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Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins—a class of natural products with weak activity and limited spectrum—to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections. Chemical optimization of arylomycins results in an inhibitor of bacterial type I signal peptidase that shows activity both against multidrug-resistant clinical isolates of Gram-negative bacteria in vitro and in several in vivo infection models.

The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family. Crystal structures of the ABC transporter MsbA in complex with two selective small-molecule antagonists reveal an unprecedented allosteric mechanism of inhibition.

A plasmonic modulator is a device that controls the amplitude or phase of propagating plasmons. In a pure plasmonic modulator, the presence or absence of a plasmonic pump wave controls the amplitude of a plasmonic probe wave through a channel. This control has to be mediated by an interaction between disparate plasmonic waves, typically requiring the integration of a nonlinear material. In this work, we demonstrate a 2D semiconductor nonlinear plasmonic modulator based on a WSe 2 monolayer integrated on top of a lithographically defined metallic waveguide. We utilize the strong interaction between the surface plasmon polaritons (SPPs) and excitons in the WSe 2 to give a 73 % change in transmission through the device. We demonstrate control of the propagating SPPs using both optical and SPP pumps, realizing a 2D semiconductor nonlinear plasmonic modulator, with an ultrafast response time of 290 fs. Plasmonic modulators have many possible applications in optical-frequency devices. Here the authors report a 2D semiconductor nonlinear plasmonic modulator enabled through strong interaction between the surface plasmon polaritons and excitons in a monolayer semiconductor integrated on top of a metallic waveguide.

Interlayer excitons (IXs) in MoSe 2 –WSe 2 heterobilayers have generated interest as highly tunable light emitters in transition metal dichalcogenide (TMD) heterostructures. Previous reports of spectrally narrow (<1 meV) photoluminescence (PL) emission lines at low temperature have been attributed to IXs localized by the moiré potential between the TMD layers. We show that spectrally narrow IX PL lines are present even when the moiré potential is suppressed by inserting a bilayer hexagonal boron nitride (hBN) spacer between the TMD layers. We compare the doping, electric field, magnetic field, and temperature dependence of IXs in a directly contacted MoSe 2 –WSe 2 region to those in a region separated by bilayer hBN. The doping, electric field, and temperature dependence of the narrow IX lines are similar for both regions, but their excitonic g-factors have opposite signs, indicating that the origin of narrow IX PL is not the moiré potential. The spectrally narrow photoluminescence lines occurring in transition metal dichalcogenides (TMD) heterostructures at low temperature have been attributed to interlayer excitons (IXs) localized by the moiré potential between the TMD layers. Here, the authors show that these lines are present even when the moiré potential is suppressed by inserting an hBN spacer between the TMD layers.

To increase granularity in human neuroimaging science, we designed and built a next-generation 7 Tesla magnetic resonance imaging scanner to reach ultra-high resolution by implementing several advances in hardware. To improve spatial encoding and increase the image signal-to-noise ratio, we developed a head-only asymmetric gradient coil (200 mT m −1 , 900 T m −1 s −1 ) with an additional third layer of windings. We integrated a 128-channel receiver system with 64- and 96-channel receiver coil arrays to boost signal in the cerebral cortex while reducing g-factor noise to enable higher accelerations. A 16-channel transmit system reduced power deposition and improved image uniformity. The scanner routinely performs functional imaging studies at 0.35–0.45 mm isotropic spatial resolution to reveal cortical layer functional activity, achieves high angular resolution in diffusion imaging and reduces acquisition time for both functional and structural imaging. A combination of hardware developments has increased the achievable spatial resolution in 7 Tesla human neuroimaging to about 0.4 mm.

Spectrally narrow optical resonances can be used to generate slow light, i.e., a large reduction in the group velocity. In a previous work, we developed hybrid 2D semiconductor plasmonic structures, which consist of propagating optical frequency surface-plasmon polaritons interacting with excitons in a semiconductor monolayer. Here, we use coupled exciton-surface plasmon polaritons (E-SPPs) in monolayer WSe 2 to demonstrate slow light with a 1300 fold decrease of the SPP group velocity. Specifically, we use a high resolution two-color laser technique where the nonlinear E-SPP response gives rise to ultra-narrow coherent population oscillation (CPO) resonances, resulting in a group velocity on order of 10 5  m/s. Our work paves the way toward on-chip actively switched delay lines and optical buffers that utilize 2D semiconductors as active elements. Slow light effects are interesting for telecommunications and quantum photonics applications. Here, the authors use coupled exciton-surface plasmon polaritons (SPPs) in a hybrid monolayer WSe 2 -metallic waveguide structure to demonstrate a 1300-fold reduction of the SPP group velocity.

Atomically thin transition metal dichalcogenides (TMDs) are currently receiving significant attention due to their promising opto-electronic properties. Tuning optical and electrical properties of mono and few-layer TMDs, such as tungsten diselenide (WSe 2 ), by controlling the defects, is an intriguing opportunity to synthesize next generation two dimensional material opto-electronic devices. Here, we report the effects of focused helium ion beam irradiation on the structural, optical and electrical properties of few-layer WSe 2 , via high resolution scanning transmission electron microscopy, Raman spectroscopy and electrical transport measurements. By controlling the ion irradiation dose, we selectively introduce precise defects in few-layer WSe 2 thereby locally tuning the resistivity and transport properties of the material. Hole transport in the few layer WSe 2 is degraded more severely relative to electron transport after helium ion irradiation. Furthermore, by selectively exposing material with the ion beam, we demonstrate a simple yet highly tunable method to create lateral homo-junctions in few layer WSe 2 flakes, which constitutes an important advance towards two dimensional opto-electronic devices.

