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  • 2018  (11)
  • Health Reference Center Academic (Gale)  (11)
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  • 2018  (11)
  • 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
    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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  • 3
    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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  • 4
    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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  • 5
    Language: English
    In: Frontiers in Microbiology, 2018, Vol.9, p.1929
    Description: Over the last 60 years, soil microbiologists have accumulated a wealth of experimental data showing that the usual bulk, macroscopic parameters used to characterize soils (e.g., granulometry, pH, soil organic matter and biomass contents) provide insufficient information to describe quantitatively the activity of soil microorganisms and some of its outcomes, like the emission of greenhouse gases. Clearly, new, more appropriate macroscopic parameters are needed, which reflect better the spatial heterogeneity of soils at the microscale (i.e., the pore scale). For a long time, spectroscopic and microscopic tools were lacking to quantify processes at that scale, but major technological advances over the last 15 years have made suitable equipment available to researchers. In this context, the objective of the present article is to review progress achieved to date in the significant research program that has ensued. This program can be rationalized as a sequence of steps, namely the quantification and modeling of the physical-, (bio)chemical-, and microbiological properties of soils, the integration of these different perspectives into a unified theory, its upscaling to the macroscopic scale, and, eventually, the development of new approaches to measure macroscopic soil characteristics. At this stage, significant progress has been achieved on the physical front, and to a lesser extent on the (bio)chemical one as well, both in terms of experiments and modeling. In terms of microbial aspects, whereas a lot of work has been devoted to the modeling of bacterial and fungal activity in soils at the pore scale, the appropriateness of model assumptions cannot be readily assessed because relevant experimental data are extremely scarce. For the overall research to move forward, it will be crucial to make sure that research on the microbial components of soil systems does not keep lagging behind the work on the physical and (bio)chemical characteristics. Concerning the subsequent steps in the program, very little integration of the various disciplinary perspectives has occurred so far, and, as a result, researchers have not yet been able to tackle the scaling up to the macroscopic level. Many challenges, some of them daunting, remain on the path ahead.Fortunately, a number of these challenges may be resolved by brand new measuring equipment that will become commercially available in the very near future.
    Keywords: Life Sciences ; X-Ray Computed ; Upscaling ; Biodiversity ; Soil Microbiology ; Tomography ; Single-Cell Genomics ; Nanosims Imaging ; Biology
    ISSN: 1664-302X
    E-ISSN: 1664-302X
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  • 6
    Language: English
    In: Nature, 22 February 2018, Vol.554(7693), pp.423
    Keywords: Soil ; Plant Roots -- Chemistry
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 7
    In: Ecohydrology, September 2018, Vol.11(6), pp.n/a-n/a
    Description: By applying the newly developed flow cell (FC) concept, this study investigated the impact of small‐scale spatial variations (millimetre to centimetre) in organic matter (OM) composition (diffusive reflectance infrared Fourier transform spectroscopy), biological activity (zymography), and wettability (contact angle [CA]) on transport processes (tracer experiments, radiography). Experiments were conducted in five undisturbed soil slices (millimetre apart), consisting of a sandy matrix with an embedded loamy band. In the loamy band increased enzyme activities and OM (10 mm apart) were found compared with the sand matrix, with no interrelations although spatial autocorrelation ranges were up to 7 cm. CAs were increased (0–110°) above the loamy band and were negatively correlated with acid phosphatase. Missing correlations were probably attributed to texture variations between soil slices. A general correlation between CA and C content (bulk) were confirmed. Variability in texture and hydraulic properties led to the formation of heterogeneous flow patterns and probably to heterogeneously distributed interfacial properties. The new FC concept allows process evaluation on the millimetre scale to analyse spatial relations, that is, between small‐scale textural changes on transport processes and biological responses. The concept has been proved as a versatile tool to analyse spatial distribution of biological and interfacial soil properties in conjunction with the analysis of complex micro‐hydraulic processes for undisturbed soil samples. The concept may be improved by additional nondestructive imaging methods, which is especially challenging for the detection of small‐scale textural changes.
