Now showing items 1-20 of 3425

    • The avid competitors of memory inflation.

      Abassi, Leila; Cicin-Sain, Luka; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier, 2020-10-08)
      Cytomegaloviruses (CMV) coevolve with their hosts and latently persist in the vast majority of adult mammals. Therefore, persistent T-cell responses to CMV antigens during virus latency offer a fascinating perspective on the evolution of the T-cell repertoire in natural settings. We addressed here the life-long interactions between CMV antigens presented on MHC-I molecules and the CD8 T-cell response. We present the mechanistic evidence from the murine model of CMV infection and put it in context of clinical laboratory results. We will highlight the remarkable parallels in T-cell responses between the two biological systems, and focus in particular on memory inflation as a result of competitive processes, both between viral antigenic peptides and between T-cell receptors on the host’s cytotoxic lymphocytes
    • Biosynthesis of oxygenated brasilane terpene glycosides involves a promiscuous N-acetylglucosamine transferase.

      Feng, Jin; Surup, Frank; Hauser, Maurice; Miller, Anna; Wennrich, Jan-Peer; Stadler, Marc; Cox, Russell J; Kuhnert, Eric; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Royal Sciety of Chemistry, 2020-09-16)
      Investigation of the metabolome of the ascomycete Annulohypoxylon truncatum led to the identification of novel oxygenated brasilane glycosides and the revision of the stereochemistry of the brasilane A octahydro-1H-indene core scaffold to trans. The bra biosynthetic gene cluster containing five genes (braA-braE) was identified and verified by heterologous expression experiments in Aspergillus oryzae demonstrating that BraC is a multifunctional P450 monooxygenase. In vitro studies of BraB revealed it to be a very rare fungal UDP-GlcNAc dependent N-acetylglucosamine transferase. UDP-glucose is also accepted as a donor, and a broad acceptor substrate tolerance for various primary and secondary alcohols was observed.
    • Anosmia in COVID-19 patients.

      Hornuss, D; Lange, B; Schröter, N; Rieg, S; Kern, W V; Wagner, D; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier, 2020-05-22)
      No abstract available.
    • Diversely Functionalised Cytochalasins through Mutasynthesis and Semi-Synthesis.

      Wang, Chongqing; Lambert, Christopher; Hauser, Maurice; Deuschmann, Adrian; Zeilinger, Carsten; Rottner, Klemens; Stradal, Theresia E B; Stadler, Marc; Skellam, Elizabeth J; Cox, Russell J; et al. (Wiley-VCH, 2020-06-02)
      Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4'-substituted cytochalasin analogues in titres as high as the wild-type system (≈60 mg L-1 ). Halogenated, O-alkyl, O-allyl and O-propargyl examples were formed, as well as a 4'-azido analogue. 4'-O-Propargyl and 4'-azido analogues reacted smoothly in Huisgen cycloaddition reactions, whereas p-Br and p-I compounds reacted in Pd-catalysed cross-coupling reactions. A series of examples of biotin-linked, dye-linked and dimeric cytochalasins was rapidly created. In vitro and in vivo bioassays of these compounds showed that the 4'-halogenated and azido derivatives retained their cytotoxicity and antifungal activities; but a unique 4'-amino analogue was inactive. Attachment of larger substituents attenuated the bioactivities. In vivo actin-binding studies with adherent mammalian cells showed that actin remains the likely intracellular target. Dye-linked compounds revealed visualisation of intracellular actin structures even in the absence of phalloidin, thus constituting a potential new class of actin-visualisation tools with filament-barbed end-binding specificity.
    • Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation.

      Iljazovic, Aida; Roy, Urmi; Gálvez, Eric J C; Lesker, Till R; Zhao, Bei; Gronow, Achim; Amend, Lena; Will, Sabine E; Hofmann, Julia D; Pils, Marina C; et al. (Springer Nature, 2020-05-20)
      Diverse microbial signatures within the intestinal microbiota have been associated with intestinal and systemic inflammatory diseases, but whether these candidate microbes actively modulate host phenotypes or passively expand within the altered microbial ecosystem is frequently not known. Here we demonstrate that colonization of mice with a member of the genus Prevotella, which has been previously associated to colitis in mice, exacerbates intestinal inflammation. Our analysis revealed that Prevotella intestinalis alters composition and function of the ecosystem resulting in a reduction of short-chain fatty acids, specifically acetate, and consequently a decrease in intestinal IL-18 levels during steady state. Supplementation of IL-18 to Prevotella-colonized mice was sufficient to reduce intestinal inflammation. Hence, we conclude that intestinal Prevotella colonization results in metabolic changes in the microbiota, which reduce IL-18 production and consequently exacerbate intestinal inflammation, and potential systemic autoimmunity.
    • Protein-Templated Hit Identification through an Ugi Four-Component Reaction.

