiliser les revenus agricoles restent d'une grande pertinence pour les agriculteurs de l'Union europeenne dans la mesure ou ils continuent de representer une part importante du revenu agricole total. Notre enquete sur le point de vue des agriculteurs allemands en matiere de paiements directs en temoigne egalement, ce qui montre l'importance de ces paiements dans leur situation financiere. Plusieurs economistes ont toutefois souligne le defaut de justification pour des paiements directs mal cibles vers la realisation d'objectifs societaux, a savoir la fourniture de biens d'interet public apprecies. En particulier, les agriculteurs allemands interroges ont egalement reconnu que la societe desapprouve le systeme de paiements directs. Il reste qu'en l'absence de paiements directs, l'agriculture allemande ferait probablement l'objet d'un changement structurel accelere, conduisant a des exploitations plus grandes et moins diversifiees et a une agriculture plus intensive, ce qui contraste avec les attentes de la societe allemande pour le secteur agricole. Les contribuables allemands participant de maniere substantielle au financement de la PAC, le regime de paiements directs devrait accorder une plus grande priorite aux attentes de la societe en matiere de bien‐etre animal et de services environnementaux. Ce dernier objectif pourrait etre atteint par un ciblage plus precis des paiements directs, offrant une compensation aux agriculteurs produisant des biens d'interet public agro‐environnementaux et / ou contribuant clairement a l'amelioration du bien‐etre des animaux. Nach mehreren Reformen der Gemeinsamen Agrarpolitik (GAP) und der schrittweisen Liberalisierung bleiben Direktzahlungen, die der Stabilisierung der landwirtschaftlichen Einkommen dienen, fur EU‐Landwirte von groser Bedeutung, da sie weiterhin einen hohen Anteil am gesamten landwirtschaftlichen Einkommen ausmachen. Dies spiegelt sich auch in unserer Umfrage zu Direktzahlungen aus Sicht der Landwirte wider, die aufzeigt, wie wichtig diese Zahlungen fur ihre finanzielle Situation sind. Eine Reihe von Okonomen hat jedoch darauf hingewiesen, dass es keine Rechtfertigung fur Direktzahlungen gibt, sofern sie nicht auf die Erreichung gesellschaftlicher Ziele ausgerichtet sind. Diese Ziele beinhalten speziell die Bereitstellung von offentlichen Gutern. Die befragten deutschen Landwirte nahmen demgegenuber aber besonders auch die gesellschaftliche Ablehnung des Direktzahlungssystems wahr. Ohne Direktzahlungen ware jedoch ein beschleunigter Strukturwandel in der deutschen Landwirtschaft sehr wahrscheinlich. Dieser wurde zu groseren, weniger diversifizierten Betrieben und zu einer intensiveren Landwirtschaft fuhren, was im Gegensatz zu den gesellschaftlichen Erwartungen in Deutschland an den Agrarsektor steht. Da die deutschen Steuerzahler einen wesentlichen Beitrag zur Finanzierung der GAP leisten, sollten die gesellschaftlichen Erwartungen im Hinblick auf die Themen Tierschutz und okologische Dienstleistungen im Direktzahlungssystem einen hoheren Stellenwert erhalten. Letzteres konnte durch eine zielgerichtete Ausgestaltung der Direktzahlungen erreicht werden, die eine Entschadigung fur die Landwirte vorsieht, die entweder offentliche Agrarumweltguter bereitstellen und/oder einen deutlichen Beitrag zum verbesserten Tierschutz leisten.