Pseudomonas aeruginosa causes life-threatening infections that are associated with antibiotic failure. Previously, we identified the antibiotic G2637, an analog of arylomycin, targeting bacterial type I signal peptidase, which has moderate potency against P. aeruginosa. We hypothesized that an antibody-antibiotic conjugate (AAC) could increase its activity by colocalizing P. aeruginosa bacteria with high local concentrations of G2637 antibiotic in the intracellular environment of phagocytes. Using a novel technology of screening for hybridomas recognizing intact bacteria, we identified monoclonal antibody 26F8, which binds to lipopolysaccharide O antigen on the surface of P. aeruginosa bacteria. This antibody was engineered to contain 6 cysteines and was conjugated to the G2637 antibiotic via a lysosomal cathepsin-cleavable linker, yielding a drug-to-antibody ratio of approximately 6. The resulting AAC delivered a high intracellular concentration of free G2637 upon phagocytosis of AAC-bound P. aeruginosa by macrophages, and potently cleared viable P. aeruginosa bacteria intracellularly. The molar concentration of AAC-associated G2637 antibiotic that resulted in elimination of bacteria inside macrophages was approximately 2 orders of magnitude lower than the concentration of free G2637 required to eliminate extracellular bacteria. This study demonstrates that an anti-P. aeruginosa AAC can locally concentrate antibiotic and kill P. aeruginosa inside phagocytes, providing additional therapeutic options for antibiotics that are moderately active or have an unfavorable pharmacokinetics or toxicity profile. Antibiotic treatment of life-threatening P. aeruginosa infections is associated with low clinical success, despite the availability of antibiotics that are active in standard microbiological assays, affirming the need for new therapeutic approaches. Antibiotics often fail in the preclinical stage due to insufficient efficacy against P. aeruginosa. One potential strategy is to enhance the local concentration of antibiotics with limited inherent anti-P. aeruginosa activity. This study presents proof of concept for an antibody-antibiotic conjugate, which releases a high local antibiotic concentration inside macrophages upon phagocytosis, resulting in potent intracellular killing of phagocytosed P. aeruginosa bacteria. This approach may provide new therapeutic options for antibiotics that are dose limited.

Background The purpose of the present study was to examine the effectiveness of the injury awareness and prevention programme P.A.R.T.Y. (Prevent Alcohol and Risk-Related Trauma in Youth) in Germany. On a designated P.A R.T.Y. day, school classes spend a day in a trauma hospital experiencing the various wards through which a seriously injured person goes. A further goal of the study was to reveal indications of the programme’s mechanism of action by testing theory-based impact models of fear appeals and cognitive beliefs. Methods In a quasi-experimental longitudinal study with three measurement times the participants of 19 P.A.R.T.Y. days ( n  = 330), as well as pupils who did not attend the programme ( n  = 244), were interviewed with a standardised questionnaire. They reported risk behaviour, feelings of threat and cognitive beliefs about road traffic. The data were analysed using a meta-analytical approach to estimate an average effect size across the different P.A.R.T.Y. days. Path models were used to identify possible mechanisms of action. Results For most of the parameters, small positive effects could be proven immediately after the P.A.R.T.Y. intervention. However, after four to 5 months only one statistically significant effect was found. Using path analytical models, important predictors for behavioural changes (e.g. self-efficacy) could be identified. But for these predictors no or only short-term effects were observed in the meta-analysis. Conclusions Fear appeals as used primarily in the P.A.R.T.Y. programme appear to cause behavioural changes only to a limited extent and only in the short-term, especially if the strengthening of psychosocial resources is not given sufficient consideration. The participants must also cognitively process the experiences in the hospital. Accordingly, consideration should be given to how the P.A.R.T.Y. program could be adapted to complement the fear appeal with cognitive components.

Evaluation of multislice-CT (MSCT) during diagnosis and therapeutic decision-making in patients with suspected non-occlusive mesenteric ischemia (NOMI). Retrospective, institutional review board-approved study of 30 patients (20 men, 10 women, mean age 64.6±14.2 years, range 24-87 years) undergoing biphasic abdominal MSCT followed by digital subtraction angiography (DSA) due to suspected NOMI. MSCT and DSA were qualitatively and quantitatively evaluated independently by two radiologists with respect to the possible diagnosis of NOMI. MSCT analysis included quantitative measurements, qualitative evaluation of contrast enhancement and assessment of secondary findings (bowel wall thickening, hypo-enhancement, intestinal pneumatosis). MSCT diagnosis and secondary findings were compared against DSA diagnosis. NOMI was diagnosed in a total of n = 28 patients. No differences were found when comparing the R1-rated MSCT diagnosis (p = 0.09) to the \"gold standard\", while MSCT diagnosis was slightly inferior with R2 (p = 0.02). With R1, vessel-associated parameters revealed the best correlation, i.e. qualitative vessel width (r = -0.39;p = 0.03) and vessel contrast (r = 0.45;p = 0.01). Moderate correlations were found for quantitative vessel diameters in the middle segments (r = -0.48,p = 0.01), increasing to almost high correlations in the distal (r = -0.66;p<0.00001) superior mesenteric artery (SMA) segments. No significant correlation was apparent from secondary findings. MSCT is an appropriate non-invasive method for diagnosing NOMI and leads to adequate and immediate therapeutic stratification.