      Mancini, Federica; Unver, M Yagiz; Elgaher, Walid A M; Jumde, Varsha R; Alhayek, Alaa; Lukat, Peer; Herrmann, Jennifer; Witte, Martin D; Köck, Matthias; Blankenfeldt, Wulf; et al. (Wiley-VCH, 2020-05-19)
    • Acute neonatal Listeria monocytogenes infection causes long-term, organ-specific changes in immune cell subset composition.

      Zou, Mangge; Yang, Juhao; Wiechers, Carolin; Huehn, Jochen; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Akadémiai Kiadó, 2020-06-19)
      Listeria monocytogenes (Lm) is a food-borne pathogen with a high chance of infecting neonates, pregnant women, elderly and immunocompromised individuals. Lm infection in neonates can cause neonatal meningitis and sepsis with a high risk of severe neurological and developmental sequelae and high mortality rates. However, whether an acute neonatal Lm infection causes long-term effects on the immune system persisting until adulthood has not been fully elucidated. Here, we established a neonatal Lm infection model and monitored the composition of major immune cell subsets at defined time points post infection (p.i.) in secondary lymphoid organs and the intestine. Twelve weeks p.i., the CD8+ T cell population was decreased in colon and mesenteric lymph nodes (mLNs) with an opposing increase in the spleen. In the colon, we observed an accumulation of CD4+ and CD8+ effector/memory T cells with an increase of T-bet+ T helper 1 (Th1) cells. In addition, 12 weeks p.i. an altered composition of innate lymphoid cell (ILC) and dendritic cell (DC) subsets was still observed in colon and mLNs, respectively. Together, these findings highlight organ-specific long-term consequences of an acute neonatal Lm infection on both the adaptive and innate immune system.
    • A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate.

      Zahorska, Eva; Kuhaudomlarp, Sakonwan; Minervini, Saverio; Yousaf, Sultaan; Lepsik, Martin; Kinsinger, Thorsten; Hirsch, Anna K H; Imberty, Anne; Titz, Alexander; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Royal Sciety of Chemistry, 2020-07-06)
      Chronic infections with Pseudomonas aeruginosa are associated with the formation of bacterial biofilms. The tetrameric P. aeruginosa lectin LecA is a virulence factor and an anti-biofilm drug target. Increasing the overall binding affinity by multivalent presentation of binding epitopes can enhance the weak carbohydrate-ligand interactions. Low-nanomolar divalent LecA ligands/inhibitors with up to 260-fold valency-normalized potency boost and excellent selectivity over human galectin-1 were synthesized from d-galactose pentaacetate and benzaldehyde-based linkers in four linear steps.
    • Global discovery of bacterial RNA-binding proteins by RNase-sensitive gradient profiles reports a new FinO domain protein.

      Gerovac, Milan; El Mouali, Youssef; Kuper, Jochen; Kisker, Caroline; Barquist, Lars; Vogel, Jörg; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (Cold Spring Habor Laboratory Press and RNA Society, 2020-07-09)
      RNA-binding proteins (RBPs) play important roles in bacterial gene expression and physiology but their true number and functional scope remain little understood even in model microbes. To advance global RBP discovery in bacteria, we here establish glycerol gradient sedimentation with RNase treatment and mass spectrometry (GradR). Applied to Salmonella enterica, GradR confirms many known RBPs such as CsrA, Hfq, and ProQ by their RNase-sensitive sedimentation profiles, and discovers the FopA protein as a new member of the emerging family of FinO/ProQ-like RBPs. FopA, encoded on resistance plasmid pCol1B9, primarily targets a small RNA associated with plasmid replication. The target suite of FopA dramatically differs from the related global RBP ProQ, revealing context-dependent selective RNA recognition by FinO-domain RBPs. Numerous other unexpected RNase-induced changes in gradient profiles suggest that cellular RNA helps to organize macromolecular complexes in bacteria. By enabling poly(A)-independent generic RBP discovery, GradR provides an important element in the quest to build a comprehensive catalog of microbial RBPs.
    • Murine cytomegaloviruses m139 targets DDX3 to curtail interferon production and promote viral replication.

