Verbesserung des Angiotensin II-induzierten kardialen Schadens durch die kurzkettige Fettsäure Propionat – einen Metaboliten der Darmmikrobiota

Hintergrund: Darmbakterien produzieren eine Vielzahl von Metaboliten, die durch den Wirt resorbiert werden und Auswirkungen auf dessen Physiologie haben. Kurzkettige Fettsäuren (engl. short-chain fatty acids, SCFA) wie z. B. Propionat (C3) sind Metabolite, die durch bakterielle Fermentierung aus nicht verdaulichen Polysacchariden (sogenannte Ballaststoffe oder Fasern) produziert werden. C3 ist durch seine Wirkung auf T-Zellen, insbesondere auf anti-inflammatorisch wirkende regulatorische T-Zellen (TREG), gekennzeichnet. Die essentielle Hypertonie (HTN) und der damit assoziierte kardiale Organschaden sind durch eine pro-inflammatorische Auslenkung der T-Zell-Homöostase charakterisiert. Experimentelle Strategien, welche die Funktion von TREG verbessern, vermindern bekanntermaßen den durch die HTN verursachten Endorganschaden. Die zugrundeliegende Hypothese ist somit, dass die SCFA C3 den hypertensiven kardialen Schaden positiv beeinflussen kann. Methodik: Zur Induktion der HTN in 12 Wochen alten männlichen NMRI Mäusen erfolgte die Implantation einer subkutanen osmotischen Minipumpe, die über 14 Tage 1,44mg/kg/d Angiotensin (Ang) II freisetzt. Um die intestinale bakteriellen Produktion von SCFA zu supprimieren, erhielten die Mäuse ein faserarmes Futter. Um die Effekte von C3 spezifisch zu untersuchen, wurden die Tiere entweder mit Natriumpropionat oder Natriumchlorid als Kontrolle im Trinkwasser behandelt. Die Inflammation wurde mittels Durchflusszytometrie, die kardiale Schädigung, mittels Echokardiographie, Immunfluoreszenz, Genexpressionsanalyse und in vivo elektrophysiologischer Untersuchung quantifiziert. Eine Blutdruckmessung erfolgte kontinuierlich mittels Telemetrie. TREG wurden durch anti-CD25 Antikörper (PC61) in mit Ang II infundierten C3-behandelten Mäusen depletiert, um den Wirkmechanismus von C3 aufzuklären. Ergebnisse: Die Behandlung mit C3 führte zu einem signifikant verbesserten Überleben nach 14 Tagen. C3 reduzierte sowohl die systemische inflammatorische Antwort auf Ang II, als auch die kardiale Hypertrophie und Fibrose. Begleitend kam es zu einer Reduktion der ins kardiale Gewebe infiltrierenden T-Helferzellen, zytotoxische T-Zellen und Makrophagen. Die Behandlung mit C3 bewirkte zudem einen reduzierten Anteil an Typ17-T-Helferzellen (TH17) in Herz und Milz. Dies führte zu einer reduzierten Anfälligkeit für ventrikuläre Tachyarrhythmien in C3-behandelten Mäusen. Die Verbesserung des kardialen Schadens und der Inflammation waren in TREG-depletierten Mäusen abgeschwächt. C3 führte außerdem unabhängig von der Wirkung auf TREG zu einer verzögert eintretenden, moderaten Reduktion des Blutdruckes. Schlussfolgerung: Die Daten unterstreichen die Bedeutung von aus unverdaulichen Polysacchariden gewonnenen bakteriellen Metaboliten für die kardiale Gesundheit. Die Wirkung dieser Metabolite auf TREG spielt beim kardioprotektiven Effekt von C3 eine zentrale Rolle. Die orale Gabe von C3 sowie die Förderung der intestinalen Produktion von C3 könnten eine vielversprechende Option in der Behandlung der hypertensiven Herzkrankheit darstellen.Background: Gut microbiota release a plethora of metabolites into the host and thereby affect the host physiology. Short-chain fatty acids (SCFA) such as propionate (C3) are metabolites produced from otherwise indigestible polysaccharides (so-called fiber) by bacterial fermentation in the intestine. C3 has been shown to influence immune cells, especially anti-inflammatory regulatory T cells (TREG). Essential hypertension (HTN) is characterized by a pro-inflammatory T cell response which promotes the damage to important organs such as the heart. Experimental approaches promoting TREG function have been shown to ameliorate hypertensive end-organ damage. We hypothesized that the SCFA C3 attenuates hypertensive cardiac damage. Methods: To induce hypertension in 12-week-old male NMRI mice, Angiotensin (Ang) II (1,44mg/kg/d) was infused subcutaneously for 14 days using osmotic minipumps. Mice were fed a fiber-depleted diet to suppress intestinal bacterial SCFA production. To specifically examine the effect of C3, mice were either administered sodium propionate or sodium chloride as control in drinking water. The inflammatory response was analyzed by flow cytometry. Cardiac organ damage was assessed using echocardiography, in vivo electrophysiology, and immunofluorescence. Blood pressure was measured by radiotelemetry. To assess the mode of action of C3, TREG were depleted in Ang II-infused C3-treated mice using an anti-CD25 antibody (PC61). Results: C3 treatment significantly improved survival along with a reduced inflammatory response to Ang II and ameliorated cardiac hypertrophy and fibrosis. Fewer T helper cells, cytotoxic T cells and macrophages infiltrated the hearts of C3-treated mice. C3 reduced the amount of T-helper type 17 (TH17) cells in hearts and spleens. This led to a reduced susceptibility to cardiac ventricular tachyarrhythmias. Improvement of cardiac damage and inflammation by C3 was abrogated in TREG-depleted mice. C3 had a moderate blood pressure-lowering effect confined to the second week of Ang II infusion, which was preserved in TREG-depleted mice. Conclusion: Our data highlight the importance of fiber-derived gut bacterial metabolites for cardiac health. TREG are central to the cardioprotective effect of C3 in hypertension. Treatment with C3 and/or augmentation of intestinal C3 production may prove of benefit in the treatment of hypertensive heart disease

