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Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity.
Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment.
Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with
portal hypertension but without obesity. This study investigated the additional role of obesity in this
model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week
old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis
was assessed using standard techniques. Hepatic expression of transforming growth factor-β1
(TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as
the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed.
Assessment of portal and systemic hemodynamics was performed using the colored microsphere
technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red
O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were
increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this
increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1)
mRNA expression levels. Of note, portal pressure increased with the duration of WD compared
to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular
resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that
transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver
fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with
macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably
due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway.The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of
fibrosis and portal hypertension in NAFLD with obesity
Swine are regarded as promising biomedical models, but the dynamics of theirgastrointestinal microbiome have been much less investigated than that of humans or mice. The aimof this study was to establish an integrated multi-omics protocol to investigate the fecal microbiomeof healthy swine. To this end, a preparation and analysis protocol including integrated samplepreparation for meta-omics analyses of deep-frozen feces was developed. Subsequent data integrationlinked microbiome composition with function, and metabolic activity with protein inventories, i.e.,16S rRNA data and expressed proteins, and identified proteins with corresponding metabolites.16S rRNA gene amplicon and metaproteomics analyses revealed a fecal microbiome dominated byPrevotellaceae,Lactobacillaceae,Lachnospiraceae,RuminococcaceaeandClostridiaceae.Similar microbiomecompositions in feces and colon, but not ileum samples, were observed, showing that feces can serveas minimal-invasive proxy for porcine colon microbiomes. Longitudinal dynamics in composition,e.g., temporal decreased abundance ofLactobacillaceaeandStreptococcaceaeduring the experiment,were not reflected in microbiome function. Instead, metaproteomics and metabolomics showed arather stable functional state, as evident from short-chain fatty acids (SCFA) profiles and associatedmetaproteome functions, pointing towards functional redundancy among microbiome constituents.In conclusion, our pipeline generates congruent data from different omics approaches on the taxonomyand functionality of the intestinal microbiome of swine.
Streptococcus pneumoniaeinfections lead to high morbidity and mortality rates worldwide.Pneumococcal polysaccharide conjugate vaccines significantly reduce the burden of disease but havea limited range of protection, which encourages the development of a broadly protective protein-basedalternative. We and others have shown that immunization with pneumococcal lipoproteins that lackthe lipid anchor protects against colonization. Since immunity againstS. pneumoniaeis mediatedthrough Toll-like receptor 2 signaling induced by lipidated proteins, we investigated the effects ofa lipid modification on the induced immune responses in either intranasally or subcutaneouslyvaccinated mice. Here, we demonstrate that lipidation of recombinant lipoproteins DacB and PnrAstrongly improves their immunogenicity. Mice immunized with lipidated proteins showed enhancedantibody concentrations and different induction kinetics. The induced humoral immune responsewas modulated by lipidation, indicated by increased IgG2/IgG1 subclass ratios related to Th1-typeimmunity. In a mouse model of colonization, immunization with lipidated antigens led to a moderatebut consistent reduction of pneumococcal colonization as compared to the non-lipidated proteins,indicating that protein lipidation can improve the protective capacity of the coupled antigen. Thus,protein lipidation represents a promising approach for the development of a serotype-independentpneumococcal vaccine.
Permafrost-affected soil stores a significant amount of organic carbon. Identifying the biological constraints of soil organic matter transformation, e.g., the interaction of major soil microbial soil organic matter decomposers, is crucial for predicting carbon vulnerability in permafrost-affected soil. Fungi are important players in the decomposition of soil organic matter and often interact in various mutualistic relationships during this process. We investigated four different soil horizon types (including specific horizons of cryoturbated soil organic matter (cryoOM)) across different types of permafrost-affected soil in the Western Canadian Arctic, determined the composition of fungal communities by sequencing (Illumina MPS) the fungal internal transcribed spacer region, assigned fungal lifestyles, and by determining the co-occurrence of fungal network properties, identified the topological role of keystone fungal taxa. Compositional analysis revealed a significantly higher relative proportion of the litter saprotroph Lachnum and root-associated saprotroph Phialocephala in the topsoil and the ectomycorrhizal close-contact exploring Russula in cryoOM, whereas Sites 1 and 2 had a significantly higher mean proportion of plant pathogens and lichenized trophic modes. Co-occurrence network analysis revealed the lowest modularity and average path length, and highest clustering coefficient in cryoOM, which suggested a lower network resistance to environmental perturbation. Zi-Pi plot analysis suggested that some keystone taxa changed their role from generalist to specialist, depending on the specific horizon concerned, Cladophialophora in topsoil, saprotrophic Mortierella in cryoOM, and Penicillium in subsoil were classified as generalists for the respective horizons but specialists elsewhere. The litter saprotrophic taxon Cadophora finlandica played a role as a generalist in Site 1 and specialist in the rest of the sites. Overall, these results suggested that fungal communities within cryoOM were more susceptible to environmental change and some taxa may shift their role, which may lead to changes in carbon storage in permafrost-affected soil.
Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation
(2021)
The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.
The increasing demand for new and effective antibiotics requires intelligent strategies to obtain a wide range of potential candidates. Laccase-catalyzed reactions have been successfully applied to synthesize new β-lactam antibiotics and other antibiotics. In this work, laccases from three different origins were used to produce new aminoglycoside antibiotics. Kanamycin, tobramycin and gentamicin were coupled with the laccase substrate 2,5-dihydroxy-N-(2-hydroxyethyl)-benzamide. The products were isolated, structurally characterized and tested in vitro for antibacterial activity against various strains of Staphylococci, including multidrug-resistant strains. The cytotoxicity of these products was tested using FL cells. The coupling products showed comparable and, in some cases, better antibacterial activity than the parent antibiotics in the agar diffusion assay, and they were not cytotoxic. The products protected mice against infection with Staphylococcus aureus, which was lethal to the control animals. The results underline the great potential of laccases in obtaining new biologically active compounds, in this case new antibiotic candidates from the class of aminoglycosides.
Osmotic changes are common challenges for marine microorganisms. Bacteria have developed numerous ways of dealing with this stress, including reprogramming of global cellular processes. However, specific molecular adaptation mechanisms to osmotic stress have mainly been investigated in terrestrial model bacteria. In this work, we aimed to elucidate the basis of adjustment to prolonged salinity challenges at the proteome level in marine bacteria. The objects of our studies were three representatives of bacteria inhabiting various marine environments, Shewanella baltica, Vibrio harveyi and Aliivibrio fischeri. The proteomic studies were performed with bacteria cultivated in increased and decreased salinity, followed by proteolytic digestion of samples which were then subjected to liquid chromatography with tandem mass spectrometry analysis. We show that bacteria adjust at all levels of their biological processes, from DNA topology through gene expression regulation and proteasome assembly, to transport and cellular metabolism. The finding that many similar adaptation strategies were observed for both low- and high-salinity conditions is particularly striking. The results show that adaptation to salinity challenge involves the accumulation of DNA-binding proteins and increased polyamine uptake. We hypothesize that their function is to coat and protect the nucleoid to counteract adverse changes in DNA topology due to ionic shifts.
We analyzed the proteomic response of the Gram-negative fish pathogen A. salmonicida to iron limitation, an elevated incubation temperature, and the antibiotic florfenicol. Proteins from different subcellular fractions (cytosol, inner membrane, outer membrane, extracellular and outer membrane vesicles) were enriched and analyzed. We identified several iron-regulated proteins that were not reported in the literature for A. salmonicida before. We could also show that hemolysin, an oxidative-stress-resistance chaperone, a putative hemin receptor, an M36 peptidase, and an uncharacterized protein were significantly higher in abundance not only under iron limitation but also with an elevated incubation temperature. This may indicate that these proteins involved in the infection process of A. salmonicida are induced by both factors. The analysis of the outer membrane vesicles (OMVs) with and without applied stresses revealed significant differences in the proteomes. OMVs were smaller and contained more cytoplasmic proteins after antibiotic treatment. After cultivation with low iron availability, several iron-regulated proteins were found in the OMVs, indicating that A. salmonicida OMVs potentially have a function in iron acquisition, as reported for other bacteria. The presence of iron-regulated transporters further indicates that OMVs obtained from ‘stressed’ bacteria might be suitable vaccine candidates that induce a protective anti-virulence immune response.