      Puhach, Olha; Ostermann, Eleonore; Krisp, Christoph; Frascaroli, Giada; Schlüter, Hartmut; Brinkmann, Melanie M; Brune, Wolfram; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (PLOS, 2020-10-08)
      Cytomegaloviruses (CMV) infect many different cell types and tissues in their respective hosts. Monocytes and macrophages play an important role in CMV dissemination from the site of infection to target organs. Moreover, macrophages are specialized in pathogen sensing and respond to infection by secreting cytokines and interferons. In murine cytomegalovirus (MCMV), a model for human cytomegalovirus, several genes required for efficient replication in macrophages have been identified, but their specific functions remain poorly understood. Here we show that MCMV m139, a gene of the conserved US22 gene family, encodes a protein that interacts with the DEAD box helicase DDX3, a protein involved in pathogen sensing and interferon (IFN) induction, and the E3 ubiquitin ligase UBR5. DDX3 and UBR5 also participate in the transcription, processing, and translation of a subset of cellular mRNAs. We show that m139 inhibits DDX3-mediated IFN-α and IFN-β induction and is necessary for efficient viral replication in bone-marrow derived macrophages. In vivo, m139 is crucial for viral dissemination to local lymph nodes and to the salivary glands. An m139-deficient MCMV also replicated to lower titers in SVEC4-10 endothelial cells. This replication defect was not accompanied by increased IFN-β transcription, but was rescued by knockout of either DDX3 or UBR5. Moreover, m139 co-localized with DDX3 and UBR5 in viral replication compartments in the cell nucleus. These results suggest that m139 inhibits DDX3-mediated IFN production in macrophages and antagonizes DDX3 and UBR5-dependent functions related to RNA metabolism in endothelial cells.
    • Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model.

      Park, Yu Mi; Meyer, Markus R; Müller, Rolf; Herrmann, Jennifer; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (MDPI, 2020-09-29)
      Zebrafish (Danio rerio) larvae have gained attention as a valid model to study in vivo drug metabolism and to predict human metabolism. The microinjection of compounds, oligonucleotides, or pathogens into zebrafish embryos at an early developmental stage is a well-established technique. Here, we investigated the metabolism of zebrafish larvae after microinjection of methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7'N-5F-ADB) as a representative of recently introduced synthetic cannabinoids. Results were compared to human urine data and data from the in vitro HepaRG model and the metabolic pathway of 7'N-5F-ADB were reconstructed. Out of 27 metabolites detected in human urine samples, 19 and 15 metabolites were present in zebrafish larvae and HepaRG cells, respectively. The route of administration to zebrafish larvae had a major impact and we found a high number of metabolites when 7'N-5F-ADB was microinjected into the caudal vein, heart ventricle, or hindbrain. We further studied the spatial distribution of the parent compound and its metabolites by mass spectrometry imaging (MSI) of treated zebrafish larvae to demonstrate the discrepancy in metabolite profiles among larvae exposed through different administration routes. In conclusion, zebrafish larvae represent a superb model for studying drug metabolism, and when combined with MSI, the optimal administration route can be determined based on in vivo drug distribution.
    • SARS-CoV-2 outbreak investigation in a German meat processing plant.

      Günther, Thomas; Czech-Sioli, Manja; Indenbirken, Daniela; Robitaille, Alexis; Tenhaken, Peter; Exner, Martin; Ottinger, Matthias; Fischer, Nicole; Grundhoff, Adam; Brinkmann, Melanie M; et al. (EMBO Press, 2020-10-04)
      We describe a multifactorial investigation of a SARS-CoV-2 outbreak in a large meat processing complex in Germany. Infection event timing, spatial, climate and ventilation conditions in the processing plant, sharing of living quarters and transport, and viral genome sequences were analyzed. Our results suggest that a single index case transmitted SARS-CoV-2 to co-workers over distances of more than 8 meters, within a confined work area in which air is constantly recirculated and cooled. Viral genome sequencing shows that all cases share a set of mutations representing a novel sub-branch in the SARS-CoV-2 C20 clade. We identified the same set of mutations in samples collected in the time period between this initial infection cluster and a subsequent outbreak within the same factory, with the largest number of confirmed SARS-CoV-2 cases in a German meat processing facility reported so far. Our results indicate climate conditions, fresh air exchange rates, and airflow as factors that can promote efficient spread of SARS-CoV-2 via long distances and provide insights into possible requirements for pandemic mitigation strategies in industrial workplace settings.
    • Mechanical Control of Cell Proliferation Increases Resistance to Chemotherapeutic Agents.