Microscopy with undetected photons in the mid-infrared

Owing to its capacity for unique (bio)-chemical specificity, microscopy withmid-IR illumination holds tremendous promise for a wide range of biomedical and industrial applications. The primary limitation, however, remains detection; with current mid-IR detection technology often marrying inferior technical capabilities with prohibitive costs. This has lead to approaches that shift detection towavelengths into the visible regime, where vastly superior silicon-based cameratechnology is available. Here, we experimentally show how nonlinear interferometry with entangled light can provide a powerful tool for mid-IR microscopy, while only requiring near-infrared detection with a standard CMOS camera. In this proof-of-principle implementation, we demonstrate intensity imaging overa broad wavelength range covering 3.4-4.3um and demonstrate a spatial resolution of 35um for images containing 650 resolved elements. Moreover, we demonstrate our technique is fit for purpose, acquiring microscopic images of biological tissue samples in the mid-IR. These results open a new perspective for potential relevance of quantum imaging techniques in the life sciences.Comment: back-to-back submission with arXiv:2002.05956, Anna V. Paterova, Sivakumar M. Maniam, Hongzhi Yang, Gianluca Grenci, and Leonid A. Krivitsky, "Hyperspectral Infrared Microscopy With Visible Light

Anatomy and the type concept in biology show that ontologies must be adapted to the diagnostic needs of research

Background: In times of exponential data growth in the life sciences, machine-supported approaches are becoming increasingly important and with them the need for FAIR (Findable, Accessible, Interoperable, Reusable) and eScience-compliant data and metadata standards. Ontologies, with their queryable knowledge resources, play an essential role in providing these standards. Unfortunately, biomedical ontologies only provide ontological definitions that answer What is it? questions, but no method-dependent empirical recognition criteria that answer How does it look? questions. Consequently, biomedical ontologies contain knowledge of the underlying ontological nature of structural kinds, but often lack sufficient diagnostic knowledge to unambiguously determine the reference of a term. Results: We argue that this is because ontology terms are usually textually defined and conceived as essentialistic classes, while recognition criteria often require perception-based definitions because perception-based contents more efficiently document and communicate spatial and temporal information—a picture is worth a thousand words. Therefore, diagnostic knowledge often must be conceived as cluster classes or fuzzy sets. Using several examples from anatomy, we point out the importance of diagnostic knowledge in anatomical research and discuss the role of cluster classes and fuzzy sets as concepts of grouping needed in anatomy ontologies in addition to essentialistic classes. In this context, we evaluate the role of the biological type concept and discuss its function as a general container concept for groupings not covered by the essentialistic class concept. Conclusions: We conclude that many recognition criteria can be conceptualized as text-based cluster classes that use terms that are in turn based on perception-based fuzzy set concepts. Finally, we point out that only if biomedical ontologies model also relevant diagnostic knowledge in addition to ontological knowledge, they will fully realize their potential and contribute even more substantially to the establishment of FAIR and eScience-compliant data and metadata standards in the life sciences

