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Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.
No full textExcessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. Itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection
New Deoxyenhygrolides from Provide Insights into Butenolide Core Biosynthesis.
No full textMarine myxobacteria present a virtually unexploited reservoir for the discovery of natural products with diverse biological functions and novel chemical scaffolds. We report here the isolation and structure elucidation of eight new deoxyenhygrolides (1-8) from the marine myxobacterium Plesiocystis pacifica DSM 14875T. The herein described deoxyenhygrolides C-J (1-8) feature a butenolide core with an ethyl residue at C-3 of the γ-lactone in contrast to the previously described derivatives, deoxyenhygrolides A and B, which feature an isobutyl residue at this position. The butenolide core is 2,4-substituted with a benzyl (1, 2 and 7), benzoyl (3 and 4) or benzyl alcohol (5, 6 and 8) moiety in the 2-position and a benzylidene (1-6) or benzylic hemiketal (7 and 8) in the 4-position. The description of these new deoxyenhygrolide derivatives, alongside genomic in silico investigation regarding putative biosynthetic genes, provides some new puzzle pieces on how this natural product class might be formed by marine myxobacteria
Mitochondria: at the crossroads of regulating lung epithelial cell function in chronic obstructive pulmonary disease.
No full textDisturbances in mitochondrial structure and function in lung epithelial cells have been implicated in the pathogenesis of various lung diseases, including chronic obstructive pulmonary disease (COPD). Such disturbances affect not only cellular energy metabolism but also alter a range of indispensable cellular homeostatic functions in which mitochondria are known to be involved. These range from cellular differentiation, cell death pathways, and cellular remodeling to physical barrier function and innate immunity, all of which are known to be impacted by exposure to cigarette smoke and have been linked to COPD pathogenesis. Next to their well-established role as the first physical frontline against external insults, lung epithelial cells are immunologically active. Malfunctioning epithelial cells with defective mitochondria are unable to maintain homeostasis and respond adequately to further stress or injury, which may ultimately shape the phenotype of lung diseases. In this review, we provide a comprehensive overview of the impact of cigarette smoke on the development of mitochondrial dysfunction in the lung epithelium and highlight the consequences for cell function, innate immune responses, epithelial remodeling, and epithelial barrier function in COPD. We also discuss the applicability and potential therapeutic value of recently proposed strategies for the restoration of mitochondrial function in the treatment of COPD
Description of three bacterial strains belonging to the new genus Novipirellula gen. nov., reclassificiation of Rhodopirellula rosea and Rhodopirellula caenicola and readjustment of the genus threshold of the phylogenetic marker rpoB for Planctomycetaceae.
No full textAccess to axenic cultures of Planctomycetes is crucial for further investigating their complex lifestyle, uncommon cell biology and primary and secondary metabolism. As a contribution to achieve this goal in the future, we here describe three strains belonging to the novel genus Novipirellula gen. nov. The strains were isolated from biotic and abiotic surfaces in the Baltic Sea and from the island Heligoland in the North Sea. Colony colours range from white to light pink. Cells are acorn-shaped and grew optimally at neutral pH and temperatures between 27 and 30 °C. Phylogenetic analyses revealed that the isolated strains represent three novel species belonging to a new genus, Novipirellula gen. nov. Beyond that, our analysis suggests that Rhodopirellula rosea LHWP3T, Rhodopirellula caenicola YM26-125T and Rhodopirellula maiorica SM1 are also members of this novel genus. Splitting the current genus Rhodopirellula into a more strictly defined genus Rhodopirellula and Novipirellula also allowed readjusting the genus threshold value for the gene rpoB, encoding the RNA polymerase β-subunit, which is used as phylogenetic marker for Planctomycetales. A threshold range of 75.5-78% identity of the analysed partial rpoB sequence turned out to be reliable for differentiation of genera within the family Planctomycetaceae
APPLICATIONS OF COMPUTERS TO THE INDIRECT MEASUREMENT OF BIOMASS CONCENTRATION AND GROWTH RATE BY COMPONENT BALANCING
No full textThe true advantage to the interfacing of computers to fermentation processes is the
dynamic optimization of the fermentation using model reference control techniques.
