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Peronospora aquilegiicola is a destructive pathogen of columbines and has wiped out most Aquilegia cultivars in several private and public gardens throughout Britain. The pathogen, which is native to East Asia was noticed in England and Wales in 2013 and quickly spread through the country, probably by infested plants or seeds. To our knowledge, the pathogen has so far not been reported from other parts of Europe. Here, we report the emergence of the pathogen in the northwest of Germany, based on morphological and phylogenetic evidence. As the pathogen was found in a garden in which no new columbines had been planted recently, we assume that the pathogen has already spread from its original point of introduction in Germany. This calls for an increased attention to the further spread of the pathogen and the eradication of infection spots to avoid the spread to naturally occurring columbines in Germany and to prevent another downy mildew from becoming a global threat, like Peronospora belbahrii and Plasmopara destructor, the downy mildews of basil and balsamines, respectively.
Peronospora belbahrii is one of the most destructive downy mildew diseases that has emerged throughout the past two decades. Due to the lack of quarantine regulations and its possible seed-borne nature, it has spread globally and is now present in most areas in which basil is produced. While most obligate biotrophic, plant parasitic oomycetes are highly host-specific, there are a few that have a wider host range, e.g. Albugo candida, Bremia tulasnei, and Pseudoperonospora cubensis. Recently, it was shown that Peronospora belbahrii is able to infect Rosmarinus, Nepetia, and Micromeria in Israel in cross-infection trials, hinting an extended host range for also this pathogen. In this study, a newly occurring downy mildew pathogen on lavender was investigated with respect to its morphology and phylogeny, and it is shown that it belongs to Peronospora belbahrii as well. Thus, it seems that Peronospora belbahrii is currently extending its host range to additional members of the tribe Mentheae and Ocimeae. Therefore, it seems advisable to scrutinise all commonly used members of these tribes in order to avoid further spread of virulent genotypes.
Members of the ATP‐binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP‐binding cassette in the nucleotide‐binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs:
Die Hippocampusformation ist eine wichtige Hirnstruktur für die Gedächtnisakquisition und -konsolidierung, insbesondere beim räumlichen Lernen spielt sie eine essentielle Rolle. Langzeitpotenzierung (LTP) gilt als das elektrophysiologische Korrelat der synaptischen Plastizität, dem langfristigen Umbau synaptischer Verbindungen, der letztlich zur Ausbildung stabiler, langanhaltender Erinnerungen führt. Signalübertragung über den cAMP/PKA/MAPK/CREB-Weg stellt den wichtigsten molekularen Mechanismus der Langzeitpotenzierung dar, CREB gilt als die zentrale Komponente und Schnittstelle dieser Übertragung. Neuronale Plastizität ist abhängig von de-novo-Pro-teinbiosynthese, an deren Regulation Veränderungen der Chromatinstruktur durch Histonmodifikationen beteiligt ist, in die der genannte Signalweg mündet.
Circadiane Rhythmen sind in den meisten Spezies in vielen verschiedenen Organen und Geweben nachgewiesen und manifestieren sich als Einflüsse auf zahlreiche Parameter des Verhaltens, so auch auf die Leistung beim Erlernen neuer Information. Ihr zentraler Taktgeber ist der Nucleus suprachiasmaticus (SCN). Melatonin ist ein wichtiges Effektorsignal des circadianen Systems und hat gleichzeitig Rückkopplungsfunktion. Seine unmittelbare Wirkung übt es über die beiden G-Protein-gekoppelten Melatonin-rezeptoren MT1 und MT2 aus. Es hat direkten Einfluss auf das Lernen und stellt damit einen Schnittpunkt zwischen Signalwegen der synaptischen Plastizität und des circadianen Systems dar.
Der Lernerfolg vieler Tierarten ist bekanntermaßen während deren subjektivem Tag höher als während der Nacht. In dieser Arbeit konnte gezeigt werden, dass beim räumlichen Lernen bereits ein einmaliger Stimulus ausreicht, um im Hippocampus der verwendeten C3H-Mäuse eine stabile Induktion der Phosphorylierung von CREB sowie der transkriptionsaktivierenden Histonmodifikationen H3K9ac und H3K14ac zu erzeugen. Ein einmaliger Stimulus hat also verstärkte Signaltransduktion und Protein-syntheseaktivität als Zeichen synaptischer Plastizität zur Folge. Dies geschieht nur tagsüber, nachts zeigt sich kein Effekt. Somit spiegelt sich der Phänotyp in diesen molekularen Markern wider. Anhand eines Mausmodells mit genetischem Knockout der beiden membrangebundenen Melatoninrezeptoren MT1 und MT2 (MT1/2−/−) wurde der Einfluss von Melatonin auf die molekularen Prozesse des hippocampalen Lernens näher beleuchtet. Über MT1/2−/−-Mäuse ist bekannt, dass ihr Lernerfolg in den benutzten Verhaltensversuchen zu jeder Tageszeit auf dem Niveau der C3H-Mäuse während der Nacht liegt. Zunächst zeigt sich, dass in MT1/2−/−-Mäusen die Grundrhythmen der meisten untersuchten Proteine und Histonmodifikationen verändert, teilweise phasenverschoben und abgeflacht sind. Eine Induktion von pCREB und H3K9ac und H3K14ac ist in diesen Tieren nicht mehr erreichbar und somit nach einem einmaligen Lernstimulus keine vermehrte Signalübertragung oder synaptischer Umbau nachweisbar. Auch hier besteht eine gute Korrelation mit dem Lernphänotyp. Weiterhin wurden Unterschiede im Aktivitätsmuster der beiden Mäusestämme gezeigt, MT1/2−/−-Mäuse sind abhängig von der Situation weniger oder gleich aktiv wie C3H-Tiere. Im Angstverhalten als möglichem Störfaktor besteht kein Unterschied zwischen beiden Tierstämmen.
Melatoninrezeptoren wirken über inhibitorische G-Proteine auf die Adenylatcyclase und hemmen den cAMP/CREB-Signalübertragung, was die schlechtere Lernperformance während der Nacht erklärt, wenn der Melatoninspiegel seinen natürlichen Höhepunkt erreicht. Durch Melatonin lassen sich auch tagsüber bei Mäusen und Zebrafischen LTP und räumliches Lernen unterdrücken. Jedoch lässt sich durch diese akute Wirkung von Melatonin nur ein Teil der Ergebnisse erklären, so zum Beispiel die veränderte Aktivität von PKA und PKC. Um das scheinbar paradoxe verschlechterte Lernverhalten der MT1/2−/−-Mäuse und die fehlende Induzierbarkeit von pCREB und Chromatinremodelling zu erklären, muss ein längerfristiger Effekt von Melatonin bestehen, der über dessen maximale Konzentration hinaus anhält und in seiner Abwesenheit zu verbesserter Signalübertragung führt. Hierfür ist eine Sensibilisierung der Adenylatcyclase durch prolongierte Melatoninexposition, wie sie beispielsweise in Zellen der Pars tuberalis nachgewiesen wurde, beschrieben worden. Es konnte in dieser Arbeit gezeigt werden, dass Melatonin vielfältigen Einfluss auf das hippocampale Lernen hat und dieses mit der inneren Uhr verbindet.
