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  • 2018  (14)
  • Vogel, J.  (14)
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  • 2018  (14)
  • 1
    Language: English
    In: Science (New York, N.Y.), 07 December 2018, Vol.362(6419), pp.1156-1160
    Description: Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
    Keywords: Drug Resistance, Bacterial ; Host-Pathogen Interactions -- Immunology ; Macrophages -- Immunology ; Salmonella Infections -- Drug Therapy ; Salmonella Typhimurium -- Metabolism ; Type III Secretion Systems -- Metabolism
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    In: EMBO Journal, 02 July 2018, Vol.37(13), pp.n/a-n/a
    Description: Long non‐coding s (lncs) play important roles in many cellular pathways, but their contribution to the defense of eukaryotic cells against pathogens remains poorly understood. A new study from Imamura in reports that infection in human cells impacts nuclear decay, which in turn drives the accumulation of otherwise unstable nuclear lncs, some of which may have protective effects against this common bacterial pathogen. These unexpected findings demand more efforts to fully decrypt the molecular functions of lncs in innate and adaptive immunity. infection impairs the nuclear RNA decay machinery in human cells, increasing the abundance of long non‐coding RNAs with a role in innate immunity.
    Keywords: Pathogens ; Immunity ; Infections ; Pathogens ; Molecular Chains ; Salmonella ; Bacterial Infections ; Pathogens ; Ribonucleic Acid–RNA ; Ribonucleic Acid–RNA ; Adaptive Immunity;
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 3
    Language: English
    In: Nature, November 2018, Vol.563(7729), pp.121-125
    Description: Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses-Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing-that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation.
    Keywords: Antigenic Variation -- Genetics ; Chromatin -- Genetics ; DNA, Protozoan -- Metabolism ; Genome -- Genetics ; Trypanosoma Brucei Brucei -- Genetics
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 4
    Language: English
    In: Nature Reviews Microbiology, 2018, Vol.16(10), pp.601-615
    Description: RNA-binding proteins (RBPs) are central to most if not all cellular processes, dictating the fate of virtually all RNA molecules in the cell. Starting with pioneering work on ribosomal proteins, studies of bacterial RBPs have paved the way for molecular studies of RNA-protein interactions. Work over the years has identified major RBPs that act on cellular transcripts at the various stages of bacterial gene expression and that enable their integration into post-transcriptional networks that also comprise small non-coding RNAs. Bacterial RBP research has now entered a new era in which RNA sequencing-based methods permit mapping of RBP activity in a truly global manner in vivo. Moreover, the soaring interest in understudied members of host-associated microbiota and environmental communities is likely to unveil new RBPs and to greatly expand our knowledge of RNA-protein interactions in bacteria.
    Keywords: Medical And Health Sciences ; Basic Medicine ; Microbiology In The Medical Area ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Mikrobiologi Inom Det Medicinska Området
    ISSN: 1740-1526
    E-ISSN: 17401534
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  • 5
    In: EMBO Journal, 03 December 2018, Vol.37(23), pp.n/a-n/a
    Description: While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress‐dependent inhibition of binding to host cells. Interestingly, stress caused by intracellular replication also results in remodeling of the host cell membrane, and , which precludes re‐infection by this and other non‐motile pathogens. In contrast, Typhimurium overcomes the shortage of permissive entry sites by gathering effectively at the remaining platforms through its flagellar motility. Overall, our findings reveal host membrane remodeling as a novel stress‐responsive cell‐autonomous defense mechanism that protects epithelial cells from infection by non‐motile bacterial pathogens. Stress‐induced host membrane remodeling constitutes a novel cell‐autonomous defensive mechanism that protects epithelial cells from infection by and other non‐motile bacterial pathogens. Host oxidative stress strongly reduces S. flexneri binding to epithelial cells. Stress leads to host membrane remodeling, via activation of the acid sphingomyelinase by the MAPK p38 pathway, resulting in the formation of ceramide domains. Intracellular Shigella replication induces remodeling of the host cell membrane, in vitro and in vivo. Stress‐induced host membrane remodeling precludes re‐infection by non‐motile pathogens; motile pathogens are able to overcome this barrier through flagellar motility. Host membrane remodeling is a cell‐autonomous defense mechanism that protects epithelial cells from infection by .
    Keywords: Acid Sphingomyelinase ; Host Stress Response ; Membrane Remodeling ; Salmonella ; Shigella
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 6
    Language: English
    In: Molecular Cell, 07 June 2018, Vol.70(5), pp.785-799
    Description: Bacteria are an exceedingly diverse group of organisms whose molecular exploration is experiencing a renaissance. While the classical view of bacterial gene expression was relatively simple, the emerging view is more complex, encompassing extensive post-transcriptional control involving riboswitches, RNA thermometers, and regulatory small RNAs (sRNAs) associated with the RNA-binding proteins CsrA, Hfq, and ProQ, as well as CRISPR/Cas systems that are programmed by RNAs. Moreover, increasing interest in members of the human microbiota and environmental microbial communities has highlighted the importance of understudied bacterial species with largely unknown transcriptome structures and RNA-based control mechanisms. Collectively, this creates a need for global RNA biology approaches that can rapidly and comprehensively analyze the RNA composition of a bacterium of interest. We review such approaches with a focus on RNA-seq as a versatile tool to investigate the different layers of gene expression in which RNA is made, processed, regulated, modified, translated, and turned over. RNA-seq-based approaches are revolutionizing how bacterial RNA biology can be studied. Hör, Gorski, and Vogel review the available global methods that can be used to chart the increasingly diverse number of RNA species and functions in any microbe of interest.
