Vergleich eines konventionellen EEG-Systems mit einem neuartigen Schwämmchen-EEG für den klinischen Routineeinsatz

In dieser head-to-head-EEG-Studie wurde untersucht, ob ein neuartiges Schwämmchen (sp-) EEG-System einfacher und schneller zu applizieren ist als ein konventionelles (c-) EEG-System - ohne dabei einen Qualitätsverlust des EEG-Signals bei pathologischen Graphoelementen bei Patient:innen mit Epilepsie hinnehmen zu müssen. Hintergrund dieser Studie ist die klinische Notwendigkeit für ein neues EEG-System, das schnell, einfach und von EEG- unerfahrenem Personal angewendet werden kann. EEG-Aufzeichnungen mit einem sp-EEG-System und einem c-EEG-System wurden bei 18 Patient:innen mit einer bekannten Epilepsie durchgeführt. Die Applikationszeit, bis alle Elektroden angemessene Impedanzen (< 100 kΩ für das sp-EEG und < 20 kΩ für das c-EEG) aufwiesen, wurde gestoppt. Die resultierenden 36 EEG-Kurven wurden von sieben EEG-erfahrenen und verblindeten Neurolog:innen visuell auf pathologische Graphoelemente untersucht. Außerdem wurden die Neurolog:innen gefragt, ob sie allein durch die Inspektion der EEG-Kurven zwischen den verschiedenen Systemen unterscheiden könnten. Zusätzlich wurde in den Aufzeichnungen beider EEG- Systeme bei einer Patientin mit einer generalisierten Epilepsie das Signal-to-noise-Verhältnis und die Delta-Power und die Alpha-Power berechnet. Es zeigte sich, dass das sp-EEG im Durchschnitt mehr als doppelt so schnell appliziert werden konnte (sp-EEG = 4,69 Minuten vs. c-EEG = 13,18 Minuten, s. Abbildung 12). Es war den EEG-erfahrenen Neurolog:innen nicht möglich zu unterscheiden, ob eine EEG-Aufzeichnung mit einem sp-EEG oder einem c-EEG durchgeführt wurde. Es konnten alle pathologischen Graphoelemente in beiden EEG-Systemen ohne Qualitätsverlust identifiziert werden. Die Impedanzen des sp-EEGs waren höher mit einem Mittelwert von 43,01 ± 67,21 kΩ als die des c-EEGs, die jedoch nicht exakt berechnet werden konnten. Die SNR-Werte lagen eng beieinander (sp-EEG von 1,22 und im c-EEG von 1,36), sodass eine Vergleichbarkeit angenommen werden durfte. Außerdem bestand eine starke Korrelation von Delta (r = 0,65) und Alpha (r = 0,79). Das Schwämmchenelektrodenhaubensystem war einfacher zu applizieren und wurde weniger durch Bewegungen der Patient:innen beeinflusst. Die einzelnen Elektroden waren jedoch nicht individuell verstellbar, sodass es nicht bei allen Patient:innen optimal verwendet werden konnte. Das sp-EEG stellt ein EEG-System dar, das im klinischen Alltag schnell und einfach eingesetzt werden kann, insbesondere in Zeiten, in denen kein oder wenig EEG-erfahrenes Personal zur Verfügung steht. Folglich könnte der Einsatz eines sp-EEGs in der Akut- und Routinediagnostik einer Epilepsie oder eines Status Epilepticus die allgemeine EEG-Verfügbarkeit erhöhen und damit die Patient:innenversorgung verbessern

Multiple-charge transfer and trapping in DNA dimers

We investigate the charge transfer characteristics of one and two excess charges in a DNA base-pair dimer using a model Hamiltonian approach. The electron part comprises diagonal and off-diagonal Coulomb matrix elements such a correlated hopping and the bond-bond interaction, which were recently calculated by Starikov [E. B. Starikov, Phil. Mag. Lett. {\bf 83}, 699 (2003)] for different DNA dimers. The electronic degrees of freedom are coupled to an ohmic or a super-ohmic bath serving as dissipative environment. We employ the numerical renormalization group method in the nuclear tunneling regime and compare the results to Marcus theory for the thermal activation regime. For realistic parameters, the rate that at least one charge is transferred from the donor to the acceptor in the subspace of two excess electrons significantly exceeds the rate in the single charge sector. Moreover, the dynamics is strongly influenced by the Coulomb matrix elements. We find sequential and pair transfer as well as a regime where both charges remain self-trapped. The transfer rate reaches its maximum when the difference of the on-site and inter-site Coulomb matrix element is equal to the reorganization energy which is the case in a GC-GC dimer. Charge transfer is completely suppressed for two excess electrons in AT-AT in an ohmic bath and replaced by damped coherent electron-pair oscillations in a super-ohmic bath. A finite bond-bond interaction $W$ alters the transfer rate: it increases as function of $W$ when the effective Coulomb repulsion exceeds the reorganization energy (inverted regime) and decreases for smaller Coulomb repulsion