This study deals with 3D laser investigation on the border between the human lymph node T-zone and germinal centre. Only a few T-cells specific for antigen selected B-cells are allowed to enter germinal centres. This selection process is guided by sinus structures, chemokine gradients and inherent motility of the lymphoid cells. We measured gaps and wall-like structures manually, using IMARIS, a 3D image software for analysis and interpretation of microscopy datasets. In this paper, we describe alpha-actin positive and semipermeable walls and wall-like structures that may hinder T-cells and other cell types from entering germinal centres. Some clearly defined holes or gaps probably regulate lymphoid traffic between T- and B-cell areas. In lymphadenitis, the morphology of this border structure is clearly defined. However, in case of malignant lymphoma, the wall-like structure is disrupted. This has been demonstrated exemplarily in case of angioimmunoblastic T-cell lymphoma. We revealed significant differences of lengths of the wall-like structures in angioimmunoblastic T-cell lymphoma in comparison with wall-like structures in reactive tissue slices. The alterations of morphological structures lead to abnormal and less controlled T- and B-cell distributions probably preventing the immune defence against tumour cells and infectious agents by dysregulating immune homeostasis.
Die Coronakrise und die Eindämmungspolitik der Nationalstaaten hat gravierende wirtschaftliche Folgen. Nicht alle EU-Mitgliedsstaaten sind in gleicher Weise gewappnet und manche werden derzeit heftiger von der Coronakrise getroffen als andere. Eine Möglichkeit, europäische Solidarität zu organisieren, ist die Ausgabe von Gemeinschaftsanleihen, so genannter Corona-Bonds. Dieser Beitrag diskutiert das Für und Wider der Corona-Bonds und ihrer Alternativen: Weder Gemeinschaftsanleihen noch eine Ausweitung des EZB-Engagements sollten das Mittel der Wahl sein. Wir plädieren vielmehr für direkte, auf europäischer Ebene koordinierte Transferzahlungen an bedürftige Mitgliedsstaaten.
The B-cell receptor (BCR) signaling pathway is a crucial pathway of B cells, both for their survival and for antigen-mediated activation, proliferation and differentiation. Its activation is also critical for the genesis of many lymphoma types. BCR-mediated lymphoma proliferation may be caused by activating BCR-pathway mutations and/or by active or tonic stimulation of the BCR. BCRs of lymphomas have frequently been described as polyreactive. In this review, the role of specific target antigens of the BCRs of lymphomas is highlighted. These antigens have been found to be restricted to specific lymphoma entities. The antigens can be of infectious origin, such as H. pylori in gastric MALT lymphoma or RpoC of M. catarrhalis in nodular lymphocyte predominant Hodgkin lymphoma, or they are autoantigens. Examples of such autoantigens are the BCR itself in chronic lymphocytic leukemia, LRPAP1 in mantle cell lymphoma, hyper-N-glycosylated SAMD14/neurabin-I in primary central nervous system lymphoma, hypo-phosphorylated ARS2 in diffuse large B-cell lymphoma, and hyper-phosphorylated SLP2, sumoylated HSP90 or saposin C in plasma cell dyscrasia. Notably, atypical posttranslational modifications are often responsible for the immunogenicity of many autoantigens. Possible therapeutic approaches evolving from these specific antigens are discussed.
DnaK3, a highly conserved cyanobacterial chaperone of the Hsp70 family, binds to cyanobacterial thylakoid membranes, and an involvement of DnaK3 in the biogenesis of thylakoid membranes has been suggested. As shown here, light triggers synthesis of DnaK3 in the cyanobacterium Synechocystis sp. PCC 6803, which links DnaK3 to the biogenesis of thylakoid membranes and to photosynthetic processes. In a DnaK3 depleted strain, the photosystem content is reduced and the photosystem II activity is impaired, whereas photosystem I is regular active. An impact of DnaK3 on the activity of other thylakoid membrane complexes involved in electron transfer is indicated. In conclusion, DnaK3 is a versatile chaperone required for biogenesis and/or maintenance of thylakoid membrane-localized protein complexes involved in electron transfer reactions. As mentioned above, Hsp70 proteins are involved in photoprotection and repair of PS II in chloroplasts.
Nonribosomal peptides produced by minimal and engineered synthetases with terminal reductase domains
(2020)
Nonribosomal peptide synthetases (NRPSs) use terminal reductase domains for 2‐electron reduction of the enzyme‐bound thioester releasing the generated peptides as C‐terminal aldehydes. Herein, we reveal the biosynthesis of a pyrazine that originates from an aldehyde‐generating minimal NRPS termed ATRed in entomopathogenic Xenorhabdus indica. Reductase domains were also investigated in terms of NRPS engineering and, although no general applicable approach was deduced, we show that they can indeed be used for the production of similar natural and unnatural pyrazinones.
Mitochondria have a central role in regulating a range of cellular activities and host responses upon bacterial infection. Multiple pathogens affect mitochondria dynamics and functions to influence their intracellular survival or evade host immunity. On the other side, major host responses elicited against infections are directly dependent on mitochondrial functions, thus placing mitochondria centrally in maintaining homeostasis upon infection. In this review, we summarize how different bacteria and viruses impact morphological and functional changes in host mitochondria and how this manipulation can influence microbial pathogenesis as well as the host cell metabolism and immune responses.
A new pseudopolymorph of perchlorinated neopentasilane: the benzene monosolvate Si(SiCl3)4·C6H6
(2020)
A new pseudopolymorph of dodecachloropentasilane, namely a benzene monosolvate, Si5Cl12·C6H6, is described. There are two half molecules of each kind in the asymmetric unit. Both Si5Cl12 molecules are completed by crystallographic twofold symmetry. One of the benzene molecules is located on a twofold rotation axis with two C—H groups located on this rotation axis. The second benzene molecule has all atoms on a general position: it is disordered over two equally occupied orientations. No directional interactions beyond normal van der Waals contacts occur in the crystal.
The one-dimensionality of econometric data: the Frankfurt School and the critique of quantification
(2020)
Econometric data are used to produce authoritative facts about the world. Yet, as numbers enjoy a central place in modern reasoning (particularly in government as their presumed objectivity and neutrality assist impartial decision-making), it is important that they receive scrutiny. Using methodological techniques from Western Marxism, with special reference to the work of Lukács, Horkheimer and Adorno, and Marcuse to inform a critique of Acemoglu and Robinson, I argue that the historical emergence of econometrics as a mode of mediated knowledge is a reified practice within the broader technical administration of social life, a practice that is not a transparent representation of social phenomena. This is because when econometrics transforms the thing being measured into a statistical indicator it eclipses political disputes with technical disputes, sidestepping good faith democratic deliberation about what goods are worth pursuing. Effectively, one-dimensional thought cannot perceive the origins of items put into circulation and so ideology is produced – what seems value-free is value-laden.