      Rizzuti, Ilaria Francesca; Mascheroni, Pietro; Arcucci, Silvia; Ben-Mériem, Zacchari; Prunet, Audrey; Barentin, Catherine; Rivière, Charlotte; Delanoë-Ayari, Hélène; Hatzikirou, Haralampos; Guillermet-Guibert, Julie; et al. (American Physical Society, 2020-09-18)
      While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.
    • The Arp2/3 complex is critical for colonisation of the mouse skin by melanoblasts.

      Papalazarou, Vassilis; Swaminathan, Karthic; Jaber-Hijazi, Farah; Spence, Heather; Lahmann, Ines; Nixon, Colin; Salmeron-Sanchez, Manuel; Arnold, Hans-Henning; Rottner, Klemens; Machesky, Laura M; et al. (Company of Biologists, 2020-10-07)
      The Arp2/3 complex is essential for the assembly of branched filamentous actin but its role in physiology and development is surprisingly little understood. Melanoblasts deriving from the neural crest migrate along the developing embryo and traverse the dermis to reach the epidermis colonising the skin and eventually homing within the hair follicles. We have previously established that Rac1 and Cdc42 direct melanoblast migration in vivo We hypothesised that the Arp2/3 complex might be the main downstream effector of these small GTPases. Arp3 depletion in the melanocyte lineage results in severe pigmentation defects in dorsal and ventral regions of the mouse skin. Arp3 null melanoblasts demonstrate proliferation and migration defects and fail to elongate as their wild-type counterparts. Conditional deletion of Arp3 in primary melanocytes causes improper proliferation, spreading, migration and adhesion to extracellular matrix. Collectively, our results suggest that the Arp2/3 complex is absolutely indispensable in the melanocyte lineage in mouse development, and indicate a significant role in developmental processes that require tight regulation of actin-mediated motility.
    • Expression of the MexXY aminoglycoside efflux pump and presence of an aminoglycoside modifying enzyme in clinical isolates are highly correlated.

      Seupt, Alexander; Schniederjans, Monika; Tomasch, Jürgen; Häussler, Susanne; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (ASM, 2020-10-12)
      The impact of MexXY efflux pump expression on aminoglycoside resistance in clinical Pseudomonas aeruginosa isolates has been debated. In this study, we found that in general, elevated mexXY gene expression levels in clinical P. aeruginosa isolates confer to slight increases in aminoglycoside MIC levels, however those levels rarely lead to clinically relevant resistance phenotypes. The main driver of resistance in the clinical isolates studied here was the acquisition of aminoglycoside modifying enzymes (AMEs). Nevertheless, acquisition of an AME was strongly associated with mexY overexpression. In line with this observation, we demonstrate that the introduction of a gentamicin acetyl-transferase confers to full gentamicin resistance levels in a P. aeruginosa type strain only if the MexXY efflux pump was active. We discuss that increased mexXY activity in clinical AME harboring P. aeruginosa isolates might affect ion fluxes at the bacterial cell membrane and thus might play a role in the establishment of enhanced fitness that extends beyond aminoglycoside resistance.
    • Reprogramming of host glutamine metabolism during Chlamydia trachomatis infection and its key role in peptidoglycan synthesis.

      Rajeeve, Karthika; Vollmuth, Nadine; Janaki-Raman, Sudha; Wulff, Thomas F; Baluapuri, Apoorva; Dejure, Francesca R; Huber, Claudia; Fink, Julian; Schmalhofer, Maximilian; Schmitz, Werner; et al. (Nature publishing group (NPG), 2020-08-03)
      Obligate intracellular bacteria such as Chlamydia trachomatis undergo a complex developmental cycle between infectious, non-replicative elementary-body and non-infectious, replicative reticulate-body forms. Elementary bodies transform to reticulate bodies shortly after entering a host cell, a crucial process in infection, initiating chlamydial replication. As Chlamydia fail to replicate outside the host cell, it is unknown how the replicative part of the developmental cycle is initiated. Here we show, using a cell-free approach in axenic media, that the uptake of glutamine by the bacteria is crucial for peptidoglycan synthesis, which has a role in Chlamydia replication. The increased requirement for glutamine in infected cells is satisfied by reprogramming the glutamine metabolism in a c-Myc-dependent manner. Glutamine is effectively taken up by the glutamine transporter SLC1A5 and metabolized via glutaminase. Interference with this metabolic reprogramming limits the growth of Chlamydia. Intriguingly, Chlamydia failed to produce progeny in SLC1A5-knockout organoids and mice. Thus, we report on the central role of glutamine for the development of an obligate intracellular pathogenic bacterium and the reprogramming of host glutamine metabolism, which may provide a basis for innovative anti-infection strategies.
    • Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV.

