Bacterial evolution of antibiotic hypersensitivity.

The evolution of resistance to a single antibiotic is frequently accompanied by increased resistance to multiple other antimicrobial agents. In sharp contrast, very little is known about the frequency and mechanisms underlying collateral sensitivity. In this case, genetic adaptation under antibiotic stress yields enhanced sensitivity to other antibiotics. Using large-scale laboratory evolutionary experiments with Escherichia coli, we demonstrate that collateral sensitivity occurs frequently during the evolution of antibiotic resistance. Specifically, populations adapted to aminoglycosides have an especially low fitness in the presence of several other antibiotics. Whole-genome sequencing of laboratory-evolved strains revealed multiple mechanisms underlying aminoglycoside resistance, including a reduction in the proton-motive force (PMF) across the inner membrane. We propose that as a side effect, these mutations diminish the activity of PMF-dependent major efflux pumps (including the AcrAB transporter), leading to hypersensitivity to several other antibiotics. More generally, our work offers an insight into the mechanisms that drive the evolution of negative trade-offs under antibiotic selection

A generalized exponential relationship between the surface-enhanced Raman scattering (SERS) efficiency of gold/silver nanoisland arrangements and their non-dimensional interparticle distance/particle diameter ratio

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Effects of 1-year anti-TNF-α therapies on bone mineral density and bone biomarkers in rheumatoid arthritis and ankylosing spondylitis

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Measurement of the cross-section for Z → e⁺e^- production in pp collisions at &#8730;<span style="text-decoration:overline">s</span>=7 TeV

A measurement of the cross-section for pp → Z → e+e− is presented using data at s√=7 TeV corresponding to an integrated luminosity of 0.94 fb−1. The process is measured within the kinematic acceptance p T &#62; 20 GeV/c and 2 &#60; η &#60; 4.5 for the daughter electrons and dielectron invariant mass in the range 60–120 GeV/c 2. The cross-section is determined to be σ(pp→Z→e+e−)=76.0±0.8±2.0±2.6pb where the first uncertainty is statistical, the second is systematic and the third is the uncertainty in the luminosity. The measurement is performed as a function of Z rapidity and as a function of an angular variable which is closely related to the Z transverse momentum. The results are compared with previous LHCb measurements and with theoretical predictions from QCD

The M-current contributes to high threshold membrane potential oscillations in a cell type-specific way in the pedunculopontine nucleus of mice.

The pedunculopontine nucleus is known as a cholinergic nucleus of the reticular activating system, participating in regulation of sleep and wakefulness. Besides cholinergic neurons, it consists of GABAergic and glutamatergic neurons as well. According to classical and recent studies, more subgroups of neurons were defined. Groups based on the neurotransmitter released by a neuron are not homogenous, but can be further subdivided. The PPN neurons do not only provide cholinergic and non-cholinergic inputs to several subcortical brain areas but they are also targets of cholinergic and other different neuromodulatory actions. Although cholinergic neuromodulation has been already investigated in the nucleus, one of its characteristic targets, the M-type potassium current has not been described yet. Using slice electrophysiology, we provide evidence in the present work that cholinergic neurons possess M-current, whereas GABAergic neurons lack it. The M-current contributes to certain functional differences of cholinergic and GABAergic neurons, as spike frequency adaptation, action potential firing frequency or the amplitude difference of medium afterhyperpolarizations (AHPs). Furthermore, we showed that high threshold membrane potential oscillation with high power, around 20 Hz frequency is a functional property of almost all cholinergic cells, whereas GABAergic neurons have only low amplitude oscillations. Blockade of the M-current abolished the oscillatory activity at 20 Hz, and largely diminished it at other frequencies. Taken together, the M-current seems to be characteristic for PPN cholinergic neurons. It provides a possibility for modulating gamma band activity of these cells, thus contributing to neuromodulatory regulation of the reticular activating system

Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing

Extracellular ATP binds to and signals through P2X7 receptors (P2X7Rs) to modulate immune function in both inflammasome-dependent and -independent manners. In this study, P2X7-/- mice, the pharmacological agonists ATP-magnesium salt (Mg-ATP; 100 mg/kg, EC50 ≈ 1.32 mM) and benzoylbenzoyl-ATP (Bz-ATP; 10 mg/kg, EC50 ≈ 285 μM), and antagonist oxidized ATP (oxi-ATP; 40 mg/kg, IC50 ≈ 100 μM) were used to show that P2X7R activation is crucial for the control of mortality, bacterial dissemination, and inflammation in cecal ligation and puncture-induced polymicrobial sepsis in mice. Our results with P2X7-/- bone marrow chimeric mice, adoptive transfer of peritoneal macrophages, and myeloid-specific P2X7-/- mice indicate that P2X7R signaling on macrophages is essential for the protective effect of P2X7Rs. P2X7R signaling protects through enhancing bacterial killing by macrophages, which is independent of the inflammasome. By using the connexin (Cx) channel inhibitor Gap27 (0.1 mg/kg, IC50 ≈ 0.25 μM) and pannexin channel inhibitor probenecid (10 mg/kg, IC50 ≈ 11.7 μM), we showed that ATP release through Cx is important for inhibiting inflammation and bacterial burden. In summary, targeting P2X7Rs provides a new opportunity for harnessing an endogenous protective immune mechanism in the treatment of sepsis.-Csóka, B., Németh, Z. H., Töro, G., Idzko, M., Zech, A., Koscsó, B., Spolarics, Z., Antonioli, L., Cseri, K., Erdélyi, K., Pacher, P., Haskó, G. Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing