Momentum conservation and local field corrections for the response of interacting Fermi gases

We reanalyze the recently derived response function for interacting systems in relaxation time approximation respecting density, momentum and energy conservation. We find that momentum conservation leads exactly to the local field corrections for both cases respecting only density conservation and respecting density and energy conservation. This rewriting simplifies the former formulae dramatically. We discuss the small wave vector expansion and find that the response function shows a high frequency dependence of $\omega^{-5}$ which allows to fulfill higher order sum rules. The momentum conservation also resolves a puzzle about the conductivity which should only be finite in multicomponent systems

Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections

Spiking Patterns and Their Functional Implications in the Antennal Lobe of the Tobacco Hornworm Manduca sexta

Bursting as well as tonic firing patterns have been described in various sensory systems. In the olfactory system, spontaneous bursts have been observed in neurons distributed across several synaptic levels, from the periphery, to the olfactory bulb (OB) and to the olfactory cortex. Several in vitro studies indicate that spontaneous firing patterns may be viewed as “fingerprints” of different types of neurons that exhibit distinct functions in the OB. It is still not known, however, if and how neuronal burstiness is correlated with the coding of natural olfactory stimuli. We thus conducted an in vivo study to probe this question in the OB equivalent structure of insects, the antennal lobe (AL) of the tobacco hornworm Manduca sexta. We found that in the moth's AL, both projection (output) neurons (PNs) and local interneurons (LNs) are spontaneously active, but PNs tend to produce spike bursts while LNs fire more regularly. In addition, we found that the burstiness of PNs is correlated with the strength of their responses to odor stimulation – the more bursting the stronger their responses to odors. Moreover, the burstiness of PNs was also positively correlated with the spontaneous firing rate of these neurons, and pharmacological reduction of bursting resulted in a decrease of the neurons' responsiveness. These results suggest that neuronal burstiness reflects a physiological state of these neurons that is directly linked to their response characteristics

High Precision Electron Beam Diagnostic System for High Current Long Pulse Beams

As part of the effort to develop a multi-axis electron beam transport system using stripline kicker technology for DARHT II apploications, it is necessary to precisely determine the position and extent of long high energy beams (6-40 MeV, 1-4 kA, 2 microseconds) for accurate position control. The kicker positioning system utilizes shot-to-shot adjustments for reduction of relatively slow (<20 MHz) motion of the beam centroid. The electron beams passing through the diagnostic systems have the potential for large halo effects that tend to corrupt measurements performed using capacitive pickoff probes. Likewise, transmission line traveling wave probes have problems with multi-bounce effects due to these longer pulse widths. Finally, the high energy densities experienced in these applications distort typical foil beam position measurements

Apramycin overcomes the inherent lack of antimicrobial bactericidal activity in Mycobacterium abscessus

Antibiotic therapy of infections caused by the emerging pathogen Mycobacterium abscessus is challenging due to the organism's inherent resistance towards clinically available antimicrobials. The low bactericidal potency of currently available treatment regimens is of concern and testifies to the poor therapeutic outcome in pulmonary M. abscessus infections. Mechanistically, we here demonstrate that the acetyltransferase Eis2 is responsible for the lack of bactericidal activity of amikacin, the standard aminoglycoside used in combination treatment. In contrast, the distinct structure aminoglycoside apramycin is not modified by any of the pathogen's innate aminoglycoside resistance mechanisms nor is it affected by the multi-drug resistance regulator WhiB7. As a consequence, apramycin uniquely shows potent bactericidal activity against M. abscessus. This favourable feature of apramycin is reflected in a mouse model of M. abscessus lung infection, which demonstrates superior activity over amikacin. These findings encourage the development of apramycin for the treatment of M. abscessus infections and suggest that M. abscessus eradication in lung pulmonary disease may be within therapeutic reach

Antibodies protect against intracellular bacteria by Fc receptor-mediated lysosomal targeting

The protective effect of antibodies (Abs) is generally attributed to neutralization or complement activation. Using Legionella pneumophila and Mycobacterium bovis bacillus Calmette–Guérin as a model, we discovered an additional mechanism of Ab-mediated protection effective against intracellular pathogens that normally evade lysosomal fusion. We show that Fc receptor (FcR) engagement by Abs, which can be temporally and spatially separated from bacterial infection, renders the host cell nonpermissive for bacterial replication and targets the pathogens to lysosomes. This process is strictly dependent on kinases involved in FcR signaling but not on host cell protein synthesis or protease activation. Based on these findings, we propose a mechanism whereby Abs and FcR engagement subverts the strategies by which intracellular bacterial pathogens evade lysosomal degradation