New Topoisomerase Inhibitors:Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature

Inactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of E. coli RND (resistance-nodulation-cell division)-type transporters, efflux inhibitors, and AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux-bypassing drugs and provide AcrB targets with critical relevance for this purpose

Limited Multidrug Resistance Efflux Pump Overexpression among Multidrug-Resistant Escherichia coli Strains of ST131

Gram-negative bacteria partly rely on efflux pumps to facilitate growth under stressful conditions and to increase resistance to a wide variety of commonly used drugs. In recent years E. coli ST131 has emerged as a major cause of extraintestinal infection frequently exhibiting an MDR phenotype. The contribution of efflux to MDR in emerging E. coli MDR clones however, is not well studied. We characterized strains from an international collection of clinical MDR-E. coli isolates by MIC testing with and without the addition of the AcrAB-TolC efflux inhibitor 1-(1-naphthylmethyl)-piperazine (NMP). MIC data for 6 antimicrobial agents and their reversion by NMP were analyzed by Principal Component Analysis (PCA). PCA revealed a group of 17/34 MDR-E. coli exhibiting increased susceptibility to treatment with NMP suggesting an enhanced contribution of efflux pumps to antimicrobial resistance in these strains (termed "enhanced efflux phenotype" [EEP]). Only 1/17 EEP strains versus 12/17 non-EEP MDR strains belonged to the ST131 clonal group. Whole-genome sequencing revealed marked differences in efflux-related genes between EEP and control strains, with the majority of notable amino-acid substitutions occurring in AcrR, MarR and SoxR. qRT-PCR of multiple efflux-related genes showed significant overexpression of the AcrAB-TolC-system in EEP strains, whereas in the remaining strains we found enhanced expression of alternative efflux proteins. We conclude that a proportion of MDR E. coli exhibit an EEP, which is linked to an overexpression of the AcrAB-TolC-efflux-pump and a distinct array of genomic variations. Members of ST131, although highly successful, are less likely to exhibit the EEP

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin-GnRH-III conjugates developed for targeted drug delivery

Gonadotropin releasing hormone-III (GnRH-III), a native isoform of the human GnRH isolated from sea lamprey, specifically binds to GnRH receptors on cancer cells enabling its application as targeting moieties for anticancer drugs. Recently, we reported on the identification of a novel daunorubicin–GnRH-III conjugate (GnRH-III–[4Lys(Bu), 8Lys(Dau=Aoa)] with efficient in vitro and in vivo antitumor activity. To get a deeper insight into the mechanism of action of our lead compound, the cellular uptake was followed by confocal laser scanning microscopy. Hereby, the drug daunorubicin could be visualized in different subcellular compartments by following the localization of the drug in a time-dependent manner. Colocalization studies were carried out to prove the presence of the drug in lysosomes (early stage) and on its site of action (nuclei after 10 min). Additional flow cytometry studies demonstrated that the cellular uptake of the bioconjugate was inhibited in the presence of the competitive ligand triptorelin indicating a receptor-mediated pathway. For comparative purpose, six novel daunorubicin–GnRH-III bioconjugates have been synthesized and biochemically characterized in which 6Asp was replaced by D-Asp, D-Glu and D-Trp. In addition to the analysis of the in vitro cytostatic effect and cellular uptake, receptor binding studies with 125I-triptorelin as radiotracer and degradation of the GnRH-III conjugates in the presence of rat liver lysosomal homogenate have been performed. All derivatives showed high binding affinities to GnRH receptors and displayed in vitro cytostatic effects on HT-29 and MCF-7 cancer cells with IC50 values in a low micromolar range. Moreover, we found that the release of the active drug metabolite and the cellular uptake of the bioconjugates were strongly affected by the amino acid exchange which in turn had an impact on the antitumor activity of the bioconjugates