    Keywords: RNA-Seq ; Non-Coding RNA ; Small RNA ; Transcription ; RNA-Binding Protein ; Post-Transcriptional Control ; Biology
    ISSN: 1097-2765
    E-ISSN: 1097-4164
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  • 7
    Language: English
    In: Molecular Cell, 07 June 2018, Vol.70(5), pp.971-982.e6
    Description: The conserved RNA-binding protein ProQ has emerged as the centerpiece of a previously unknown third large network of post-transcriptional control in enterobacteria. Here, we have used UV crosslinking and RNA sequencing (CLIP-seq) to map hundreds of ProQ binding sites in and . Our analysis of these binding sites, many of which are conserved, suggests that ProQ recognizes its cellular targets through RNA structural motifs found in small RNAs (sRNAs) and at the 3′ end of mRNAs. Using the mRNA as a model for 3′ end targeting, we reveal a function for ProQ in protecting mRNA against exoribonucleolytic activity. Taken together, our results underpin the notion that ProQ governs a post-transcriptional network distinct from those of the well-characterized sRNA-binding proteins, CsrA and Hfq, and suggest a previously unrecognized, sRNA-independent role of ProQ in stabilizing mRNAs. Using CLIP-seq, Holmqvist et al. map transcriptome-wide interactions of the emerging global RNA-binding protein ProQ in and . Their data suggest ProQ to target sRNAs and mRNA 3′ UTRs primarily through a structural code and to stabilize some mRNAs by counteracting 3′ exoribonuclease activity.
    Keywords: Proq ; Clip-Seq ; RNA-Binding Protein ; 3′ Utr ; Post-Transcriptional Control ; Exoribonuclease ; Biology
    ISSN: 1097-2765
    E-ISSN: 1097-4164
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  • 8
    Language: English
    In: GigaScience, 01 September 2018, Vol.7(9)
    Description: To understand the gene regulation of an organism of interest, a comprehensive genome annotation is essential. While some features, such as coding sequences, can be computationally predicted with high accuracy based purely on the genomic sequence, others, such as promoter elements or noncoding RNAs, are harder to detect. RNA sequencing (RNA-seq) has proven to be an efficient method to identify these genomic features and to improve genome annotations. However, processing and integrating RNA-seq data in order to generate high-resolution annotations is challenging, time consuming, and requires numerous steps. We have constructed a powerful and modular tool called ANNOgesic that provides the required analyses and simplifies RNA-seq-based bacterial and archaeal genome annotation. It can integrate data from conventional RNA-seq and differential RNA-seq and predicts and annotates numerous features, including small noncoding RNAs, with high precision. The software is available under an open source license (ISCL) at https://pypi.org/project/ANNOgesic/.
    E-ISSN: 2047-217X
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  • 9
    Language: English
    In: Environmental Technology, 01 February 2018, Vol.39(3), pp.264-276
    Description: Municipal wastewater treatment commonly involves mechanical, biological and chemical treatment steps to protect humans and the environment from adverse effects. Membrane technology has gained increasing attention as an alternative to conventional wastewater treatment due to increased urbanization. Among the available membrane technologies, microfiltration (MF) and forward osmosis (FO) have been selected for this study due to their specific characteristics, such as compactness and efficient removal of particles. In this study, two treatment concepts were evaluated with regard to their specific electricity, energy and area demands. Both concepts would fulfil the Swedish discharge demands for small- and medium-sized wastewater treatment plants at full scale: (1) direct MF and (2) direct FO with seawater as the draw solution. The framework of this study is based on a combination of data obtained from bench- and pilot-scale experiments applying direct MF and FO, respectively. Additionally, available complementary data from a Swedish full-scale wastewater treatment plant and the literature were used to evaluate the concepts in depth. The results of this study indicate that both concepts are net positive with respect to electricity and energy, as more biogas can be produced compared to that using conventional wastewater treatment. Furthermore, the specific area demand is significantly reduced. This study demonstrates that municipal wastewater could be treated in a more energy- and area-efficient manner with techniques that are already commercially available and with future membrane technology.
    Keywords: Biogas Production ; Forward Osmosis ; Membrane Filtration ; Seawater ; Wastewater Treatment ; Engineering
    ISSN: 0959-3330
    E-ISSN: 1479-487X
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  • 10
    Language: English
    In: PLoS Genetics, 01 June 2018, Vol.14(6), p.e1007401
    Description: Invasion of epithelial cells by Salmonella enterica requires expression of genes located in the pathogenicity island I (SPI-1). The expression of SPI-1 genes is very tightly regulated and activated only under specific conditions. Most studies have focused on the regulatory pathways that induce SPI-1 expression. Here, we describe a new regulatory circuit involving CRP-cAMP, a widely established metabolic regulator, in silencing of SPI-1 genes under non-permissive conditions. In CRP-cAMP-deficient strains we detected a strong upregulation of SPI-1 genes in the mid-logarithmic growth phase. Genetic analyses revealed that CRP-cAMP modulates the level of HilD, the master regulator of Salmonella invasion. This regulation occurs at the post-transcriptional level and requires the presence of a newly identified regulatory motif within the hilD 3'UTR. We further demonstrate that in Salmonella the Hfq-dependent sRNA Spot 42 is under the transcriptional repression of CRP-cAMP and, when this transcriptional repression is relieved, Spot 42 exerts a positive effect on hilD expression. In vivo and in vitro assays indicate that Spot 42 targets, through its unstructured region III, the 3'UTR of the hilD transcript. Together, our results highlight the biological relevance of the hilD 3'UTR as a hub for post-transcriptional control of Salmonella invasion gene expression.
    Keywords: Biology
    ISSN: 1553-7390
    E-ISSN: 1553-7404
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