Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in <i>Leishmania</i>

Drug discovery pipelines for the "neglected diseases" are now heavily populated with nitroheterocyclic compounds. Recently, the bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compounds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compounds, but only marginally to the monocyclic nitro-drugs, nifurtimox and fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compounds and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compounds in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compound series

Preliminary Studies of the Moody and Galva Soil Series of Northwestern Iowa

Recent studies in the midwest have confirmed a relationship between the thickness and distribution of the loess and the morphological, chemical and physical properties of soils developed from loess. In southwestern Iowa studies by Hutton (2) and Ulrich (6) showed increased differentiation of soils as the distance from the loess source increased and the thickness of the loess decreased. Hunter (1) reported similar relationships between the properties of the loess and soils developed in southeastern Iowa. This paper presents the results of a preliminary study regarding the possibility of similar relationships in northwestern Iowa. Profile sites were selected on loess of varying thickness and samples were brought into the laboratory for analyses

Surfacing Small Worlds through Data-In-Place

We present findings from a five-week deployment of voting technologies in a city neighbourhood. Drawing on Marres’ (2012) work on material participation and Massey’s (2005) conceptualisation of space as dynamic, we designed the deployment such that the technologies (which were situated in residents’ homes, on the street, and available online) would work in concert, cutting across the neighbourhood to make visible, juxtapose and draw together the different ‘small worlds’ within it. We demonstrate how the material infrastructure of the voting devices set in motion particular processes and interpretations of participation, putting data in place in a way that had ramifications for the recognition of heterogeneity. We conclude that redistributing participation means not only opening up access, so that everyone can participate, or even providing a multitude of voting channels, so that people can participate in different ways. Rather, it means making visible multiplicity, challenging notions of similarity, and showing how difference may be productive

An overview of the first decade of PollyNET : an emerging network of automated Raman-polarization lidars for continuous aerosol profiling

© Author(s) 2016. This work is distributed under the Creative Commons Attribution 3.0 LicenseA global vertically resolved aerosol data set covering more than 10 years of observations at more than 20 measurement sites distributed from 63° N to 52° S and 72° W to 124° E has been achieved within the Raman and polarization lidar network PollyNET. This network consists of portable, remote-controlled multiwavelength-polarization-Raman lidars (Polly) for automated and continuous 24/7 observations of clouds and aerosols. PollyNET is an independent, voluntary, and scientific network. All Polly lidars feature a standardized instrument design with different capabilities ranging from single wavelength to multiwavelength systems, and now apply unified calibration, quality control, and data analysis. The observations are processed in near-real time without manual intervention, and are presented online at http://polly.tropos.de/. The paper gives an overview of the observations on four continents and two research vessels obtained with eight Polly systems. The specific aerosol types at these locations (mineral dust, smoke, dust-smoke and other dusty mixtures, urban haze, and volcanic ash) are identified by their Ångström exponent, lidar ratio, and depolarization ratio. The vertical aerosol distribution at the PollyNET locations is discussed on the basis of more than 55 000 automatically retrieved 30 min particle backscatter coefficient profiles at 532 nm as this operating wavelength is available for all Polly lidar systems. A seasonal analysis of measurements at selected sites revealed typical and extraordinary aerosol conditions as well as seasonal differences. These studies show the potential of PollyNET to support the establishment of a global aerosol climatology that covers the entire troposphere.Peer reviewe

Genomic and Proteomic Studies on the Mode of Action of Oxaboroles against the African Trypanosome

SCYX-7158, an oxaborole, is currently in Phase I clinical trials for the treatment of human African trypanosomiasis. Here we investigate possible modes of action against Trypanosoma brucei using orthogonal chemo-proteomic and genomic approaches. SILAC-based proteomic studies using an oxaborole analogue immobilised onto a resin was used either in competition with a soluble oxaborole or an immobilised inactive control to identify thirteen proteins common to both strategies. Cell-cycle analysis of cells incubated with sub-lethal concentrations of an oxaborole identified a subtle but significant accumulation of G2 and >G2 cells. Given the possibility of compromised DNA fidelity, we investigated long-term exposure of T. brucei to oxaboroles by generating resistant cell lines in vitro. Resistance proved more difficult to generate than for drugs currently used in the field, and in one of our three cell lines was unstable. Whole-genome sequencing of the resistant cell lines revealed single nucleotide polymorphisms in 66 genes and several large-scale genomic aberrations. The absence of a simple consistent mechanism among resistant cell lines and the diverse list of binding partners from the proteomic studies suggest a degree of polypharmacology that should reduce the risk of resistance to this compound class emerging in the field. The combined genetic and chemical biology approaches have provided lists of candidates to be investigated for more detailed information on the mode of action of this promising new drug clas

Surface matters: Limitations of CALIPSO V3 aerosol typing in coastal regions

In the CALIPSO data analysis, surface type (land/ocean) is used to augment the aerosol characterization. However, this surface-dependent aerosol typing prohibits a correct classification of marine aerosol over land that is advected from ocean to land. This might result in a systematic overestimation of the particle extinction coefficient and of the aerosol optical thickness (AOT) of up to a factor of 3.5 over land in coastal areas. We present a long-term comparison of CALIPSO and ground-based lidar observations of the aerosol conditions in the coastal environment of southern South America (Punta Arenas, Chile, 53° S), performed in December 2009–April 2010. Punta Arenas is almost entirely influenced by marine particles throughout the year, indicated by a rather low AOT of 0.02–0.04. However, we found an unexpectedly high fraction of continental aerosol in the aerosol types inferred by means of CALIOP observations and, correspondingly, too high values of particle extinction. Similar features of the CALIOP data analysis are presented for four other coastal areas around the world. Since CALIOP data serve as important input for global climate models, the influence of this systematic error was estimated by means of simplified radiative-transfer calculations

Comparative genomics of the major parasitic worms

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms

Tropospheric and stratospheric wildfire smoke profiling with lidar: Mass, surface area, CCN, and INP retrieval

We present retrievals of tropospheric and stratospheric height profiles of particle mass, volume, surface area, and number concentrations in the case of wildfire smoke layers as well as estimates of smoke-related cloud condensation nuclei (CCN) and ice-nucleating particle (INP) concentrations from backscatter lidar measurements on the ground and in space. Conversion factors used to convert the optical measurements into microphysical properties play a central role in the data analysis, in addition to estimates of the smoke extinction-to-backscatter ratios required to obtain smoke extinction coefficients. The set of needed conversion parameters for wildfire smoke is derived from AERONET observations of major smoke events, e.g., in western Canada in August 2017, California in September 2020, and southeastern Australia in January-February 2020 as well as from AERONET long-term observations of smoke in the Amazon region, southern Africa, and Southeast Asia. The new smoke analysis scheme is applied to CALIPSO observations of tropospheric smoke plumes over the United States in September 2020 and to ground-based lidar observation in Punta Arenas, in southern Chile, in aged Australian smoke layers in the stratosphere in January 2020. These case studies show the potential of spaceborne and ground-based lidars to document large-scale and long-lasting wildfire smoke events in detail and thus to provide valuable information for climate, cloud, and air chemistry modeling efforts performed to investigate the role of wildfire smoke in the atmospheric system