On Abstraction-Based Controller Design With Output Feedback

We consider abstraction-based design of output-feedback controllers for dynamical systems with a finite set of inputs and outputs against specifications in linear-time temporal logic. The usual procedure for abstraction-based controller design (ABCD) first constructs a finite-state abstraction of the underlying dynamical system, and second, uses reactive synthesis techniques to compute an abstract state-feedback controller on the abstraction. In this context, our contribution is two-fold: (I) we define a suitable relation between the original system and its abstraction which characterizes the soundness and completeness conditions for an abstract state-feedback controller to be refined to a concrete output-feedback controller for the original system, and (II) we provide an algorithm to compute a sound finite-state abstraction fulfilling this relation. Our relation generalizes feedback-refinement relations from ABCD with state-feedback. Our algorithm for constructing sound finite-state abstractions is inspired by the simultaneous reachability and bisimulation minimization algorithm of Lee and Yannakakis. We lift their idea to the computation of an observation-equivalent system and show how sound abstractions can be obtained by stopping this algorithm at any point. Additionally, our new algorithm produces a realization of the topological closure of the input/output behavior of the original system if it is finite-state realizable

Molecular investigations on a chimeric strain of Staphylococcus aureus sequence type 80

A PVL-positive, methicillin-susceptible Staphylococcus aureus was cultured from pus from cervical lymphadenitis of a patient of East-African origin. Microarray hybridisation assigned the isolate to clonal complex (CC) 80 but revealed unusual features, including the presence of the ORF-CM14 enterotoxin homologue and of an ACME-III element as well as the absence of etD and edinB. The isolate was subjected to both, Illumina and Nanopore sequencing allowing characterisation of deviating regions within the strain´s genome. Atypical features of this strain were attributable to the presence of two genomic regions that originated from other S. aureus lineages and that comprised, respectively, 3% and 1.4% of the genome. One deviating region extended from walJ to sirB. It comprised ORF-CM14 and the ACME-III element. A homologous but larger fragment was also found in an atypical S. aureus CC1/ST567 strain whose lineage might have served as donor of this genomic region. This region itself is a chimera comprising fragments from CC1 as well as fragments of unknown origin. The other deviating region comprised the region from htsB to ecfA2, i.e., another 3% of the genome. It was very similar to CC1 sequences. Either this suggests an incorporation of CC1 DNA into the study strain, or alternatively a recombination event affecting “canonical” CC80. Thus, the study strain bears witness of several recombination events affecting supposedly core genomic genes. Although the exact mechanism is not yet clear, such chimerism seems to be an additional pathway in the evolution of S. aureus. This could facilitate also a transmission of virulence and resistance factors and therefore offer an additional evolutionary advantage

Measuring the Coherent Synchrotron Radiation Far Field with Electro-Optical Techniques

For measuring the temporal profile of the coherent synchrotron radiation (CSR) a setup based on electro-optical spectral decoding (EOSD) will be installed as part of the sensor network at the KIT storage ring KARA (Karlsruhe Research Accelerator). The EOSD technique allows a single-shot, phase sensitive measurement of the complete spectrum of the CSR far field radiation at each turn. Therefore, the dynamics of the bunch evolution, e.g. the microbunching, can be observed in detail. Especially, in synchronized combination with the already established near-field EOSD, this method could provide deeper insights in the interplay of bunch profile and CSR generation for each individual electron bunch. For a successful implementation of the EOSD single shot setup, measurements with electro-optical sampling (EOS) are performed. With EOS the THz pulse shape is scanned over several turns by shifting the delay of laser and THz pulse. In this contribution different steps towards the installation of the EOSD far field setup are summarized

EBI2 is highly expressed in multiple sclerosis lesions and promotes early CNS migration of encephalitogenic CD4 T cells

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7{alpha},25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7{alpha},25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1{beta}), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs

DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis

© The Author 2015. Published by Oxford University Press. All rights reserved. Epidemiological studies indicate that N-nitroso compounds (NOC) are causally linked to colorectal cancer (CRC). NOC induce DNA alkylations, including O6-methylguanine (O6-MeG) and N-methylated purines, which are repaired by O6-MeGDNA methyltransferase (MGMT) and N-alkyladenine-DNA glycosylase (AAG)-initiated base excision repair, respectively. In view of recent evidence of nonlinear mutagenicity for NOC-like compounds, the question arises as to the existence of threshold doses in CRC formation. Here, we set out to determine the impact of DNA repair on the dose-response of alkylation-induced CRC. DNA repair proficient (WT) and deficient (Mgmt-/-, Aag-/- and Mgmt-/-/Aag-/-) mice were treated with azoxymethane (AOM) and dextran sodium sulfate to trigger CRC. Tumors were quantified by non-invasive mini-endoscopy. A non-linear increase in CRC formation was observed in WT and Aag-/- mice. In contrast, a linear dose-dependent increase in tumor frequency was found in Mgmt-/- and Mgmt-/-/Aag-/- mice. The data were corroborated by hockey stick modeling, yielding similar carcinogenic thresholds for WT and Aag-/- and no threshold for MGMT lacking mice. O6-MeG levels and depletion of MGMT correlated well with the observed dose-response in CRC formation. AOM induced dose-dependently DNA double-strand breaks in colon crypts including Lgr5-positive colon stem cells, which coincided with ATR-Chk1-p53 signaling. Intriguingly, Mgmt-/- mice displayed significantly enhanced levels of γ-H2AX, suggesting the usefulness of γ-H2AX as an early genotoxicity marker in the colorectum. This study demonstrates for the first time a non-linear dose-response for alkylation-induced colorectal carcinogenesis and reveals DNA repair by MGMT, but not AAG, as a key node in determining a carcinogenic threshold

Rapid Identification of Carbapenemase Genes in Gram-Negative Bacteria with an Oligonucleotide Microarray-Based Assay

<div><p>Rapid molecular identification of carbapenemase genes in Gram-negative bacteria is crucial for infection control and prevention, surveillance and for epidemiological purposes. Furthermore, it may have a significant impact upon determining the appropriate initial treatment and greatly benefit for critically ill patients. A novel oligonucleotide microarray-based assay was developed to simultaneously detect genes encoding clinically important carbapenemases as well as selected extended (ESBL) and narrow spectrum (NSBL) beta-lactamases directly from clonal culture material within few hours. Additionally, a panel of species specific markers was included to identify <i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>, <i>Citrobacter freundii/braakii</i>, <i>Klebsiella pneumoniae</i> and <i>Acinetobacter baumannii</i>. The assay was tested using a panel of 117 isolates collected from urinary, blood and stool samples. For these isolates, phenotypic identifications and susceptibility tests were available. An independent detection of carbapenemase, ESBL and NSBL genes was carried out by various external reference laboratories using PCR methods. In direct comparison, the microarray correctly identified 98.2% of the covered carbapenemase genes. This included <i>bla</i>VIM (13 out of 13), <i>bla</i>GIM (2/2), <i>bla</i>KPC (27/27), <i>bla</i>NDM (5/5), <i>bla</i>IMP-2/4/7/8/13/14/15/16/31 (10/10), <i>bla</i>OXA-23 (12/13), <i>bla</i>OXA-40-group (7/7), <i>bla</i>OXA-48-group (32/33), <i>bla</i>OXA-51 (1/1) and <i>bla</i>OXA-58 (1/1). Furthermore, the test correctly identified additional beta-lactamases [<i>bla</i>OXA-1 (16/16), <i>bla</i>OXA-2 (4/4), <i>bla</i>OXA-9 (33/33), OXA-10 (3/3), <i>bla</i>OXA-51 (25/25), <i>bla</i>OXA-58 (2/2), CTX-M1/M15 (17/17) and <i>bla</i>VIM (1/1)]. In direct comparison to phenotypical identification obtained by VITEK or MALDI-TOF systems, 114 of 117 (97.4%) isolates, including <i>Acinetobacter baumannii</i> (28/28), <i>Enterobacter spec</i>. (5/5), <i>Escherichia coli</i> (4/4), <i>Klebsiella pneumoniae</i> (62/63), <i>Klebsiella oxytoca</i> (0/2), <i>Pseudomonas aeruginosa</i> (12/12), <i>Citrobacter freundii</i> (1/1) and <i>Citrobacter braakii</i> (2/2), were correctly identified by a panel of species specific probes. This assay might be easily extended, adapted and transferred to point of care platforms enabling fast surveillance, rapid detection and appropriate early treatment of infections caused by multiresistant Gram-negative bacteria.</p></div

Species genotyping results of the <b>M</b>icroarray-based assay in comparison to the <b>R</b>eference method (phenotypic results were obtained from University Medical Center of Dresden, University Medical Center of Jena, German Collection of Microorganisms and Cell Cultures, Institut Pasteur and Friedrich-Loeffler-Institute).

<p>Species genotyping results of the <b><u>M</u></b>icroarray-based assay in comparison to the <b><u>R</u></b>eference method (phenotypic results were obtained from University Medical Center of Dresden, University Medical Center of Jena, German Collection of Microorganisms and Cell Cultures, Institut Pasteur and Friedrich-Loeffler-Institute).</p