Tracking key virulence loci encoding aerobactin and salmochelin siderophore synthesis in Klebsiella pneumoniae.

BACKGROUND: Klebsiella pneumoniae is a recognised agent of multidrug-resistant (MDR) healthcare-associated infections; however, individual strains vary in their virulence potential due to the presence of mobile accessory genes. In particular, gene clusters encoding the biosynthesis of siderophores aerobactin (iuc) and salmochelin (iro) are associated with invasive disease and are common amongst hypervirulent K. pneumoniae clones that cause severe community-associated infections such as liver abscess and pneumonia. Concerningly, iuc has also been reported in MDR strains in the hospital setting, where it was associated with increased mortality, highlighting the need to understand, detect and track the mobility of these virulence loci in the K. pneumoniae population. METHODS: Here, we examined the genetic diversity, distribution and mobilisation of iuc and iro loci amongst 2503 K. pneumoniae genomes using comparative genomics approaches and developed tools for tracking them via genomic surveillance. RESULTS: Iro and iuc were detected at low prevalence (< 10%). Considerable genetic diversity was observed, resolving into five iro and six iuc lineages that show distinct patterns of mobilisation and dissemination in the K. pneumoniae population. The major burden of iuc and iro amongst the genomes analysed was due to two linked lineages (iuc1/iro1 74% and iuc2/iro2 14%), each carried by a distinct non-self-transmissible IncFIBK virulence plasmid type that we designate KpVP-1 and KpVP-2. These dominant types also carry hypermucoidy (rmpA) determinants and include all previously described virulence plasmids of K. pneumoniae. The other iuc and iro lineages were associated with diverse plasmids, including some carrying IncFII conjugative transfer regions and some imported from Escherichia coli; the exceptions were iro3 (mobilised by ICEKp1) and iuc4 (fixed in the chromosome of K. pneumoniae subspecies rhinoscleromatis). Iro/iuc mobile genetic elements (MGEs) appear to be stably maintained at high frequency within known hypervirulent strains (ST23, ST86, etc.) but were also detected at low prevalence in others such as MDR strain ST258. CONCLUSIONS: Iuc and iro are mobilised in K. pneumoniae via a limited number of MGEs. This study provides a framework for identifying and tracking these important virulence loci, which will be important for genomic surveillance efforts including monitoring for the emergence of hypervirulent MDR K. pneumoniae strains

A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex.

Klebsiella pneumoniae is a leading cause of antimicrobial-resistant (AMR) healthcare-associated infections, neonatal sepsis and community-acquired liver abscess, and is associated with chronic intestinal diseases. Its diversity and complex population structure pose challenges for analysis and interpretation of K. pneumoniae genome data. Here we introduce Kleborate, a tool for analysing genomes of K. pneumoniae and its associated species complex, which consolidates interrogation of key features of proven clinical importance. Kleborate provides a framework to support genomic surveillance and epidemiology in research, clinical and public health settings. To demonstrate its utility we apply Kleborate to analyse publicly available Klebsiella genomes, including clinical isolates from a pan-European study of carbapenemase-producing Klebsiella, highlighting global trends in AMR and virulence as examples of what could be achieved by applying this genomic framework within more systematic genomic surveillance efforts. We also demonstrate the application of Kleborate to detect and type K. pneumoniae from gut metagenomes

Theoretical and Phenomenological Constraints on Form Factors for Radiative and Semi-Leptonic B-Meson Decays

We study transition form factors for radiative and rare semi-leptonic B-meson decays into light pseudoscalar or vector mesons, combining theoretical constraints and phenomenological information from Lattice QCD, light-cone sum rules, and dispersive bounds. We pay particular attention to form factor parameterisations which are based on the so-called series expansion, and study the related systematic uncertainties on a quantitative level. In this context, we also provide the NLO corrections to the correlation function between two flavour-changing tensor currents, which enters the unitarity constraints for the coefficients in the series expansion.Comment: 52 pages; v2: normalization error in (29ff.) corrected, conclusion about relevance of unitarity bounds modified; form factor fits unaffected; references added; v3: discussion on truncation of series expansion added, matches version to be published in JHEP; v4: corrected typos in Tables 5 and

