Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Comparing political futures: the rise and use of scenarios in future-oriented area studies

The predictive ability of scholars of politics has long been a subject of theoretical debate and methodological development. In theoretical debate, prediction represents a central issue regarding the extent to which the study of politics is scientific. In methodological development, much effort and resource have been devoted to a diverse range of predictive approaches, with varying degrees of success. Expectations that scholars forecast accurately come as much from the policy and media worlds as from the academy. Since the end of the Cold War, scenario development has become prevalent in future-oriented research by area studies scholars. This approach is long due critical re-assessment. For all its strengths as a policy tool, scenario development tends towards a bounded methodology, driving the process of anticipating futures along predetermined paths into a standardised range of options, and paying insufficient attention to theoretical and contextual understandings available within the relevant scholarly disciplines

DRILL CORE MINERAL ANALYSIS BY MEANS OF THE HYPERSPECTRAL IMAGING SPECTROMETER HySpex, XRD AND ASD IN PROXIMITY OF THE MÝTINA MAAR, CZECH REPUBLIC

Imaging spectroscopy is increasingly used for surface mapping. Therefore different expert systems are being utilized to identify surface cover materials. Those expert systems mainly rely on the spectral comparison between unknown and library spectra, but their performances were only limited qualified. This study aims on the comparative analysis of drill core samples from the recently discovered maar system in the Czech Republic. Drill core samples from the surrounding area of the Mýtina maar were analyzed by X-Ray diffraction (XRD) and the hyperspectral spectrometer HySpex. Additionally, soil samples were measured in-situ by the ASD FieldSpec4 and in the laboratory by the HySpex VNIR/SWIR spectrometer system. The data was then analyzed by the MICA-algorithm and the results were compared to the results of the XRD -analysis. The XRD-analysis served here as validation basis. The results of the hyperspectral and the XRD analyses were used to densify a volcanic map that also integrates in-situ soil measurements in the surrounding area of Mýtina. The comparison of the XRD- and solaroptical remote sensing results showed a good correlation of qualified minerals if the soil organic carbon content was significantly low. Contrary to XRD, smectites and muscovites were also straightforward identified that underlines the overall performance of the approach to identify minerals. Basically, in this work an operable approach is proposed that enables the fast, repeatable and detailed analysis of drill cores, drill core samples and soil samples and, hence, provides a higher performance than state-of-the-art XRD-analyses

Shift in the pattern of autonomic atrial innervation in subjects with persistent atrial fibrillation

BACKGROUND Atrial fibrillation (AF) is a multifactorial disease of the atria. OBJECTIVE We studied the differences in the atrial autonomic innervation pattern in subjects with AF compared with sinus rhythm (SR). METHODS Preparation of postmortem isolated hearts of subjects with documented persistent AF (group A) and SR (group B) included: (1) histological sectioning of predefined areas and quantification of nerve density, and (2) differentiation using immunohistochemistry in adrenergic (sympathetic, tyrosine-hydroxylase antibody), cholinergic (parasympathetic, choline-acetyltransferase antibody) and mixed (adrenergic and cholinergic staining) nerves. RESULTS Characteristics of subjects in group A (N = 15) and group B (N = 24) did not differ. The mean overall nerve density was similar between groups (A: 0.31 +/- 0.25/mm(2); B: 0.35 +/- 0.25/mm(2); P = .87). Nerve density appeared higher in the region of the pulmonary vein ostia and antrum (group A: 0.38 +/- 0.21/mm(2); group B: 0.32 +/- 0.19/mm(2),) compared with other locations of the right and left atrium. A total of 2,224 (group A: 685; group B: 1539) nerves were differentiated using immunohistochemistry. There was a high degree of colocalization of adrenergic and cholinergic nerves (group A: 80% mixed staining, group B: 69% mixed staining). In group A hearts there was a significantly lower density of predominantly cholinergic nerves (0.025 +/- 0.052/mm(2) vs. 0.058 +/- 0.099/mm(2); P = .008) and a higher density of nerves containing adrenergic components (0.24 +/- 0.18/mm(2) vs. 0.18 +/- 0.17/mm(2), P = .046). CONCLUSION Overall autonomic nerve density did not differ between atria with persistent AF compared with SR. On a morphological level, we detected a shift toward a lower density of cholinergic nerves and a higher density of nerves containing adrenergic components in AF subjects

Deep into the mud: ecological and socio-economic impacts of the dam breach in Mariana, Brazil.

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