Neural network-based estimates of North Atlantic surface pCO2 from satellite data: A methodological study

A new method is proposed to estimate ocean surface pCO2 from remotely sensed surface temperature and chlorophyll data. The method is applied to synthetic observations provided by an eddy-resolving biogeochemical model of the North Atlantic. The same model also provides a perfectly known simulated pCO2 “ground truth” used to quantitatively assess the success of the estimation method. Model output is first sampled according to realistic voluntary observing ship (VOS) and satellite coverage. The model-generated VOS “observations” are then used to train a self-organizing neural network that is subsequently applied to model-generated “satellite data” of surface temperature and surface chlorophyll in order to derive basin-wide monthly maps of surface pCO2. The accuracy of the estimated pCO2 maps is analyzed with respect to the “true” surface pCO2 fields simulated by the biogeochemical circulation model. We also investigate the accuracy of the estimated pCO2 maps as a function of VOS line coverage, remote sensing errors, and the interpolation of missing remote sensing data due to cloud cover and low solar irradiation in winter. For a simulated “sampling” corresponding to VOS lines and patterns of optical satellite coverage of the year 2005, the neural net can successfully reproduce pCO2 from model-generated “remote sensing data” of SST and Chl. Basin-wide RMS errors amount to 19.0 μatm for a hypothetical perfect interpolation scheme for remote sensing data gaps and 21.1 μatm when climatological surface temperature and chlorophyll values are used to fill in areas lacking optical satellite coverage

Proof of an Outer Membrane Target of the Efflux Inhibitor Phe-Arg-β-Naphthylamide from Random Mutagenesis

Phe-Arg-β-naphthylamide (PAβN) has been characterized as an efflux pump inhibitor (EPI) acting on the major multidrug resistance efflux transporters of Gram-negative bacteria, such as AcrB in Eschericha coli. In the present study, in vitro random mutagenesis was used to evolve resistance to the sensitizing activity of PAβN with the aim of elucidating its mechanism of action. A strain was obtained that was phenotypically similar to a previously reported mutant from a serial selection approach that had no efflux-associated mutations. We could confirm that acrB mutations in the new mutant were unrelated to PAβN resistance. The next-generation sequencing of the two mutants revealed loss-of-function mutations in lpxM. An engineered lpxM knockout strain showed up to 16-fold decreased PAβN activity with large lipophilic drugs, while its efflux capacity, as well as the efficacy of other EPIs, remained unchanged. LpxM is responsible for the last acylation step in lipopolysaccharide (LPS) synthesis, and lpxM deficiency has been shown to result in penta-acylated instead of hexa-acylated lipid A. Modeling the two lipid A types revealed steric conformational changes due to underacylation. The findings provide evidence of a target site of PAβN in the LPS layer, and prove membrane activity contributing to its drug-sensitizing potency

Recent variability of the global ocean carbon sink

We present a new observation-based estimate of the global oceanic carbon dioxide (CO2) sink and its temporal variation on a monthly basis from 1998 through 2011 and at a spatial resolution of 1×1. This sink estimate rests upon a neural network-based mapping of global surface ocean observations of the partial pressure of CO2 (pCO2) from the Surface Ocean CO2 Atlas database. The resulting pCO2 has small biases when evaluated against independent observations in the different ocean basins, but larger randomly distributed differences exist particularly in high latitudes. The seasonal climatology of our neural network-based product agrees overall well with the Takahashi et al. (2009) climatology, although our product produces a stronger seasonal cycle at high latitudes. From our global pCO2 product, we compute a mean net global ocean (excluding the Arctic Ocean and coastal regions) CO2 uptake flux of −1.42 ± 0.53 Pg C yr−1, which is in good agreement with ocean inversion-based estimates. Our data indicate a moderate level of interannual variability in the ocean carbon sink (±0.12 Pg C yr−1, 1&#x1d70e;) from 1998 through 2011, mostly originating from the equatorial Pacific Ocean, and associated with the El Nino–Southern Oscillation. Accounting for steady state riverine and Arctic Ocean carbon fluxes our estimate further implies a mean anthropogenic CO2 uptake of −1.99 ± 0.59 Pg C yr−1 over the analysis period. From this estimate plus the most recent estimates for fossil fuel emissions and atmospheric CO2 accumulation, we infer a mean global land sink of −2.82 ± 0.85 Pg C yr−1 over the 1998 through 2011 period with strong interannual variation