Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae.

Resistance in Neisseria gonorrhoeae to all available therapeutic antimicrobials has emerged and new efficacious drugs for treatment of gonorrhea are essential. The topoisomerase II inhibitor ETX0914 (also known as AZD0914) is a new spiropyrimidinetrione antimicrobial that has different mechanisms of action from all previous and current gonorrhea treatment options. In this study, the N. gonorrhoeae resistance determinants for ETX0914 were further described and the effects of ETX0914 on the growth of N. gonorrhoeae (ETX0914 wild type, single step selected resistant mutants, and efflux pump mutants) were examined in a novel in vitro time-kill curve analysis to estimate pharmacodynamic parameters of the new antimicrobial. For comparison, ciprofloxacin, azithromycin, ceftriaxone, and tetracycline were also examined (separately and in combination with ETX0914). ETX0914 was rapidly bactericidal for all wild type strains and had similar pharmacodynamic properties to ciprofloxacin. All selected resistant mutants contained mutations in amino acid codons D429 or K450 of GyrB and inactivation of the MtrCDE efflux pump fully restored the susceptibility to ETX0914. ETX0914 alone and in combination with azithromycin and ceftriaxone was highly effective against N. gonorrhoeae and synergistic interaction with ciprofloxacin, particularly for ETX0914-resistant mutants, was found. ETX0914, monotherapy or in combination with azithromycin (to cover additional sexually transmitted infections), should be considered for phase III clinical trials and future gonorrhea treatment.

On the road. Der Pilgerweg der Gerechtigkeit und des Friedens als transformative Herausforderung

Am Leitfaden der Geschichte der Emmaus-Jünger (Lk 24,13-35) wird die Botschaft der Ökumenischen Weltversammlung von Busan von 2013 in ihrer Verbindung von geistlicher Transformation der Glaubenden und politischer Transformation durch die Glaubenden am Beispiel der Nachhaltigkeitsthematik ausgelegt.

Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo

FTY720 sequesters lymphocytes in secondary lymphoid organs through effects on sphingosine-1-phosphate (S1P) receptors. However, at higher doses than are required for immunosuppression, FTY720 also functions as an anticancer agent in multiple animal models. Our published work indicates that the anticancer effects of FTY720 do not depend on actions at S1P receptors but instead stem from FTY720s ability to restrict access to extracellular nutrients by down-regulating nutrient transporter proteins. This result was significant because S1P receptor activation is responsible for FTY720s dose-limiting toxicity, bradycardia, that prevents its use in cancer patients. Here, we describe diastereomeric and enantiomeric 3- and 4-C-aryl 2-hydroxymethyl pyrrolidines that are more active than the previously known analogues. Of importance is that these compounds fail to activate S1P1 or S1P3 receptors in vivo but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Our studies reaffirm that the anticancer activity of FTY720 does not depend upon S1P receptor activation and uphold the promise of using S1P receptor-inactive azacyclic FTY720 analogues in human cancer patients.

The Kepler Problem (the road to Bohr)

The classical Kepler problem is reviewed in depth in preparation to studying the Bohr model of the atom.

The Darién Region, Connecting Road of the Americas, among the expressions of hydric wealth, land vocation and the extractive exploration on its violated forms

Colombia has oceanic waters, catchment areas, like lakes, cienagas and swamps, water flows, like rivers, gorges and streams, small rivers and groundwater. The oceanic waters are the Caribbean Sea-1600 km and the Pacific Ocean-1300 km that comprise the north and west continental territory, respectively. Actually the Region of Darién, geographically bounded by the Carribean Sea to the north is becoming to be focused by studies due to use conflicts and disputes about water and a forest reserve on its territories. Considering its location, strategic at northwestern Colombia, frontier region with Central America, several dynamics are imposed. One of them is the implantation of a road system entitled Connecting Road of the Americas. This fact means the construction of an infra-structure that will cross a special zone formed by swamps and jungle known as The Darién Gap. Evidences of such interests are revealed by projects like the constructions of Turbo's Port in the Atlantic Ocean, Department of Antioquia and Tribugá's Port in the Pacific Ocean, Department of Choco, the mountain road and the coastal conection Colombia-Venezuela attending to the main intentions of the central region of the department (Metropolitan Area of Aburrá Valley-AMVA). Human settlements form a productive system, based on small and medium familiar agriculture's production, corresponding to the western portion and piedmont of Abibe's mountain at its antioquian portion, alluvial plan that forms the rivers on this area, the littoral zone that delimits the Carribean Sea, the Darién and Baudó Mountains and the gulf that receives, among other waters, the ones from Atrato and León, as well as the exodus process constitutes a forced exit resulting from actions of several armed groups. It can be identified intense historical, cultural, political and environmental relations, specially the last one associated with strategic ecosystems that are fundamental for the hydric regulation of the region, as well as food safety of the local inhabitants. Results from two researches (UPB, 2007 y 2010) reveals this quick transformation in the spatial re-configuration, demographical and economical indicators and the exacerbated fight for resources, damaging the extractive vocation in the Region. Path to commerce of illegalities (drugs, guns) and to implementation of the agroindustrial project for biofuel production, cooperation program that involves Venezuela, Brazil and Colombia. Appropriation modes allow the existence of strategies since global interests revealing a development logic that privileges the conception of an artificialized nature. Since the smallest portion of rural areas, specific modes of resources exploration are linked to imposed interests of transnational corporations. Disparate consequences are going deeper evidenced by social, technical and nature transformations, envisioning risks for the habitability's condition