      Theobald, Sebastian J; Kreer, Christoph; Khailaie, Sahamoddin; Bonifacius, Agnes; Eiz-Vesper, Britta; Figueiredo, Constanca; Mach, Michael; Backovic, Marija; Ballmaier, Matthias; Koenig, Johannes; et al. (2020-07-15)
      Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.
    • Microfungi associated with Clematis (Ranunculaceae) with an integrated approach to delimiting species boundaries

      Phukhamsakda, Chayanard; McKenzie, Eric H. C.; Phillips, Alan J. L.; Gareth Jones, E. B.; Jayarama Bhat, D.; Stadler, Marc; Bhunjun, Chitrabhanu S.; Wanasinghe, Dhanushka N.; Thongbai, Benjarong; Camporesi, Erio; et al. (Springer Science and Business Media LLC, 2020-07-07)
      The cosmopolitan plant genus Clematis contains many climbing species that can be found worldwide. The genus occurs in the wild and is grown commercially for horticulture. Microfungi on Clematis were collected from Belgium, China, Italy, Thailand and the UK. They are characterized by morphology and analyses of gene sequence data using an integrated species concept to validate identifications. The study revealed two new families, 12 new genera, 50 new species, 26 new host records with one dimorphic character report, and ten species are transferred to other genera. The new families revealed by multigene phylogeny are Longiostiolaceae and Pseudomassarinaceae in Pleosporales (Dothideomycetes). New genera are Anthodidymella (Didymellaceae), Anthosulcatispora and Parasulcatispora (Sulcatisporaceae), Fusiformispora (Amniculicolaceae), Longispora (Phaeosphaeriaceae), Neobyssosphaeria (Melanommataceae), Neoleptosporella (Chaetosphaeriales, genera incertae sedis), Neostictis (Stictidaceae), Pseudohelminthosporium (Neomassarinaceae), Pseudomassarina (Pseudomassarinaceae), Sclerenchymomyces (Leptosphaeriaceae) and Xenoplectosphaerella (Plectosphaerellaceae). The newly described species are Alloleptosphaeria clematidis, Anthodidymella ranunculacearum, Anthosulcatispora subglobosa, Aquadictyospora clematidis, Brunneofusispora clematidis, Chaetosphaeronema clematidicola, C. clematidis, Chromolaenicola clematidis, Diaporthe clematidina, Dictyocheirospora clematidis, Distoseptispora clematidis, Floricola clematidis, Fusiformispora clematidis, Hermatomyces clematidis, Leptospora clematidis, Longispora clematidis, Massariosphaeria clematidis, Melomastia clematidis, M. fulvicomae, Neobyssosphaeria clematidis, Neoleptosporella clematidis, Neoroussoella clematidis, N. fulvicomae, Neostictis nigricans, Neovaginatispora clematidis, Parasulcatispora clematidis, Parathyridaria clematidis, P. serratifoliae, P. virginianae, Periconia verrucose, Phomatospora uniseriata, Pleopunctum clematidis, Pseudocapulatispora clematidis, Pseudocoleophoma clematidis, Pseudohelminthosporium clematidis, Pseudolophiostoma chiangraiense, P. clematidis, Pseudomassarina clematidis, Ramusculicola clematidis, Sarocladium clematidis, Sclerenchymomyces clematidis, Sigarispora clematidicola, S. clematidis, S. montanae, Sordaria clematidis, Stemphylium clematidis, Wojnowiciella clematidis, Xenodidymella clematidis, Xenomassariosphaeria clematidis and Xenoplectosphaerella clematidis. The following fungi are recorded on Clematis species for the first time: Angustimassarina rosarum, Dendryphion europaeum, Dermatiopleospora mariae, Diaporthe ravennica, D. rudis, Dichotomopilus ramosissimum, Dictyocheirospora xishuangbannaensis, Didymosphaeria rubi-ulmifolii, Fitzroyomyces cyperacearum, Fusarium celtidicola, Leptospora thailandica, Memnoniella oblongispora, Neodidymelliopsis longicolla, Neoeutypella baoshanensis, Neoroussoella heveae, Nigrograna chromolaenae, N. obliqua, Pestalotiopsis verruculosa, Pseudoberkleasmium chiangmaiense, Pseudoophiobolus rosae, Pseudoroussoella chromolaenae, P. elaeicola, Ramusculicola thailandica, Stemphylium vesicarium and Torula chromolaenae. The new combinations are Anthodidymella clematidis (≡ Didymella clematidis), A. vitalbina (≡ Didymella vitalbina), Anthosulcatispora brunnea (≡ Neobambusicola brunnea), Fuscohypha kunmingensis (≡ Plectosphaerella kunmingensis), Magnibotryascoma rubriostiolata (≡ Teichospora rubriostiolata), Pararoussoella mangrovei (≡ Roussoella mangrovei), Pseudoneoconiothyrium euonymi (≡ Roussoella euonymi), Sclerenchymomyces jonesii (≡ Neoleptosphaeria jonesii), Stemphylium rosae (≡ Pleospora rosae), and S. rosae-caninae (≡ Pleospora rosae-caninae). The microfungi on Clematis is distributed in several classes of Ascomycota. The analyses are based on morphological examination of specimens, coupled with phylogenetic sequence data. To the best of our knowledge, the consolidated species concept approach is recommended in validating species.
    • Evolutionary Stabilization of Cooperative Toxin Production through a Bacterium-Plasmid-Phage Interplay.