For decades, intranuclear inclusions in many normal and neoplastic cells have been considered to be mere invaginations of cytoplasm into the nucleus without any notable function or influence on disease. We investigated such inclusions in 75 specimens of hepatocellular carcinoma (HCC). In this context we demonstrate that these inclusions are true inclusions, completely closed and delimited by the nuclear membrane, containing degenerate cell organelles and lysosomal proteins. Moreover, their occurrence was positively associated with patient survival but not with tumour grade or stage. In a standardised area a mean of 124 inclusions per specimen was present in the tumorous liver tissue in contrast to 5 inclusions in the non-tumorous adjacent section and 89% of all scrutinised HCC showed at least one membrane-bound nuclear inclusion. Ultrastructural characterisation by transmission electron microscopy revealed degenerative materials such as residues of lysosomes, endoplasmic reticulum and Golgi apparatus within the inclusions. Due to the fact that the content of the inclusions appears to be more condensed than cytoplasm and contains fewer intact cell organelles, we assume that they are not mere invaginations of cytoplasm. Three dimensional (3D) reconstruction of isolated and immunofluorescence stained nuclei showed that the inclusions are completely located within the nucleus without any connection to the cytoplasm. The limiting membrane of the inclusions contained lamin B suggesting nuclear membrane origin. The content of the inclusions stained for the autophagy-associated proteins p62, ubiquitin, LC3B, cathepsin B and cathepsin D. Triple immunofluorescence staining followed by 3D reconstruction revealed co-localisation of p62, ubiquitin and LC3B in the same inclusion. Our observations uncover that these inclusions are real inclusions completely surrounded by the nucleus. We propose that the presence of autophagy-associated proteins and proteases within the inclusions contribute to beneficial survival. OA Förderung 2019

Background Rising life expectancy in the western population is increasing the prevalence of heart valve diseases (HVD). Hypothesis The level of awareness and initial screening for HVD should be sufficient. The potential impact of HVD on the daily activities of the elderly population in Europe might affect our society. Methods and Results A survey was conducted, including a total of 12 832 people aged ≥ 60 years in 11 European countries. Of all the people surveyed, 5.6% could correctly describe aortic valve stenosis. Most participants (75.0%) claimed they regularly do activities like sports or social activities, 29.2% provide care for a family member, friend or acquaintance. The majority (69.2%) would be prevented from doing these activities by symptoms such as chest pain, fatigue or shortness of breath. Having chest pain (76.5%) and shortness of breath (57.8%) were reasons for most people to arrange an appointment with their GP, whereas only 26.2% would visit a GP for fatigue. 67.6% of respondents claimed to be checked with a stethoscope by their GP occasionally, never, or only when they ask. The preferred treatment option for HVD is a keyhole procedure (45.8%), whereas open heart surgery would only be preferred by 7.0%. Conclusion Knowledge about HVD is still low. Neither appointments with a GP driven by symptoms nor regular use of a stethoscope are a reliable guarantee for early diagnosis. With the over 60s in Europe playing an active role in social life, awareness campaigns and regular heart health checks may guarantee early diagnosis and treatment of HVD.

BACKGROUND: Compromised renal function is a major risk factor that is strongly associated with poor outcome in patients with mitral regurgitation (MR) and heart failure. Cystatin C, a cysteine protease inhibitor, has been used as a specific and sensitive biomarker of renal function. Neutrophil gelatinase‐associated lipocalin (NGAL) is another sensitive biomarker that specifically indicates functional and structural kidney damage. The aim of the present study was to determine the predictive value of serum cystatin C and urinary NGAL as indicators of mortality in patients undergoing percutaneous mitral valve repair (PMVR). METHODS: A total of 120 consecutive patients (age: 77.3 years [±11.2]) undergoing PMVR using the MitraClip system were included in this study. Venous blood and urinary samples were collected for biomarker analysis prior to PMVR. Physiological parameters, medication use, safety events, and all‐cause mortality were assessed 12 months after the procedure. RESULTS: Twelve months after PMVR, there was a significant reduction in the severity of MR (P < 0.001), and an improvement in the New York Heart Association class (P < 0.01) was documented. Baseline levels of serum cystatin C (nonsurvivors: 2.4 mg/L [interquartile, IQR: 1.7;3.1] vs survivors: 1.7 mg/L [IQR: 1,3;2.1], P < 0.001) and urinary NGAL (nonsurvivors: 242.0 ng/mL [IQR: 154.5;281.5] vs survivors: 132.0 ng/mL [IQR:107.0;177.3], P < 0.001) were significantly higher in patients who died during the 12‐month follow‐up period. CONCLUSION: Cystatin C and urinary NGAL were found to be predictors of long‐term mortality in high‐risk patients undergoing PMVR. Thus, cystatin C and NGAL assessment may be helpful in risk stratification in patients undergoing PMVR.