    Keywords: Drift Spectroscopy ; Extracellular Enzyme Activity ; Flow Cell ; Soil Water Repellency ; Transport Processes ; Undisturbed Soil ; X‐Ray Radiography
    ISSN: 1936-0584
    E-ISSN: 1936-0592
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  • 8
    In: Circulation, 2018, Vol.138(Suppl_1 Suppl 1), pp.A15975-A15975
    Description: Introduction: Hypertension (HtN) is one of the major cardiovascular risk factors. Studies have shown that therapy resistant hypertension (rHtN), i.e. elevated blood pressure despite the concurrent use of three antihypertensive agents of different classes including a diuretic is an emerging phenomenon. Preclinical and clinical data suggest that stimulators of the soluble guanylate cyclase (sGC) could be a therapeutic alternative for those patients poorly or not responding to antihypertensive standard of care (SoC).Hypothesis: The sGC stimulator BAY412272 might be a new therapeutic option for patients with rHtN by efficacious blood pressure lowering on top of SoC.Methods: A novel canine animal model of rHtN was established. Therefore 6 beagle dogs were treated with one-sided renal wrapping followed by renal artery occlusion. Innovative telemetry systems were implanted to cover relevant physiologic parameters, including blood pressure (BP) in conscious animals. Following HtN progression period, used standard antihypertensive medications and the sGC stimulator BAY412272 were administered orally and the acute effect on blood pressure was assessed.Results: Following both procedures the animals developed a phenotype of low renin HtN according to standard classification. Mean blood pressure (MBP) was increased from 93.1 +/- 3.6 mmHg from baseline to 123.4 +/- 10.0 mmHg in maximum. Serum creatinine increased from baseline 74.8 +/- 2.4 μmol/l to 148.8 +/-23.2 μmol/l in maximum. The standard medications showed varying results. The sGC stimulator BAY412272 administered as monotherapy as well as in combinational therapy restored HtN (- 12.4 +/- 5.0 mmHg), only amlodipine (-19.6 +/- 12.4 mmHg) showed a similar effect. BP effects were strictly dose dependent.Conclusions: We established a new low renin canine animal model for HtN, which also reflects important features of rHTN. This model will improve preclinical drug discovery & development especially for HtN not responding to SoC. Furthermore we demonstrated that sGC stimulation by BAY412272 is an efficacious antihypertensive approach when administered alone or in combination with SoC. Therefore, the sGC stimulator BAY412272 might represent an efficacious treatment alternative for rHtN patients.
    ISSN: 0009-7322
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  • 9
    Language: English
    In: BMC Medical Education, 01 June 2018, Vol.18(1), pp.1-10
    Description: Abstract Background The German quality assurance programme for evaluating work capacity is based on peer review that evaluates the quality of medical experts’ reports. Low reliability is thought to be due to systematic differences among peers. For this purpose, we developed a curriculum for a standardized peer-training (SPT). This study investigates, whether the SPT increases the inter-rater reliability of social medical physicians participating in a cross-institutional peer review. Methods Forty physicians from 16 regional German Pension Insurances were subjected to SPT. The three-day training course consist of nine educational objectives recorded in a training manual. The SPT is split into a basic module providing basic information about the peer review and an advanced module for small groups of up to 12 peers training peer review using medical reports. Feasibility was tested by assessing selection, comprehensibility and subjective use of contents delivered, the trainers’ delivery and design of training materials. The effectiveness of SPT was determined by evaluating peer concordance using three anonymised medical reports assessed by each peer. Percentage agreement and Fleiss’ kappa (κm) were calculated. Concordance was compared with review results from a previous unstructured, non-standardized peer-training programme (control condition) performed by 19 peers from 12 German Pension Insurances departments. The control condition focused exclusively on the application of peer review in small groups. No specifically training materials, methods and trainer instructions were used. Results Peer-training was shown to be feasible. The level of subjective confidence in handling the peer review instrument varied between 70 and 90%. Average percentage agreement for the main outcome criterion was 60.2%, resulting in a κm of 0.39. By comparison, the average percentage concordance was 40.2% and the κm was 0.12 for the control condition. Conclusion Concordance with the main criterion was relevant but not significant (p = 0.2) higher for SPT than for the control condition. Fleiss’ kappa coefficient showed that peer concordance was higher for SPT than randomly expected. Nevertheless, a score of 0.39 for the main criterion indicated only fair inter-rater reliability, considerably lower than the conventional standard of 0.7 for adequate reliability.
    Keywords: Training Curriculum ; Peer Review ; Quality Assurance ; Work Capacity Evaluation ; Inter-Rater Reliability ; Medicine
    E-ISSN: 1472-6920
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  • 10
    In: Circulation: Cardiovascular Interventions, 2018, Vol.11(5), pp.e006258-e006258
    Description: BACKGROUND—: Heart failure (HF) remains the most common reason for hospital admission in patients aged 〉65 years. Despite modern drug therapy, mortality and readmission rates for patients hospitalized with HF remain high. This necessitates further research to identify early patients at risk for readmission to limit hospitalization by timely adjustment of medical therapy. Implantable devices can monitor left ventricular (LV) hemodynamics and remotely and continuously detect the early signs of decompensation to trigger interventions and reduce the risk of hospitalization for HF. Here, we report the first preclinical study validating a new batteryless and easy to implant LV-microelectromechanical system to assess LV performance. METHODS AND RESULTS—: A miniaturized implantable wireless pressure sensor was adapted for implantation in the LV apex. The LV-microelectromechanical system sensor was tested in a canine model of HF. The wireless pressure sensor measurements were compared with invasive left heart catheter-derived measurements at several time points. During different pharmacological challenge studies with dobutamine or vasopressin, the device was equally sensitive compared with invasive standard procedures. No adverse events or any observable reaction related to the implantation and application of the device for a period of 35 days was observed. CONCLUSIONS—: Our miniaturized wireless pressure sensor placed in the LV (LV-microelectromechanical system) has the potential to become a new telemetric tool to earlier identify patients at risk for HF decompensation and to guide the treatment of patients with HF.
    Keywords: Heart Failure -- Care And Treatment ; Heart Failure -- Drug Therapy ; Heart Failure -- Risk Factors ; Elderly Patients -- Health Aspects ; Microelectromechanical Systems -- Usage ; Left Ventricular Function -- Analysis;
    ISSN: 1941-7640
    E-ISSN: 19417632
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