      Spriewald, Stefanie; Stadler, Eva; Hense, Burkhard A; Münch, Philipp C; McHardy, Alice C; Weiss, Anna S; Obeng, Nancy; Müller, Johannes; Stecher, Bärbel; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (ASM, 2020-07-21)
      Colicins are toxins produced and released by Enterobacteriaceae to kill competitors in the gut. While group A colicins employ a division of labor strategy to liberate the toxin into the environment via colicin-specific lysis, group B colicin systems lack cognate lysis genes. In Salmonella enterica serovar Typhimurium (S. Tm), the group B colicin Ib (ColIb) is released by temperate phage-mediated bacteriolysis. Phage-mediated ColIb release promotes S. Tm fitness against competing Escherichia coli It remained unclear how prophage-mediated lysis is realized in a clonal population of ColIb producers and if prophages contribute to evolutionary stability of toxin release in S. Tm. Here, we show that prophage-mediated lysis occurs in an S. Tm subpopulation only, thereby introducing phenotypic heterogeneity to the system. We established a mathematical model to study the dynamic interplay of S. Tm, ColIb, and a temperate phage in the presence of a competing species. Using this model, we studied long-term evolution of phage lysis rates in a fluctuating infection scenario. This revealed that phage lysis evolves as bet-hedging strategy that maximizes phage spread, regardless of whether colicin is present or not. We conclude that the ColIb system, lacking its own lysis gene, is making use of the evolutionary stable phage strategy to be released. Prophage lysis genes are highly prevalent in nontyphoidal Salmonella genomes. This suggests that the release of ColIb by temperate phages is widespread. In conclusion, our findings shed new light on the evolution and ecology of group B colicin systems.IMPORTANCE Bacteria are excellent model organisms to study mechanisms of social evolution. The production of public goods, e.g., toxin release by cell lysis in clonal bacterial populations, is a frequently studied example of cooperative behavior. Here, we analyze evolutionary stabilization of toxin release by the enteric pathogen Salmonella The release of colicin Ib (ColIb), which is used by Salmonella to gain an edge against competing microbiota following infection, is coupled to bacterial lysis mediated by temperate phages. Here, we show that phage-dependent lysis and subsequent release of colicin and phage particles occurs only in part of the ColIb-expressing Salmonella population. This phenotypic heterogeneity in lysis, which represents an essential step in the temperate phage life cycle, has evolved as a bet-hedging strategy under fluctuating environments such as the gastrointestinal tract. Our findings suggest that prophages can thereby evolutionarily stabilize costly toxin release in bacterial populations.
    • Multitarget Therapeutic Strategies for Alzheimer's Disease: Review on Emerging Target Combinations.

      Maramai, Samuele; Benchekroun, Mohamed; Gabr, Moustafa T; Yahiaoui, Samir; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Hindawi, 2020-06-30)
      Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer's disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.