Anatomy and the type concept in biology show that ontologies must be adapted to the diagnostic needs of research

Background: In times of exponential data growth in the life sciences, machine-supported approaches are becoming increasingly important and with them the need for FAIR (Findable, Accessible, Interoperable, Reusable) and eScience-compliant data and metadata standards. Ontologies, with their queryable knowledge resources, play an essential role in providing these standards. Unfortunately, biomedical ontologies only provide ontological definitions that answer What is it? questions, but no method-dependent empirical recognition criteria that answer How does it look? questions. Consequently, biomedical ontologies contain knowledge of the underlying ontological nature of structural kinds, but often lack sufficient diagnostic knowledge to unambiguously determine the reference of a term. Results: We argue that this is because ontology terms are usually textually defined and conceived as essentialistic classes, while recognition criteria often require perception-based definitions because perception-based contents more efficiently document and communicate spatial and temporal information—a picture is worth a thousand words. Therefore, diagnostic knowledge often must be conceived as cluster classes or fuzzy sets. Using several examples from anatomy, we point out the importance of diagnostic knowledge in anatomical research and discuss the role of cluster classes and fuzzy sets as concepts of grouping needed in anatomy ontologies in addition to essentialistic classes. In this context, we evaluate the role of the biological type concept and discuss its function as a general container concept for groupings not covered by the essentialistic class concept. Conclusions: We conclude that many recognition criteria can be conceptualized as text-based cluster classes that use terms that are in turn based on perception-based fuzzy set concepts. Finally, we point out that only if biomedical ontologies model also relevant diagnostic knowledge in addition to ontological knowledge, they will fully realize their potential and contribute even more substantially to the establishment of FAIR and eScience-compliant data and metadata standards in the life sciences

Mitochondrial sequence data expose the putative cosmopolitan polychaete Scoloplos armiger (Annelida, Orbiniidae) as a species complex

Background Polychaetes assigned as Scoloplos armiger (Orbiniidae) show a cosmopolitan distribution and have been encountered in all zoogeographic regions. Sibling S. armiger-like species have been revealed by recent studies using RAPDs and AFLP genetic data. We sequenced a ~12 kb fragment of the Scoloplos cf. armiger mitochondrial genome and developed primers for variable regions including the 3' end of the cox3 gene, trnQ, and most of nad6. A phylogenetic analysis of this 528-nucleotide fragment was carried out for S. armiger-like individuals from the Eastern North Atlantic as well as Pacific regions. The aim of this study is to test the cosmopolitan status, as well as to clarify the systematics of this species complex in the Eastern North Atlantic, while using a few specimens from the Pacific Ocean for comparision. Results Phylogenetic analysis of the cox3-trnQ-nad6 data set recovered five different clades of Scoloplos cf. armiger. The fragment of the mitochondrial genome of Scoloplos cf. armiger is 12,042 bp long and contains 13 protein coding genes, 15 of the 22 expected tRNAs, and the large ribosomal subunit (rrnl). Conclusion The sequenced cox3-trnQ-nad6 fragment proved to be very useful in phylogenetic analyses of Scoloplos cf. armiger. Due to its larger sampling scale this study goes beyond previous analyses which used RAPD and AFLP markers. The results of this study clearly supports that Scoloplos armiger represents a species complex and not a cosmopolitan species. We find at least two S. armiger-like species within the Pacific region and three different S. armiger-like species in the North Atlantic. Implications for the taxonomy and the impact on ecological studies are discussed

Systematic comparison and reconstruction of sea urchin (Echinoidea) internal anatomy: a novel approach using magnetic resonance imaging