Aims To investigate the metabolic effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast, a clinically approved anti-inflammatory drug used for the treatment of chronic obstructive pulmonary disease. Materials and methods The metabolic effects of roflumilast were investigated in C57BL/6J mice, fed a high-fat Western-type diet and treated with or without roflumilast for a period of 12 weeks. Results Roflumilast led to a marked reduction in body weight gain, which became apparent in the second week after treatment initiation and was attributable to a pronounced increase in energy expenditure. Furthermore, roflumilast improved glucose tolerance, reduced insulin resistance and diminished steatohepatitis in mice. Mechanistically, this was associated with hepatic protein kinase A (PKA) and cAMP response element binding protein (CREB) activation, leading to peroxisome proliferator-activated receptor gamma coactivator-1α (PCG-1α)-dependent induction of mitochondrial biogenesis. Consistently, roflumilast increased the cellular respiratory capacity of hepatocytes in a PKA-dependent manner. Conclusion Roflumilast-dependent PDE4 inhibition is a new target for weight loss strategies, especially in conditions of associated comorbidities such as insulin resistance and non-alcoholic steatohepatitis.

Nitrobenzothiazinone gehoren zu den potentesten Antituberkulose-Wirkstoffen. Hier beschreiben wir eine In-vivo-Reduktion der beiden klinischen Kandidaten BTZ043 und PBTZ169, die zur Bildung von Meisenheimer-Komplexen fuhrt. Diese Reduktion ist reversibel, tritt in allen untersuchten Saugetierspezies auf und hat einen erheblichen Einfluss auf In-vivo-ADME-Charakteristiken und signifikante Auswirkungen auf das Design und die Durchfuhrung von klinischen Studien. Die Reduktion wurde durch chemische Untersuchungen verifiziert, die eine vollstandige Charakterisierung des Meisenheimer-Komplexes und dessen Folgechemie ermoglichten. Die Kombination von In-vivo-Studien mit chemischen Arbeiten, wie der LC-MS-basierten Charakterisierung und der Assay-Entwicklung, bildet die Grundlage fur eine rationale Leitstrukturoptimierung dieser vielversprechenden Klasse von Antituberkulose-Wirkstoffen.

Recently, glucagon-like peptide-1 (GLP-1) levels have been found to be increased in response to inflammatory stimuli, leading to insulin secretion and prevention of hyperglycaemia during endotoxemia in mice. In the present study, we assess the relevance of the other incretin hormone, glucose-dependent insulinotropic peptide (GIP), as a regulator of glucose metabolism under inflammatory conditions. We found that lipopolysaccharide (LPS) increased GIP secretion in a time- and dose-dependent manner in C57BL/6J mice. To elucidate the underlying mechanisms, mice were injected with inflammatory cytokines known to be released by LPS. Circulating GIP levels significantly increased in response to interleukin (IL)-1β but not IL-6 or tumour necrosis factor (TNF)-α administration. Using respective knockout mice we found that LPS-mediated GIP secretion was selectively dependent on IL-1 signalling. To evaluate the functional relevance of inflammatory GIP secretion we pretreated mice with the GIP-receptor antagonist (Pro3)GIP. This blunted LPS-induced TNF-α and IL-6 secretion but did not affect LPS-induced insulin secretion or blood glucose-lowering. In conclusion, GIP provides a novel link between the immune system and the gut, with proinflammatory-immune modulatory function but minor glucose regulatory relevance in the context of acute endotoxemia.

OBJECTIVES The purpose of the present study was to investigate whether transfemoral implantation of the balloon-expandable Edwards SAPIEN 3 device without prior balloon valvuloplasty is feasible. BACKGROUND Transcatheter aortic valve implantation (TAVI) without predilatation may be advantageous and is feasible with various transcatheter heart valves. METHODS A total of 163 consecutive patients with severe aortic stenosis undergoing transfemoral TAVI were enrolled at two sites. We assessed whether the crossing of the native aortic valve with the prosthesis without prior pre-dilation was feasible and evaluated for procedural success according to VARC-2 criteria. RESULTS Direct implantation without pre-dilatation was feasible in 154 patients (94.5%), whereas in nine patients predilatation was required due to difficulties while crossing the native aortic valve. Procedural success was achieved in 85.6%. A large proportion of the procedural failures was mainly driven by increased post-procedural gradients ≥20 mm Hg, which almost exclusively concerned the smaller prostheses sizes (23-mm 10/39 (25.6%) vs. 26-mm 5/72 (6.9%) vs. 29-mm 1/52 (1.9%); P