This has not been realized and is due in part to the absence of accurate realtime
process variable data such a biomass concentration and growth rate.Real-time techniques
employing an on-line computer were evaluated to estimate biomass concentration
and growth rate data by material balancing oxygen using the yield and maintenance
model. The results of this analysis were satisfactory for 2 metabolically simple
fermentations. However, in order to obtain estimates of equivalent accuracy for a
metabolically complex fermentation (aerobic growth of Baker's yeast), it was necessary
to correct values of Y. and My for metabolic variations by introducing a
x/0
metabolic correction function, B Z/X which is a function of respiratory quotient
THE USE OF MODELS IN FERMENTATION CONTROL
No full textRecently there has been a strong interest in the
direct digital control of fermentation processes.
More effort on identification or modeling of the
processes is indispensable to accomplish this highly
sophisticated control. This paper was written to
present a fundamental view on model construction,
process identification, parameter estimation, analysis
of model and examples of uses of model.
Models in the papers surveyed in the last five years
are presented classifying them into three categories:
subculture, subcellular and submolecular models.
Assessment of model by means of sensitivity analysis
and several approaches to modify models for process
control are discussed
DIGITAL FILTERING FOR AUTOMATIC ANALYSIS OF CELL DENSITY AND PRODUCTIVITY
No full textThe application of digital filtering techniques to the data from automatic
fermentation process analyzers is discussed. An example illustrates the application
of these methods to cell density and growth rate (productivity) estimation from
periodic measurements of fermentation broth turbidity. The method of recursive
least squares filtering was found best for the cell density estimates. A hybrid
technique which combines this method with a model for culture oxygen uptake rate
was found to have more rapid response for the cell productivity estimation. The
results of on-line use of these digital filtering techniques are included
MIAMI--a tool for non-targeted detection of metabolic flux changes for mode of action identification.
No full textElimination of Staphylococcus aureus from the bloodstream using a novel biomimetic sorbent haemoperfusion device.
No full textRemoval of bacteria from the blood by means of extracorporeal techniques has been attempted for decades. In late 2019, the European Union licensed the first ever haemoperfusion device for removal of bacteria from the blood. The active ingredient of Seraph 100 Microbind Affinity Blood Filter is ultrahigh molecular weight polyethylene beads with endpoint-attached heparin. Bacteria have been shown to bind to heparin as they would usually do to the heparan sulfate on the cell surface, thereby being removed from the blood stream. We describe the first case of a female chronic haemodialysis patient in which this device was clinically used for a Staphylococcus aureus infection that persisted for 4 days despite antibiotic therapy. After a single treatment, the bacterial load decreased and the blood cultures at the end of a 4 hour haemoperfusion exhibited no bacterial growth
AUFARBEITUNG UND ISOLIERUNG FUNKTIONELLER BIOPROTEINE
No full textDie Deckung des Eiweißbedarfes in der Ernährung ist ein wichtiger
Beitrag für Gesundheit und Lebensqualität der Menschen.
Vernunftmäßig sollte dabei der gesundheitliche Aspekt Vorrang haben,
in der Praxis wird aber der Genußwert von entscheidender Bedeutung
sein. Dies ist auch bei einer Produktentwicklung auf Basis Bioprotein
zu berücksichtigen.
Der Einsatz von Mikroorganismen in der Humanernährung hat lange
Tradition und dient zumeist der Umwandlung von tierischem oder
pflanzlichem Protein zu Produkten mit bestimmten Genußwert.
Die Diskussion aber über den direkten und umfassenden Einsatz von
Bioprotein in der Humanernährung begann eigentlich erst mit dem
Postulat der Eiweißlücke und der großtechnischen Produktion von
mikrobiellem Eiweiß