New tuberculosis drugs on the horizon

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Calcium-sensing receptor antagonism or lithium treatment ameliorates aminoglycoside-induced cell death in renal epithelial cells

AbstractThe aminoglycoside antibiotic gentamicin elicits proximal tubular toxicity and cell death. In calcium-sensing receptor (CaR)-transfected HEK-293 (CaR-HEK) cells and CaR-expressing proximal tubule-derived opossum kidney (OK) cells, chronic gentamicin treatment elicits dose-dependent, caspase-mediated apoptotic cell death. Here we investigated whether the renal cell toxicity of the CaR agonist gentamicin could be prevented by CaR antagonism or by lithium cotreatment which may interfere with receptor-mediated signalling. Chronic treatment of OK and CaR-HEK cells with low concentrations of gentamicin elicited cell death, an effect that was ameliorated by cotreatment with the CaR negative allosteric modulator (calcilytic) NPS-89636. This calcilytic also attenuated CaR agonist-induced ERK activation in these cells. In addition, 1 mM LiCl, equivalent to its therapeutic plasma concentration, also inhibited gentamicin-induced toxicity in both cell types. This protective effect of lithium was not due to the disruption of phosphatidylinositol-mediated gentamicin uptake as the cellular entry of Texas red-conjugated gentamicin into OK and CaR-HEK cells was unchanged by lithium treatment. However, the protective effect of lithium was mimicked by glycogen synthase 3β inhibition. Together, these data implicate CaR activation and a lithium-inhibitable signalling pathway in the induction of cell death by gentamicin in renal epithelial cells in culture

Acute acquired immune thrombocytopenia after cardiac surgery: A challenging case

Thrombocytopenia is a common condition that recognizes an infinite number of possible causes, especially in specific settings like the one covered in this case report: the postoperative period of cardiac surgery. We report a case of an old male with multiple comorbidities who underwent a coronary angioplasty procedure and aortic valve replacement. He showed severe thrombocytopenia in the postoperative days. Differential diagnosis required a big effort, also for the experts in the field. Our goal was to aggressively treat the patient with prednisolone, platelets, and intravenous immunoglobulins to maximize the prognosis. Our patient developed no complications and was discharged successfully

Dynamic origin of chirality transfer between chiral surface and achiral ligand in Au38 clusters

The transfer of chirality between nanomolecules is at the core of several applications in chiral technology such as sensing and catalysis. However, the origin of this phenomenon and how exactly nanoscale objects transfer chirality to molecules in their vicinity remain largely obscure. Here, we show that the transfer of chirality for the intrinsically chiral gold cluster Au38(SR)24 is site dependent; that is, it differs depending on the ligand-binding sites. This is closely related to the dynamic nature of the ligands on the cluster surface. Using a combination of NMR techniques and molecular dynamics simulations, we could assign the four symmetry- unique ligands on the cluster. The study reveals largely different conformational dynamics of the bound ligands, explaining the diverse diastereotopicities observed for the CH2 protons of the ligands. Although chirality is a structural property, our study reveals the importance of dynamics for the transfer of chirality

Development of a repressible mycobacterial promoter system based on two transcriptional repressors

Tightly regulated gene expression systems represent invaluable tools for studying gene function and for the validation of drug targets in bacteria. While several regulated bacterial promoters have been characterized, few of them have been successfully used in mycobacteria. In this article we describe the development of a novel repressible promoter system effective in both fast- and slow-growing mycobacteria based on two chromosomally encoded repressors, dependent on tetracycline (TetR) and pristinamycin (Pip), respectively. This uniqueness results in high versatility and stringency. Using this method we were able to obtain an ftsZ conditional mutant in Mycobacterium smegmatis and a fadD32 conditional mutant in Mycobacterium tuberculosis, confirming their essentiality for bacterial growth in vitro. This repressible promoter system could also be exploited to regulate gene expression during M. tuberculosis intracellular growt

Magellan Adaptive Optics first-light observations of the exoplanet beta Pic b. II. 3-5 micron direct imaging with MagAO+Clio, and the empirical bolometric luminosity of a self-luminous giant planet

Young giant exoplanets are a unique laboratory for understanding cool, low-gravity atmospheres. A quintessential example is the massive extrasolar planet $\beta$ Pic b, which is 9 AU from and embedded in the debris disk of the young nearby A6V star $\beta$ Pictoris. We observed the system with first light of the Magellan Adaptive Optics (MagAO) system. In Paper I we presented the first CCD detection of this planet with MagAO+VisAO. Here we present four MagAO+Clio images of $\beta$ Pic b at 3.1 $\mu$m, 3.3 $\mu$m, $L^\prime$, and $M^\prime$, including the first observation in the fundamental CH$_4$ band. To remove systematic errors from the spectral energy distribution (SED), we re-calibrate the literature photometry and combine it with our own data, for a total of 22 independent measurements at 16 passbands from 0.99--4.8 $\mu$m. Atmosphere models demonstrate the planet is cloudy but are degenerate in effective temperature and radius. The measured SED now covers $>$80\% of the planet's energy, so we approach the bolometric luminosity empirically. We calculate the luminosity by extending the measured SED with a blackbody and integrating to find log($L_{bol}$/$L_{Sun}$) $= -3.78\pm0.03$. From our bolometric luminosity and an age of 23$\pm$3 Myr, hot-start evolutionary tracks give a mass of 12.7$\pm$0.3 $M_{Jup}$, radius of 1.45$\pm$0.02 $R_{Jup}$, and $T_{eff}$ of 1708$\pm$23 K (model-dependent errors not included). Our empirically-determined luminosity is in agreement with values from atmospheric models (typically $-3.8$ dex), but brighter than values from the field-dwarf bolometric correction (typically $-3.9$ dex), illustrating the limitations in comparing young exoplanets to old brown dwarfs.Comment: Accepted to ApJ. 27 pages, 22 figures, 19 table