Trypanosoma cruzi, the causative agent of Chagas disease, colonizes the gut of triatomine insects, including Rhodnius prolixus. It is believed that this colonization upsets the microbiota that are normally present, presumably switching the environment to one more favorable for parasite survival. It was previously thought that one particular bacterium, Rhodococcus rhodnii, was essential for insect survival due to its ability to produce vital B-complex vitamins. However, these bacteria are not always identified in great abundance in studies on R. prolixus microbiota. Here we sequenced the microbiota of the insect anterior midgut using shotgun metagenomic sequencing in order to obtain a high-resolution snapshot of the microbes inside at two different time points and under two conditions; in the presence or absence of parasite and immediately following infection, or three days post-infection. We identify a total of 217 metagenomic bins, and recovered one metagenome-assembled genome, which we placed in the genus Dickeya. We show that, despite Rhodococcus being present, it is not the only microbe capable of synthesizing B-complex vitamins, with the genes required for biosynthesis present in a number of different microbes. This work helps to gain a new insight into the microbial ecology of R. prolixus.
Die vorliegende Arbeit zielt auch darauf ab, aus der Analyse des Konzepts der Mimesis eine Reihe von theoretischen Kanten zu gewinnen, die als normative oder transformierende Gesichtspunkte betrachtet werden können. Das heißt, Standpunkte, auf die die Theorien der Gegenwart noch zurückgreifen können, nicht nur um eine diagnostische Analyse des sozialen Ganzen vorzunehmen, sondern auch um Vorschläge zur Veränderung des sozialen Charakters zu unterbreiten. Diese Möglichkeit kann noch als normativer Ansatz in Adornos Werk bezeichnet werden. Solche theoretischen Perspektiven sind notwendige Folgen der Analyse des Begriffs der Mimesis.
Introduction: Haemophilia (HA) and rheumatoid arthritis (RA) patients may develop joint damage caused by recurrent joint bleedings in HA or by chronic inflammation in RA. Only few data exist for biomarker studies in these patients.
Aim: The objective of the present study is to assess a large array of biomarkers in peripheral blood samples obtained from HA patients without or with arthropathy and to compare pattern to RA patients and healthy controls.
Methods: A panel of biomarkers was assessed in 129 men (40 HA patients without arthropathy, 23 HA patients with arthropathy, 23 RA patients and 43 control subjects). 37 different biomarkers (cytokines, angiogenesis‐related proteins) were analysed using a multiple analyte profiling technology and supplemented by acute phase proteins, coagulation and immunological parameters.
Results: Evidence for systemic inflammation was obtained by increased acute phase reactants in all patient groups. 13 or 14 from 42 soluble parameters demonstrated significant differences (p < .05) between HA patients without arthropathy and healthy controls, or between HA patients with arthropathy and healthy controls, respectively. Largely overlapping patterns were obtained except for interleukin‐7 being increased in HA patients without arthropathy and being decreased in HA in the presence of arthropathy.
Conclusions: In addition to data supporting systemic inflammation, we provide evidence for a common biomarker profile in HA patients and RA patients compared to healthy controls. A distinctive biomarker profile for HA patients with arthropathy did not appear except for interleukin‐7 demonstrating specific changes depending on the absence or presence of arthropathy in HA patients.
Goals and pathways to achieve sustainable urban development have multiple interlinkages with human health and wellbeing. However, these interlinkages have not been examined in depth in recent discussions on urban sustainability and global urban science. This paper fills that gap by elaborating in detail the multiple links between urban sustainability and human health and by mapping research gaps at the interface of health and urban sustainability sciences. As researchers from a broad range of disciplines, we aimed to: 1) define the process of urbanization, highlighting distinctions from related concepts to support improved conceptual rigour in health research; 2) review the evidence linking health with urbanization, urbanicity, and cities and identify cross-cutting issues; and 3) highlight new research approaches needed to study complex urban systems and their links with health. This novel, comprehensive knowledge synthesis addresses issue of interest across multiple disciplines. Our review of concepts of urban development should be of particular value to researchers and practitioners in the health sciences, while our review of the links between urban environments and health should be of particular interest to those outside of public health. We identify specific actions to promote health through sustainable urban development that leaves no one behind, including: integrated planning; evidence-informed policy-making; and monitoring the implementation of policies. We also highlight the critical role of effective governance and equity-driven planning in progress towards sustainable, healthy, and just urban development.
Déterminants de l’utilisation de Acacia auriculiformis comme bois d’œuvre en Afrique de l’Ouest
(2020)
Acacia auriculiformis, un bois énergie, suscite de plus en plus des intérêts de bois d’œuvre au niveau des industriels de bois au Bénin. L’appréciation des performances de l’espèce dans les usines et en plantation est déterminante pour la vul- garisation de l’espèce comme alternative pour mitiger la déforestation en lien avec la demande en bois d’œuvre. L’objectif principal de ce travail est donc d’évaluer les conditions entourant l’adoption de Acacia auriculiformis comme espèce de bois d’œuvre au Bénin, Afrique de l’Ouest. Au total, 154 usines de bois et 25 plantations ont été enquêtées dans les zones abritant les plantations à A. auriculiformis. A. auriculiformis est l’espèce la plus fréquente dans les usines de bois (81%) suivie de Afzelia africana (55%), Tectona grandis (47%) et Khaya senegalensis (47%). Les superficies des plantations à A. auriculi- formis ont augmenté entre 1999 et 2019. Les connaissances sur l’utilisation de ce bois sont variables dans la zone d’étude. Le bois de A. auriculiformis est apprécié comme bois d’œuvre parce qu’il présente une couleur esthétique, un séchage rapide, une facilité de mise en œuvre, une imprégnabilité élevée, une densité moyenne à élevée et un bel aspect après mise en œuvre. Cependant, son bois fournit beaucoup de sciure, a beaucoup de nœuds et présente une déformabilité moyenne. Sa disponibili- té et son accessibilité sont les principaux facteurs justifiant la préférence de l’espèce par les industriels de bois d’œuvre. Cette forme d’utilisation de l’espèce est également remarquée au Togo, en Côte d’Ivoire. L’espèce présente une bonne perspective d’utilisation comme bois d’œuvre.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread from symptomatic patients with COVID-19, but also from asymptomatic individuals. Therefore, robust surveillance and timely interventions are essential for the control of virus spread within the community. In this regard the frequency of testing and speed of reporting, but not the test sensitivity alone, play a crucial role. In order to reduce the costs and meet the expanding demands in real-time RT-PCR (rRT-PCR) testing for SARS-CoV-2, complementary assays, such as rapid antigen tests, have been developed. Rigorous analysis under varying conditions is required to assess the clinical performance of these tests and to ensure reproducible results. We evaluated the sensitivity and specificity of a recently licensed rapid antigen test using 137 clinical samples in two institutions. Test sensitivity was between 88.2-89.6% when applied to samples with viral loads typically seen in infectious patients. Of 32 rRT-PCR positive samples, 19 demonstrated infectivity in cell culture, and 84% of these samples were reactive with the antigen test. Seven full-genome sequenced SARS-CoV-2 isolates and SARS-CoV-1 were detected with this antigen test, with no cross-reactivity against other common respiratory viruses. Numerous antigen tests are available for SARS-CoV-2 testing and their performance to detect infectious individuals may vary. Head-to-head comparison along with cell culture testing for infectivity may prove useful to identify better performing antigen tests. The antigen test analyzed in this study is easy-to-use, inexpensive, and scalable. It can be helpful in monitoring infection trends and thus has potential to reduce transmission.
The novel coronavirus SARS-CoV-2 is the causative agent of the acute respiratory disease COVID-19, which has become a global concern due to its rapid spread. Meanwhile, increased demand for testing has led to a shortage of reagents and supplies and compromised the performance of diagnostic laboratories in many countries. Both the World Health Organization (WHO) and the Center for Disease Control and Prevention (CDC) recommend multi-step RT-PCR assays using multiple primer and probe pairs, which might complicate the interpretation of the test results, especially for borderline cases. In this study, we describe an alternative RT-PCR approach for the detection of SARS-CoV-2 RNA that can be used for the probe-based detection of clinical isolates in diagnostics as well as in research labs using a low-cost SYBR green method. For the evaluation, we used samples from patients with confirmed SARS-CoV-2 infections and performed RT-PCR assays along with successive dilutions of RNA standards to determine the limit of detection. We identified an M-gene binding primer and probe pair highly suitable for the quantitative detection of SARS-CoV-2 RNA for diagnostic and research purposes.
We aim to understand whether Greek and Italian, two null subject languages, differ in the use and interpretation of null subjects, based on evidence from both a production and a comprehension experiment. The results of the two experiments show that the two languages differ in the extent to which they comply with the Position of Antecedent Strategy as formulated by Carminati (2002). In order to account for this difference, we introduce a principle which defines prominence of sentence constituents in terms of hierarchical height, elaborating on a recent proposal by Rizzi (2018). Then we show that the prominence of subject and object constituents in Greek and Italian reflects word-order differences between the two languages (Roussou & Tsimpli 2006). In more general terms, this paper argues in favour of a multi-factorial approach to reference interpretation, in that syntactic factors interact with discourse factors, leading to a gradient variety of reference possibilities.
Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.
We calculate the Masur–Veech volume of the gothic locus G in the stratum H(23) of genus 4. Our method is based on the use of the formulae for the Euler characteristics of gothic Teichmu ̈ller curves to determine the number of lattice points of given area. We also use this method to recal- culate the Masur–Veech volumes of the Prym loci P3 ⊂ H(4) and P4 ⊂ H(6) in genus 3 and 4.
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.
The tetraaryl μ‐hydridodiborane(4) anion [2H]− possesses nucleophilic B−B and B−H bonds. Treatment of K[2H] with the electrophilic 9‐H‐9‐borafluorene (HBFlu) furnishes the B3 cluster K[3], with a triangular boron core linked through two BHB two‐electron, three‐center bonds and one electron‐precise B−B bond, reminiscent of the prominent [B3H8]− anion. Upon heating or prolonged stirring at room temperature, K[3] rearranges to a slightly more stable isomer K[3 a]. The reaction of M[2H] (M+=Li+, K+) with MeI or Me3SiCl leads to equimolar amounts of 9‐R‐9‐borafluorene and HBFlu (R=Me or Me3Si). Thus, [2H]− behaves as a masked [:BFlu]− nucleophile. The HBFlu by‐product was used in situ to establish a tandem substitution‐hydroboration reaction: a 1:1 mixture of M[2H] and allyl bromide gave the 1,3‐propylene‐linked ditopic 9‐borafluorene 5 as sole product. M[2H] also participates in unprecedented [4+1] cycloadditions with dienes to furnish dialkyl diaryl spiroborates, M[R2BFlu].
Eine Studie, die der Politikwissenschaftler Prof. Richard Traunmüller (Universität Mannheim) zusammen mit seinem Kollegen Dr. Matthias Revers (University of Leeds) kürzlich veröffentlicht hat, hat bundesweit für Aufsehen und auch für zahlreiche Gegenstimmen gesorgt. Im Fokus der Studie stehen Soziologie-Studierende der Goethe-Universität, weshalb die Befunde zur Redeund Meinungsfreiheit in Frankfurt besonders die Gemüter bewegt haben. Der UniReport konnte Prof. Traunmüller, der einige Jahre an der Goethe-Universität geforscht und gelehrt hat, und seinen früheren Kollegen, den Soziologen Prof. Thomas Scheffer, zu einem Streitgespräch zusammenbringen.
Acute clinical deterioration of a patient with chronic liver disease remains a decisive time point both in terms of medical management and prognosis. This condition, also known as acute decompensation (AD), is an important event determining a crossroad in the trajectory of patients. A significant number of patients with AD may develop hepatic or extrahepatic organ failure, or both, which defines the syndrome acute-on-chronic liver failure (ACLF), and ACLF is associated with a high morbidity and short-term mortality. ACLF may occur at any phase during chronic liver disease and is pathogenetically defined by systemic inflammation and immune metabolic dysfunction. When organ failures develop in the presence of cirrhosis, especially extrahepatic organ failures, liver transplantation (LT) may be the only curative treatment. This review outlines the evidence supporting LT in ACLF patients, highlighting the role of timing, bridging to LT, and possible indicators of futility. Importantly, prospective studies on ACLF and transplantation are urgently needed.
Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.
Beyond their role in pathogen recognition and the initiation of immune defense, Toll-like receptors (TLRs) are known to be involved in various vascular processes in health and disease. We investigated the potential of the lipopeptide and TLR2/6 ligand macrophage activating protein of 2-kDA (MALP-2) to promote blood flow recovery in mice. Hypercholesterolemic apolipoprotein E (Apoe)-deficient mice were subjected to microsurgical ligation of the femoral artery. MALP-2 significantly improved blood flow recovery at early time points (three and seven days), as assessed by repeated laser speckle imaging, and increased the growth of pre-existing collateral arteries in the upper hind limb, along with intimal endothelial cell proliferation in the collateral wall and pericollateral macrophage accumulation. In addition, MALP-2 increased capillary density in the lower hind limb. MALP-2 enhanced endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) release from endothelial cells and improved the experimental vasorelaxation of mesenteric arteries ex vivo. In vitro, MALP-2 led to the up-regulated expression of major endothelial adhesion molecules as well as their leukocyte integrin receptors and consequently enhanced the endothelial adhesion of leukocytes. Using the experimental approach of femoral artery ligation (FAL), we achieved promising results with MALP-2 to promote peripheral blood flow recovery by collateral artery growth.
Cabozantinib (Cabometyx®) is a potent multikinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor 2, the mesenchymal-epithelial transition factor (MET) receptor, and the “anexelekto” (AXL) receptor tyrosine kinase. It is approved for the treatment of advanced hepatocellular carcinoma (HCC) after failure of sorafenib in Europe (since November 2018) and in the USA (since January 2019). The approval of cabozantinib was based on results of the randomized, placebo-controlled, phase 3 CELESTIAL trial in patients with unresectable HCC, who received one or two prior lines of treatment including sorafenib. At the second planned interim analysis, the trial was stopped, because the primary end point overall survival was clearly in favor for cabozantinib. Additionally, median progression-free survival was superior to placebo. The most common ≥ grade 3 relevant adverse events in patients with HCC treated with cabozantinib were palmar–plantar erythrodysesthesia, hypertension, fatigue, and diarrhea. In this review, current data on cabozantinib for the treatment of patients with advanced HCC, with a focus on the management of common adverse events and ongoing clinical trials, are discussed.
The post-transcriptional modification of the canonical nucleoside uridine into its rotational isomer pseudouridine occurs in non-coding as well as coding RNA and is the most abundant post-transcriptional modification in all kingdoms of life. While the occurrence of pseudouridine has been linked to the enhancement of stability and the codon-anticodon interaction in tRNAs, enhancement of the translation efficiency in rRNAs, regulatory functions in spliceosomal snRNA and nonsense codon suppression in mRNA, its exact role in many RNAs is still ambiguous. The uridine to pseudouridine isomerization can either be catalyzed by one of various standalone pseudouridylases or it can be performed in an RNA-guided manner by H/ACA ribonucleoproteins. In eukaryotes, the guide RNA always adapts a conserved bipartite, double-hairpin conformation. Each hairpin contains an internal RNA-loop motif, which can recruit a specific substrate RNA via base pairing. The catalytically active RNP is formed by the interactions of the guide RNA with four proteins. While Cbf5 forms the catalytically active center, Nop10 and Nhp2 perform auxiliary functions and Gar1 is involved in substrate turnover. Up until now, most structural knowledge about H/ACA RNPs has been derived from archaeal complexes, while the exact structure-function-relationships between RNA and proteins in eukaryotic RNPs is still ambiguous. While archaeal H/ACA RNPs share many similarities with eukaryotic RNPs and act as good model system, there are also many differences between them like eukaryotic specific protein domains as well as the overall bipartite complex structure, dictated by the snoRNA. Investigating pseudouridylation by eukaryotic H/ACA RNPs opens up a broad area of research and helps to gain a better understanding of this enzyme class – especially since malfunction of H/ACA RNPs has been linked to the genetic disease Dyskeratosis congenita as well as several types of cancer.
The main goal of this thesis was to gain new insights into the RNA/protein interactions in the eukaryotic snR81 H/ACA snoRNP from Saccharomyces cerevisiae on a structural as well as dynamical level. In the first part of this thesis, the main goal was to in vitro prepare a functionally active snR81 H/ACA RNP. The guiding snoRNA was prepared by in vitro transcription and purification, while the Saccharomyces cerevisiae proteins were recombinantly expressed from Escherichia coli. Apart from the full length, bipartite snR81 snoRNP, several sub-complexes of the RNP were reconstituted. Therefore, snoRNA constructs were designed and prepared, which only contained a single hairpin motif of the complex. Furthermore, snoRNA constructs in which the apical hairpin stem was replaced by a stable tetraloop were prepared, to investigate the influence of the apical stem on protein binding and activity. Also, for the eukaryotic proteins, a shortened version of Gar1 (Gar1Δ) was utilized, which lacks the eukaryotic specific RGG domains, that have been characterized as accessory RNA binding motifs. Reconstituted snoRNPs were utilized in catalytic activity assays, monitoring the turnover rate of uridine to pseudouridine. For this purpose, radioactively labeled substrate RNAs were prepared by phosphorylation and splinted ligation of oligonucleotides and were objected to reconstituted H/ACA RNPs under single as well as multiple turnover conditions. In the second part of this thesis, the RNA/protein interactions were dissected via single molecule FRET spectroscopy. Therefore, the snoRNA was labeled with an acceptor fluorophore via NHS ester/amine-reaction. Furthermore, the snoRNA contained a biotin-handle, allowing immobilization of the complex during the experimental time-window of the spectroscopic analysis. Eukaryotic specific protein Nhp2 was labeled with a donor fluorophore via “click” chemistry, which included the chemical synthesis and incorporation by genetic code expansion of non-canonical amino acids. The interactions of Nhp2 with the different snoRNA constructs (standalone-hairpins “H5” and “H3”, as well as hairpins lacking the apical binding motif “H5Δ” and “H3Δ”) were monitored on a single molecule level.
In summary, it was possible to gain new insights into the complex structure and the dynamical behavior of the still sparsely characterized eukaryotic H/ACA RNPs. Especially, new knowledge could be obtained about the hairpin specific behavior on the bipartite RNA complex structure, including the rather ambiguous role of the protein Nhp2 and the contribution of the eukaryotic specific features of Gar1 in their interaction with the guide/substrate RNA.
Correction to: Scientifc Reports https://doi.org/10.1038/s41598-019-43857-5, published online 17 May 2019. In the original version of this Article, Jan-Hendrik Trösemeier was incorrectly affiliated with ‘Division of Allergology, Paul Ehrlich Institut, Langen, Germany’. Te correct afliations are listed below...
Es gibt zwei Leitmotive, die sich konsequent in der Rhetorik der Forschungsliteratur zu Anselm Kiefer beobachten lassen: zum einen die Auseinandersetzung des Künstlers mit dem Nationalsozialismus und in der Folge mit der nordisch-germanischen Mythologie und zum anderen die Beschäftigung mit dem Judentum und der jüdischen Mystik. Innerhalb des Gesamtoeuvres sind jedoch diejenigen Arbeiten, die sich augenscheinlich und sehr offensichtlich mit dem Nationalsozialismus beschäftigen nur eine sehr kleine Gruppe. In seiner 50 Jahre umfassenden künstlerischen Laufbahn hat er lediglich in den ersten Jahren eine offensive Auseinandersetzung mit der NS-Vergangenheit Deutschlands gesucht. Sie bildet gleichsam den Startpunkt seiner künstlerischen Karriere. Mittlerweile ist der Künstler Anselm Kiefer mit der Aufarbeitung des Nationalsozialismus und den Begrifflichkeiten Vergangenheitsbewältigung, Erinnerungsarbeit und Trauerarbeit kanonisiert. Doch je länger der Schaffensprozess von Kiefer andauert und je weiter man auf sein produktives Œuvre zurückblicken kann, umso deutlicher erkennt man nachweisbar zwei ganz andere bildimmanente Leitkategorien in diversen Facetten und Nuancen, die in ihrer Überordnung eine völlig neue Dimension einschlagen: die Dimension von Zeit und Raum respektive Zeitlichkeit und Räumlichkeit in Kiefers gesamtem Werkkomplex.
Insistent beschäftigt sich Kiefer mit allgemeingültigen Themen der Vergangenheit, Gegenwart und Zukunft oder diskutiert zeitlose und damit verbunden auch schwer zugängliche Inhalte. Zeitlos meint in diesem Fall, dass er sich nicht mehr mit den ihm vorher typischen Referenzen der Historie und Geschichte (wie eben dem Nationalsozialismus) beschäftigt, sondern vielmehr auch mit zeitlichen Dimensionen wie der kosmologischen, geologischen oder Lebens-Zeit. Zunehmens treten ab Mitte der achtziger Jahre Raumbezogene Kosmos- und Genesisthemen aus dem Alten Testament oder der Kabbala in den Mittelpunkt. Raum und Zeit als zwei Leitkategorien breiten sich wie eine Art Dach über Kiefers gesamtes Œuvre und über die üblichen ikonografischen Interpretationsmodelle aus. Sie werden von mir als alternative Lesart der Forschung empfohlen.
Jedes Bildwerk besitzt neben seiner räumlichen Gestalt und seinem kompositorischen Bildaufbau auch eine implizite Bildzeit. Beide Determinanten bedingen als Ordnungsraster nicht nur die jeweilige formale Bildgestalt, sondern auch den strukturellen Bildgehalt in Form eines zeitlich-räumlichen Ausdrucks. Raum und Zeit sind als normativ zu verstehen, im Sinne eines Standards, gleichsam als eine Regel, die grundsätzlich für die Annäherung und Interpretation der Kieferschen Arbeiten angewendet werden kann. Die Wahrnehmung von Raum und Zeit bei Kiefer kann gleichsam übergreifend in die folgenden drei Kategorien eingeteilt werden: 1.) die thematische Referenz auf die beiden Dimensionen, 2.) der tatsächlich motivische Bezug oder 3.) die faktische Umsetzung anhand der Dimension des Bildträgers oder der Entstehungszeit des Werkes. Raum und Zeit liegen zudem ganz grundsätzlich dem kosmologischen Weltentwurf zugrunde, da Alles in Zeit und Raum ist. Die beiden Dimensionen sind dem Kieferschen Sternenbild qua seiner Existenz daher schon anhaftig.
Kiefer hat in den Jahren 1995 bis 2010 eine beachtliche Anzahl an Sternenbildern geschaffen. Er fertigt die Bilder vor allem seriell an, so dass diese Fülle auf Basis diverser formaler Bildanlagen von mir in zwei Gruppen unterteilt wurde.
Die erste Gruppe folgt einer traditionellen Bildform, indem sie grundsätzlich den Bildträger kompositorisch in eine irdische und eine stellare räumliche Zone unterteilen. Der nächtliche Sternenhimmel breitet sich darin geschlossen über einer Landschaft oder einem Innenraum aus. Der Betrachter wird gleichsam von seinem irdischen Standpunkt aus auf den Blick gen Sternenhimmel gelenkt. Die Sternenbilder aus irdischer Perspektive versammeln philosophisches und literarisches Gedankengut der historischen Personen Immanuel Kant, Ingeborg Bachmann und Pierre Corneille. Die zweite Gruppe umfasst jene Arbeiten, die den irdischen Standpunkt verlassen und keine Horizontlinie mehr aufweisen. Bei diesen Arbeiten begreift Kiefer den Bildträger in seiner kompletten Dimensionalität als rein stellaren Bildraum. In den Werken wird als Konsequenz eine für Kiefers Sternenbilder neue bildräumliche Perspektive obligat.
Die Sternenbilder Kiefers fokussieren grundsätzlich kosmologische Fragestellungen, seien sie philosophisch, literaturwissenschaftlich, naturphilosophisch, naturwissenschaftlich oder religiös konnotiert. Damit folgen sie der Tradition vorangegangener Künstlergenerationen. In einem Einführungskapitel, welches für die Verortung Kiefers in die Tradition des Sternenbildes wichtig ist, wird aufgezeigt, dass das Bild der Sterne stets in enger Verbindung mit den eben genannten Disziplinen steht, durch diese maßgeblich beeinflusst wurde und weiterhin wird. Den Künstlern ist die Tatsache gemein, dass sie mit ihrer Darstellung des Sternenhimmels der Frage nach einer räumlichen und zeitlichen Ordnung der Welt, gleichsam als Kosmos verstanden, sowie ihrer Entstehungsursache und des „Bauplans“ nachgehen. Den Sternenbildern scheint gemein zu sein, dass sie realiter durch Beobachtungen, Erkenntnisse und Ergebnisse Wissensräume sichtbar machen, determinieren und das jeweilige Wissen transportieren.
Kiefers kosmologischer Diskurs verläuft in dem großen Bereich des Nicht-Wissens, mit dem Versuch einen ontologischen Sinn herzustellen. Die Arbeiten, die auf Kant referenzieren, auf Bachmann und auf Corneille zeugen von Kiefers kosmologischer Auseinandersetzung, seiner Frage nach Gott, seiner Verortung im Kosmos, seiner Beschäftigung mit dem Darstellbaren und Un-Darstellbaren und einer damit verbundenen Sinnsuche.
Objectives: Evaluation of surgical and non-surgical air-polishing in vitro efficacy for implant surface decontamination.
Material and methods: One hundred eighty implants were distributed to three differently angulated bone defect models (30°, 60°, 90°). Biofilm was imitated using indelible red color. Sixty implants were used for each defect, 20 of which were air-polished with three different types of glycine air powder abrasion (GAPA1–3) combinations. Within 20 equally air-polished implants, a surgical and non-surgical (with/without mucosa mask) procedure were simulated. All implants were photographed to determine the uncleaned surface. Changes in surface morphology were assessed using scanning electron micrographs (SEM).
Results: Cleaning efficacy did not show any significant differences between GAPA1–3 for surgical and non-surgical application. Within a cleaning method significant (p < 0.001) differences for GAPA2 between 30° (11.77 ± 2.73%) and 90° (7.25 ± 1.42%) in the non-surgical and 30° (8.26 ± 1.02%) and 60° (5.02 ± 0.84%) in the surgical simulation occurred. The surgical use of air-polishing (6.68 ± 1.66%) was significantly superior (p < 0.001) to the non-surgical (10.13 ± 2.75%). SEM micrographs showed no surface damages after use of GAPA.
Conclusions: Air-polishing is an efficient, surface protective method for surgical and non-surgical implant surface decontamination in this in vitro model. No method resulted in a complete cleaning of the implant surface.
Clinical relevance: Air-polishing appears to be promising for implant surface decontamination regardless of the device.
Global landscapes are changing due to human activities with consequences for both biodiversity and ecosystems. For single species, terrestrial mammal population densities have shown mixed responses to human pressure, with both increasing and decreasing densities reported in the literature. How the impacts of human activities on mammal populations translates into altered global density patterns remains unclear. Here we aim to disentangle the effect of human impacts on large-scale patterns of mammal population densities using a global dataset of 6729 population density estimates for 468 mammal species (representing 59% and 44% of mammalian orders and families). We fitted a mixed effect model to explain the variation in density based on a 1-degree resolution as a function of the human footprint index (HFI), a global proxy of direct and indirect human disturbances, while accounting for body mass, trophic level and primary productivity (normalized vegetation index; NDVI). We found a significant positive relationship between population density and HFI, where population densities were higher in areas with a higher HFI (e.g. agricultural or suburban areas – no populations were located in very high HFI urban areas) compared to areas with a low HFI (e.g. wilderness areas). We also tested the effect of the individual components of the HFI and still found a consistent positive effect. The relationships remained positive even across populations of the same species, although variability among species was high. Our results indicate shifts in mammal population densities in human modified landscapes, which is due to the combined effect of species filtering, increased resources and a possible reduction in competition and predation. Our study provides further evidence that macroecological patterns are being altered by human activities, where some species will benefit from these activities, while others will be negatively impacted or even extirpated.
The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the primary focus for vaccine development. In this study, we combined cryo–electron tomography, subtomogram averaging, and molecular dynamics simulations to structurally analyze S in situ. Compared with the recombinant S, the viral S was more heavily glycosylated and occurred mostly in the closed prefusion conformation. We show that the stalk domain of S contains three hinges, giving the head unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and potentially to the development of safe vaccines.
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the major focus for vaccine development. We combine cryo electron tomography, subtomogram averaging and molecular dynamics simulations to structurally analyze S in situ. Compared to recombinant S, the viral S is more heavily glycosylated and occurs predominantly in a closed pre-fusion conformation. We show that the stalk domain of S contains three hinges that give the globular domain unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and the development of safe vaccines. The large scale tomography data set of SARS-CoV-2 used for this study is therefore sufficient to resolve structural features to below 5 Ångstrom, and is publicly available at EMPIAR-10453.
What is in Umbilicaria pustulata? A metagenomic approach to reconstruct the holo-genome of a lichen
(2020)
Lichens are valuable models in symbiosis research and promising sources of biosynthetic genes for biotechnological applications. Most lichenized fungi grow slowly, resist aposymbiotic cultivation, and are poor candidates for experimentation. Obtaining contiguous, high-quality genomes for such symbiotic communities is technically challenging. Here, we present the first assembly of a lichen holo-genome from metagenomic whole-genome shotgun data comprising both PacBio long reads and Illumina short reads. The nuclear genomes of the two primary components of the lichen symbiosis—the fungus Umbilicaria pustulata (33 Mb) and the green alga Trebouxia sp. (53 Mb)—were assembled at contiguities comparable to single-species assemblies. The analysis of the read coverage pattern revealed a relative abundance of fungal to algal nuclei of ∼20:1. Gap-free, circular sequences for all organellar genomes were obtained. The bacterial community is dominated by Acidobacteriaceae and encompasses strains closely related to bacteria isolated from other lichens. Gene set analyses showed no evidence of horizontal gene transfer from algae or bacteria into the fungal genome. Our data suggest a lineage-specific loss of a putative gibberellin-20-oxidase in the fungus, a gene fusion in the fungal mitochondrion, and a relocation of an algal chloroplast gene to the algal nucleus. Major technical obstacles during reconstruction of the holo-genome were coverage differences among individual genomes surpassing three orders of magnitude. Moreover, we show that GC-rich inverted repeats paired with nonrandom sequencing error in PacBio data can result in missing gene predictions. This likely poses a general problem for genome assemblies based on long reads.
(1) Background: Oncological gastrectomy requires complex multidisciplinary management. Clinical pathways (CPs) can potentially facilitate this task, but evidence related to their use in managing oncological gastrectomy is limited. This study evaluated the effect of a CP for oncological gastrectomy on process and outcome quality. (2) Methods: Consecutive patients undergoing oncological gastrectomy before (n = 64) or after (n = 62) the introduction of a CP were evaluated. Assessed parameters included catheter and drain management, postoperative mobilization, resumption of diet and length of stay. Morbidity, mortality, reoperation and readmission rates were used as indicators of outcome quality. (3) Results: Enteral nutrition was initiated significantly earlier after CP implementation (5.0 vs. 7.0 days, p < 0.0001). Readmission was more frequent before CP implementation (7.8% vs. 0.0%, p = 0.05). Incentive spirometer usage increased following CP implementation (100% vs. 90.6%, p = 0.11). Mortality, morbidity and reoperation rates remained unchanged. (4) Conclusions: After implementation of an oncological gastrectomy CP, process quality improved, while indicators of outcome quality such as mortality and reoperation rates remained unchanged. CPs are a promising tool to standardize perioperative care for oncological gastrectomy
Mit einem um die Behandlungskapazität des Gesundheitssystems erweiterten epidemiologischen SIRD-Modell werden Mechanismen und Dynamik einer Virusepidemie wie Corona anhand von stilisierten politischen Reaktionsmustern (Ignore, Shutdown, Ignore-Shutdown-Relax) simuliert. Ferner werden aus dem Modell Lehren für die statistische Analyse von Corona gezogen, wie die Aussagekraft publizierter Verdopplungszeiten und Reproduktionszahlen. Die Dunkelziffer unbestätigter Fälle und die im Epidemieverlauf variable Genauigkeit von medizinischen Infektionstests werden diskutiert. Zur Messung der medizinischen Kosten von Corona sowie für regionale und internationale Vergleiche wird ein Schadensindex der verlorenen Lebenszeit vorgeschlagen. Zuletzt geht die Arbeit kurz auf die ökonomischen Kosten von Corona in Deutschland ein.
Discussions regarding the planned European Deposit Insurance Scheme (EDIS), the missing third pillar of the European Banking Union, have been ongoing since the Commission published its initial legisla-tive proposal in 2015. A breakthrough in negotiations has yet to be achieved. The gridlock on EDIS is most commonly attributed to moral hazard concerns over insufficient risk reduction harboured on the side of northern member states, particularly Germany, due to the weak state of some other member states’ banking sectors. While moral hazard based on uneven risk reduction is helpful for explaining divergent member-state preferences on the scope of necessary risk reduction, this does not explain preferences on the institutional design of EDIS. In this paper, we argue that contrary to persistent differences on necessary risk reduction, preferences regarding the institutional design of EDIS have become more closely aligned. We analyse how preferences on EDIS developed in the key member states of Germany, France, and Italy. In all sampled countries, we find path-dependent benefits con-nected to the current design of national Deposit Guarantee Schemes (DGS) that shifted preferences of the banking sector or significant subsectors in favour of retaining national DGSs. Overall, given that a compromise on risk-reduction can be accomplished, we argue that current preferences in these key member states provide an opportunity to implement EDIS in the form of a reinsurance system that maintains national DGSs in combination with a supranational fund.
The permeability and inflammatory tissue reaction to Mucomaix® matrix (MM), a non- cross-linked collagen-based matrix was evaluated in both ex vivo and in vivo settings. Liquid platelet rich fibrin (PRF), a blood concentrate system, was used to assess its capacity to absorb human proteins and interact with blood cells ex vivo. In the in vivo aspect, 12 Wister rats had MM implanted subcutaneously, whereas another 12 rats (control) were sham-operated without biomaterial implantation. On days 3, 15 and 30, explantation was completed (four rats per time-point) to evaluate the tissue reactions to the matrix. Data collected were statistically analyzed using analysis of variance (ANOVA) and Tukey multiple comparisons tests (GraphPad Prism 8). The matrix absorbed the liquid PRF in the ex vivo study. Day 3 post-implantation revealed mild tissue inflammatory reaction with presence of mononuclear cells in the implantation site and on the biomaterial surface (mostly CD68-positive macrophages). The control group at this stage had more mononuclear cells than the test group. From day 15, multinucleated giant cells (MNGCs) were seen in the implantation site and the outer third of the matrix with marked increase on day 30 and spread to the matrix core. The presence of these CD68-positive MNGCs was associated with significant matrix vascularization. The matrix degraded significantly over the study period, but its core was still visible as of day 30 post-implantation. The high permeability and fast degradation properties of MM were highlighted.
The miRNA biogenesis is tightly regulated to avoid dysfunction and consequent disease development. Here, we describe modulation of miRNA processing as a novel noncanonical function of the 5-lipoxygenase (5-LO) enzyme in monocytic cells. In differentiated Mono Mac 6 (MM6) cells, we found an in situ interaction of 5-LO with Dicer, a key enzyme in miRNA biogenesis. RNA sequencing of small noncoding RNAs revealed a functional impact, knockout of 5-LO altered the expression profile of several miRNAs. Effects of 5-LO could be observed at two levels. qPCR analyses thus indicated that (a) 5-LO promotes the transcription of the evolutionarily conserved miR-99b/let-7e/miR-125a cluster and (b) the 5-LO-Dicer interaction downregulates the processing of pre-let-7e, resulting in an increase in miR-125a and miR-99b levels by 5-LO without concomitant changes in let-7e levels in differentiated MM6 cells. Our observations suggest that 5-LO regulates the miRNA profile by modulating the Dicer-mediated processing of distinct pre-miRNAs. 5-LO inhibits the formation of let-7e which is a well-known inducer of cell differentiation, but promotes the generation of miR-99b and miR-125a known to induce cell proliferation and the maintenance of leukemic stem cell functions.