Neurogenesis Drives Stimulus Decorrelation in a Model of the Olfactory Bulb

The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb -- the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells -- are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures

Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.This work was supported by National Institutes of Health grants R01-CA122443, P50-CA136393, P30-CA15083, and the Fred C. and Katherine B. Andersen Foundation. We thank Gary Kenney, M.D. for pathology review of tumor tissue. We thank Craig Luccarini, Caroline Baynes from University of Cambridge for assisting our sample sequencing

Heat shock proteins in chronic kidney disease

Heat shock proteins (HSP) form a heterogenous, evolutionarily conserved group of molecules with high sequence homology. They mainly act as intracellular chaperones, protecting the protein structure and folding under stress conditions. The extracellular HSP, released in the course of damage or necrosis, play a pivotal role in the innate and adaptive immune responses. They also take part in many pathological processes. The aim of this review is to update the recent developments in the field of HSP in chronic kidney disease (CKD), in regard to three different aspects. The first is the assessment of the role of HSP, either positive or deleterious, in the pathogenesis of CKD and the possibilities to influence its progression. The second is the impact of dialysis, being a potentially modifiable stressor, on HSP and the attempt to assess the value of these proteins as the biocompatibility markers. The last area is that of kidney transplantation and the potential role of HSP in the induction of the immune tolerance in kidney recipients

Genetic diversity, mobilisation and spread of the yersiniabactin-encoding mobile element ICEKp in Klebsiella pneumoniae populations.

Mobile genetic elements (MGEs) that frequently transfer within and between bacterial species play a critical role in bacterial evolution, and often carry key accessory genes that associate with a bacteria's ability to cause disease. MGEs carrying antimicrobial resistance (AMR) and/or virulence determinants are common in the opportunistic pathogen Klebsiella pneumoniae, which is a leading cause of highly drug-resistant infections in hospitals. Well-characterised virulence determinants in K. pneumoniae include the polyketide synthesis loci ybt and clb (also known as pks), encoding the iron-scavenging siderophore yersiniabactin and genotoxin colibactin, respectively. These loci are located within an MGE called ICEKp, which is the most common virulence-associated MGE of K. pneumoniae, providing a mechanism for these virulence factors to spread within the population. Here we apply population genomics to investigate the prevalence, evolution and mobility of ybt and clb in K. pneumoniae populations through comparative analysis of 2498 whole-genome sequences. The ybt locus was detected in 40 % of K. pneumoniae genomes, particularly amongst those associated with invasive infections. We identified 17 distinct ybt lineages and 3 clb lineages, each associated with one of 14 different structural variants of ICEKp. Comparison with the wider population of the family Enterobacteriaceae revealed occasional ICEKp acquisition by other members. The clb locus was present in 14 % of all K. pneumoniae and 38.4 % of ybt+ genomes. Hundreds of independent ICEKp integration events were detected affecting hundreds of phylogenetically distinct K. pneumoniae lineages, including at least 19 in the globally-disseminated carbapenem-resistant clone CG258. A novel plasmid-encoded form of ybt was also identified, representing a new mechanism for ybt dispersal in K. pneumoniae populations. These data indicate that MGEs carrying ybt and clb circulate freely in the K. pneumoniae population, including among multidrug-resistant strains, and should be considered a target for genomic surveillance along with AMR determinants

Small IncQ1 and Col-Like Plasmids Harboring bla KPC-2 and Non-Tn4401 Elements (NTEKPC-IId) in High-Risk Lineages of Klebsiella pneumoniae CG258.

A retrospective genomic study led to the identification of two carbapenem-resistant K. pneumoniae isolates (KPN535 and KPC45) carrying bla KPC-2 genes on non-conjugative plasmids.…