<p>Abstract</p> <p>Background</p> <p>Traditional comparative morphological analyses and subsequent three-dimensional reconstructions suffer from a number of drawbacks. This is particularly evident in the case of soft tissue studies that are technically demanding, time-consuming, and often prone to produce artefacts. These problems can partly be overcome by employing non-invasive, destruction-free imaging techniques, in particular micro-computed tomography or magnetic resonance imaging.</p> <p>Results</p> <p>Here, we employed high-field magnetic resonance imaging techniques to gather numerous data from members of a major marine invertebrate taxon, the sea urchins (Echinoidea). For this model study, 13 of the 14 currently recognized high-ranking subtaxa (orders) of this group of animals were analyzed. Based on the acquired datasets, interactive three-dimensional models were assembled. Our analyses reveal that selected soft tissue characters can even be used for phylogenetic inferences in sea urchins, as exemplified by differences in the size and shape of the gastric caecum found in the Irregularia.</p> <p>Conclusion</p> <p>The main focus of our investigation was to explore the possibility to systematically visualize the internal anatomy of echinoids obtained from various museum collections. We show that, in contrast to classical preparative procedures, magnetic resonance imaging can give rapid, destruction-free access to morphological data from numerous specimens, thus extending the range of techniques available for comparative studies of invertebrate morphology.</p

Phylogeny and mitochondrial gene order variation in Lophotrochozoa in the light of new mitogenomic data from Nemertea

<p>Abstract</p> <p>Background</p> <p>The new animal phylogeny established several taxa which were not identified by morphological analyses, most prominently the Ecdysozoa (arthropods, roundworms, priapulids and others) and Lophotrochozoa (molluscs, annelids, brachiopods and others). Lophotrochozoan interrelationships are under discussion, e.g. regarding the position of Nemertea (ribbon worms), which were discussed to be sister group to e.g. Mollusca, Brachiozoa or Platyhelminthes. Mitochondrial genomes contributed well with sequence data and gene order characters to the deep metazoan phylogeny debate.</p> <p>Results</p> <p>In this study we present the first complete mitochondrial genome record for a member of the Nemertea, <it>Lineus viridis</it>. Except two <it>trnP </it>and <it>trnT</it>, all genes are located on the same strand. While gene order is most similar to that of the brachiopod <it>Terebratulina retusa</it>, sequence based analyses of mitochondrial genes place nemerteans close to molluscs, phoronids and entoprocts without clear preference for one of these taxa as sister group.</p> <p>Conclusion</p> <p>Almost all recent analyses with large datasets show good support for a taxon comprising Annelida, Mollusca, Brachiopoda, Phoronida and Nemertea. But the relationships among these taxa vary between different studies. The analysis of gene order differences gives evidence for a multiple independent occurrence of a large inversion in the mitochondrial genome of Lophotrochozoa and a re-inversion of the same part in gastropods. We hypothesize that some regions of the genome have a higher chance for intramolecular recombination than others and gene order data have to be analysed carefully to detect convergent rearrangement events.</p

The central nervous system of Oweniidae (Annelida) and its implications for the structure of the ancestral annelid brain

Figure S1: Histology Orrhage’s Owenia fusiformis. A: slide showing sections of Owenia fusiformis. B: Intermediate filaments (if) cross the neuropil of the brain (br). The ecm of the epidermis is less prominent where the neuropil layer is above it. C: Posterior part of the brain (br). if: intermediate filaments. (JPG 10649 kb

Mitochondrial genome sequence and gene order of Sipunculus nudus give additional support for an inclusion of Sipuncula into Annelida

<p>Abstract</p> <p>Background</p> <p>Mitochondrial genomes are a valuable source of data for analysing phylogenetic relationships. Besides sequence information, mitochondrial gene order may add phylogenetically useful information, too. Sipuncula are unsegmented marine worms, traditionally placed in their own phylum. Recent molecular and morphological findings suggest a close affinity to the segmented Annelida.</p> <p>Results</p> <p>The first complete mitochondrial genome of a member of Sipuncula, <it>Sipunculus nudus</it>, is presented. All 37 genes characteristic for metazoan mtDNA were detected and are encoded on the same strand. The mitochondrial gene order (protein-coding and ribosomal RNA genes) resembles that of annelids, but shows several derivations so far found only in Sipuncula. Sequence based phylogenetic analysis of mitochondrial protein-coding genes results in significant bootstrap support for Annelida <it>sensu lato</it>, combining Annelida together with Sipuncula, Echiura, Pogonophora and Myzostomida.</p> <p>Conclusion</p> <p>The mitochondrial sequence data support a close relationship of Annelida and Sipuncula. Also the most parsimonious explanation of changes in gene order favours a derivation from the annelid gene order. These results complement findings from recent phylogenetic analyses of nuclear encoded genes as well as a report of a segmental neural patterning in Sipuncula.</p