The term fatigue is not only used to describe a sleepy state with a lack of drive, as observed in patients with chronic physical illnesses, but also a state with an inhibition of drive and central nervous system (CNS) hyperarousal, as frequently observed in patients with major depression. An electroencephalogram (EEG)-based algorithm has been developed to objectively assess CNS arousal and to disentangle these pathophysiologically heterogeneous forms of fatigue. The aim of this study was to test the hypothesis that fatigued patients with CNS hyperarousal score higher on depressive symptoms than those without this neurophysiological pattern. Methods: Subjects with fatigue (Multidimensional Fatigue Inventory sum-score > 40) in the context of cancer, neuroinflammatory, or autoimmune diseases were drawn from the 60+ cohort of the Leipzig Research Center for Civilization Diseases. CNS arousal was assessed by automatic EEG-vigilance stage classification using the Vigilance Algorithm Leipzig (VIGALL 2.1) based on 20 min EEG recordings at rest with eyes closed. Depression was assessed by the Inventory of Depressive Symptomatology (IDS-SR). Results: Sixty participants (33 female; median age: 67.5 years) were included in the analysis. As hypothesized, fatigued patients with CNS hyperarousal had higher IDS-SR scores than those without hyperarousal (F1,58 = 18.34; p < 0.0001, η2 = 0.240). Conclusion: hyperaroused fatigue in patients with chronic physical illness may be a sign of comorbid depression.
Development of treatment strategies of chronic inflammatory disorders relies on on-going progress in drug discovery approaches and related molecular biologics. This study presents a gene reporter-based approach of phenotypic screening for anti-inflammatory compounds in the context of rheumatoid arthritis (RA).
CEBPD gene, used as the target gene for the screening readout, encodes CCAAT/enhancer binding protein delta (C/EBPδ) transcription factor (TF). Structural and regulatory characteristics of CEBPD gene as well as function of C/EBPδ TF in the context of inflammation satisfied assay requirements. C/EBPδ TF acts as a key regula-tor of inflammatory gene transcription in macrophages (Mϕ) and is observed to con-tribute to disease development in both a rodent model of RA and RA patient biopsies.
Despite well-described pro-inflammatory effects of C/EBPδ TF, it functions as a cell context-specific signal integrator showing also an anti-inflammatory activity. Conse-quently, both activation and inhibition of CEBPD alike may display a desired anti-inflammatory effect. The aim of this study was to develop a high-throughput screening assay for
CEBPD-modulating compounds and confirm hit compounds’ anti-inflammatory effects via gene expression analysis.
Generation and characterization of a multi-gene-reporter cassette 1.0 encoding enzy-matic secreted alkaline phosphatase (SEAP) gene reporter was a priority during the assay development. Chemiluminescent SEAP assay demonstrating high assay sensitivi-ty, broad linear range, high reproducibility and repeatability was chosen to monitor activity of the defined CEBPD promoter (CEBPD::SEAP). PMA-differentiated and M1-polarized THP-1-derived Mϕ stably expressing multi-gene-reporter cassette 1.0 were used as the assay’s cellular system. mRNA expression of both reporter CEBPD::SEAP and endogenous CEBPD mirrored each other in response to a LPS and IFN-g-triggered inflammatory stimulus (M1 treatment), even though the defined CEBPD promoter re-gion, utilized in the assay, contained only the most proximal and known regulatory se-quences. SEAP chemiluminescence in the reporter cells´ supernatant reliably correlat-ed with the M1 treatment-induced CEBPD::SEAP gene expression. The final screening protocol was developed for semi-automatic screening in the 384-well format.
In total, 2054 compounds from LOPAC®1280 and ENZO®774 libraries were screened twice
using the enzymatic SEAP readout with subsequent analysis of 18 selected compounds: nine with the highest and nine with the lowest signals, further characterized by qPCR. Gene expression levels of endogenous CEBPD, CEBPD::SEAP reporter as well as, IL-6,
IL-1β, and CCL2 as inflammatory markers were quantified. qPCR assays failed to corre-late to SEAP readout in 15 compounds within three standard deviations (SDs) from sol-vent control: nine low signal and six high signal compounds. Demonstrating both assay sensitivity and specificity, a correlation between qPCR gene expression and SEAP readout was observed for three hit compounds with signals above three SDs: BET inhib-itors (BETi) GSK 1210151A and Ro 11-1464 as well as an HDAC inhibitor (HDACi) vori-nostat. The control compound trichostatin A (TSA) that reproducibly upregulated SEAP readout is also an HDAC inhibitor with a similar structure to vorinostat and was there-fore included in the anti-inflammatory phenotype analysis.
The observed suppression of IL-6, IL-1ß, and CCL2 gene expression by hit compounds suggested their anti-inflammatory effect in THP-1 reporter Mϕ. mRNA expression of
IL-6 and CCL2 was suppressed by HDACi and BETi at both 4 and 24 hours, while BETi reduced IL-1β mRNA expression 24 hour time point. BETi significantly upregulated gene expression of both reporter CEBPD::SEAP and endogenous CEBPD, 4 hours after M1 treatment. At the same time point, HDACi completely abolished the mRNA expres-sion of the endogenous CEBPD, while simultaneously upregulating mRNA expression of the reporter CEBPD::SEAP. The use of the most proximal 300 base pairs region of en-dogenous CEBPD promoter, making the upstream regulatory elements unavailable in the assay, may account for differential expression levels of SEAP and C/EBPδ TF. This observation corroborated the need to include a longer and more extensive CEBPD´s gene regulatory area. Thus, an improved multi-gene-reporter cassette 2.0 was gener-ated to be used on the basis of a bacterial artificial chromosome (BAC) covering CE-BPD´s genomic area of about 200,000 base pairs.
The generated screening assay is flexible, reliable, and sensitive displaying potential for drug discovery and drug repurposing. The pharmacological modulation of CEBPD gene expression, first reported for GSK 1210151A, Ro 11-1464, and vorinostat, contrib-utes to the understanding of inflammatory responses in Mϕ and may have RA thera-peutic applications.
In the context of data science, data projection and clustering are common procedures. The chosen analysis method is crucial to avoid faulty pattern recognition. It is therefore necessary to know the properties and especially the limitations of projection and clustering algorithms. This report describes a collection of datasets that are grouped together in the Fundamental Clustering and Projection Suite (FCPS). The FCPS contains 10 datasets with the names "Atom", "Chainlink", "EngyTime", "Golfball", "Hepta", "Lsun", "Target", "Tetra", "TwoDiamonds", and "WingNut". Common clustering methods occasionally identified non-existent clusters or assigned data points to the wrong clusters in the FCPS suite. Likewise, common data projection methods could only partially reproduce the data structure correctly on a two-dimensional plane. In conclusion, the FCPS dataset collection addresses general challenges for clustering and projection algorithms such as lack of linear separability, different or small inner class spacing, classes defined by data density rather than data spacing, no cluster structure at all, outliers, or classes that are in contact. This report describes a collection of datasets that are grouped together in the Fundamental Clustering and Projection Suite (FCPS). It is designed to address specific problems of structure discovery in high-dimensional spaces.