52 research outputs found
Next generation sequencing analysis of nine Corynebacterium ulcerans isolates reveals zoonotic transmission and a novel putative diphtheria toxin-encoding pathogenicity island
Background: Toxigenic Corynebacterium ulcerans can cause a diphtheria-like illness in humans and have been found in domestic animals, which were suspected to serve as reservoirs for a zoonotic transmission. Additionally, toxigenic C. ulcerans were reported to take over the leading role in causing diphtheria in the last years in many industrialized countries. Methods: To gain deeper insights into the tox gene locus and to understand the transmission pathway in detail, we analyzed nine isolates derived from human patients and their domestic animals applying next generation sequencing and comparative genomics. Results: We provide molecular evidence for zoonotic transmission of C. ulcerans in four cases and demonstrate the superior resolution of next generation sequencing compared to multi-locus sequence typing for epidemiologic research. Additionally, we provide evidence that the virulence of C. ulcerans can change rapidly by acquisition of novel virulence genes. This mechanism is exemplified by an isolate which acquired a prophage not present in the corresponding isolate from the domestic animal. This prophage contains a putative novel virulence factor, which shares high identity with the RhuM virulence factor from Salmonella enterica but which is unknown in Corynebacteria so far. Furthermore, we identified a putative pathogenicity island for C. ulcerans bearing a diphtheria toxin gene. Conclusion: The novel putative diphtheria toxin pathogenicity island could provide a new and alternative pathway for Corynebacteria to acquire a functional diphtheria toxin-encoding gene by horizontal gene transfer, distinct from the previously well characterized phage infection model. The novel transmission pathway might explain the unexpectedly high number of toxigenic C. ulcerans
Search For Exotic Tau-decays
The Crystal Ball detector at the Doris II storage ring at DESY was used to search for the exotic decay processes tau -> e gamma, tau -> e pi0, tau -> e eta. No signal was observed. We obtained the following 90% CL upper limits on the branching fractions:B(tau -> e gamma)< 2.0x10^(-4),B(tau -> e pi0) < 1.4x10^(-4),B(tau -> e eta) < 2.4x10^(-4)
Female Behaviour Drives Expression and Evolution of Gustatory Receptors in Butterflies
Secondary plant compounds are strong deterrents of insect oviposition and feeding, but may also be attractants for specialist herbivores. These insect-plant interactions are mediated by insect gustatory receptors (Grs) and olfactory receptors (Ors). An analysis of the reference genome of the butterfly Heliconius melpomene, which feeds on passion-flower vines (Passiflora spp.), together with whole-genome sequencing within the species and across the Heliconius phylogeny has permitted an unprecedented opportunity to study the patterns of gene duplication and copy-number variation (CNV) among these key sensory genes. We report in silico gene predictions of 73 Gr genes in the H. melpomene reference genome, including putative CO2, sugar, sugar alcohol, fructose, and bitter receptors. The majority of these Grs are the result of gene duplications since Heliconius shared a common ancestor with the monarch butterfly or the silkmoth. Among Grs but not Ors, CNVs are more common within species in those gene lineages that have also duplicated over this evolutionary time-scale, suggesting ongoing rapid gene family evolution. Deep sequencing (∼1 billion reads) of transcriptomes from proboscis and labial palps, antennae, and legs of adult H. melpomene males and females indicates that 67 of the predicted 73 Gr genes and 67 of the 70 predicted Or genes are expressed in these three tissues. Intriguingly, we find that one-third of all Grs show female-biased gene expression (n = 26) and nearly all of these (n = 21) are Heliconius-specific Grs. In fact, a significant excess of Grs that are expressed in female legs but not male legs are the result of recent gene duplication. This difference in Gr gene expression diversity between the sexes is accompanied by a striking sexual dimorphism in the abundance of gustatory sensilla on the forelegs of H. melpomene, suggesting that female oviposition behaviour drives the evolution of new gustatory receptors in butterfly genomes
Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond
We target the gatekeeper MET146 of
c-Jun N-terminal kinase 3 (JNK3)
to exemplify the applicability of X···S halogen bonds
in molecular design using computational, synthetic, structural and
biophysical techniques. In a designed series of aminopyrimidine-based
inhibitors, we unexpectedly encounter a plateau of affinity. Compared
to their QM-calculated interaction energies, particularly bromine
and iodine fail to reach the full potential according to the size
of their σ-hole. Instead, mutation of the gatekeeper residue
into leucine, alanine, or threonine reveals that the heavier halides
can significantly influence selectivity in the human kinome. Thus,
we demonstrate that, although the choice of halogen may not always
increase affinity, it can still be relevant for inducing selectivity.
Determining the crystal structure of the iodine derivative in complex
with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond
donated by the ligand and the back-pocket residue MET115. Incipient
repulsion from the too short halogen bond increases the flexibility
of C<sub>ε</sub> of MET146, whereas the rest of the residue
fails to adapt being fixed by the chalcogen bond. This effect can
be useful to induce selectivity, as the necessary combination of methionine
residues only occurs in 9.3% of human kinases, while methionine is
the predominant gatekeeper (39%)
*Measurement of the Branching Ratios for the Decays Tau->Hadron Pi-0-Nu and Tau->Hadron Pi-0-Pi-0-Nu
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Design, Synthesis, and Biological Evaluation of Novel Type I<sup>1</sup>/<sub>2</sub> p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R‑Spine
We recently reported <b>1a</b> (skepinone-L) as a type I p38α MAP kinase inhibitor with high
potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor,
it is entirely ATP-competitive and shows just a moderate residence
time. Thus, the scope was to develop a new class of advanced compounds
maintaining the structural binding features of skepinone-L scaffold
like inducing a glycine flip at the hinge region and occupying both
hydrophobic regions I and II. Extending this scaffold with suitable
residues resulted in an interference with the kinase’s R-Spine.
By synthesizing 69 compounds, we could significantly prolong the target
residence time with one example to 3663 s, along with an excellent
selectivity score of 0.006 and an outstanding potency of 1.0 nM. This
new binding mode was validated by cocrystallization, showing all binding
interactions typifying type I<sup>1</sup>/<sub>2</sub> binding. Moreover,
microsomal studies showed convenient metabolic stability of the most
potent, herein reported representatives
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