[Thrombotic microangiopathies in surgical intensive care medicine with special consideration of atypical hemolytic uremic syndrome]. / Thrombotische Mikroangiopathien in der operativen Intensivmedizin unter besonderer Berücksichtigung des atypischen hämolytisch-urämischen Syndroms.

Thrombotic microangiopathies (TMA) are rare diseases, which are defined by the triad microangiopathic hemolytic anemia, thrombocytopenia and organ damage, and are associated with high morbidity and mortality. The recognition of a TMA and the distinction of important differential diagnoses are key factors, particularly in a perioperative context and in routine clinical intensive care. The further differentiation of the different TMA subtypes, such as thrombotic thrombocytopenic purpura (TTP), Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) and atypical hemolytic uremic syndrome (aHUS), based on the underlying pathophysiology and the development of new targeted treatment options in recent years have significantly improved the prognosis. A close interdisciplinary cooperation between critical care specialists and specialist disciplines experienced in the treatment of TMA, is essential for a prompt diagnosis and the initiation of the appropriate treatment.

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 (1) for VL.

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.

Cross-Inhibition of Norrin and TGF-ß Signaling Modulates Development of Retinal and Choroidal Vasculature.

Purpose: Norrin is essential for the formation of the retinal vasculature during development and promotes its repair after damage via activation of Wnt/ß-catenin signaling. Since retinal TGF-ß signaling has essentially opposite effects on the retinal vasculature we investigated if and how Norrin inhibits TGF-ß signaling, and vice versa. Methods: Eyes from transgenic mice with an overexpression of Norrin (ßB1-Norrin) and/or active TGF-ß (ßB1-TGF-ß1) in the lens were generated and analyzed by light microscopy, immunohistochemistry, and TUNEL. Further on, protein as well as mRNA levels were investigated by Western blot analyses and real-time RT-PCR, respectively. Results: In ßB1-TGF-ß1 mice, the lack of retinal vascular development and choriocapillaris maintenance was rescued when transgenic Norrin was additionally overexpressed in the eye. In addition, retinal Wnt/ß-catenin signaling and the levels of SMAD7, an inhibitor of the canonical TGF-ß pathway, were substantially suppressed in retinae of ßB1-TGF-ß1 mice. In contrast, Norrin normalized Wnt/ß-catenin signaling and SMAD7 levels in double transgenic mice. Moreover, in retinae of ßB1-TGF-ß1 mice, the amounts of phosphorylated SMAD3, a downstream mediator of TGF-ß signaling, were increased compared to those of ßB1-Norrin/ßB1-TGF-ß1 mice. In vitro, Norrin substantially reduced the TGF-ß-mediated induction of target genes, an effect that was blocked by Dickkopf-1, a specific inhibitor of Wnt/ß-catenin signaling. Conclusions: High amounts of TGF-ß in the eye cause a substantial reduction in the activity of Wnt/ß-catenin signaling. This effect is inhibited in the presence of high amounts of Norrin, which further induce the expression of SMAD7 to inhibit TGF-ß signaling.

Export of algal biomass from the melting Arctic sea ice.

In the Arctic, under-ice primary production is limited to summer months and is restricted not only by ice thickness and snow cover but also by the stratification of the water column, which constrains nutrient supply for algal growth. Research Vessel Polarstern visited the ice-covered eastern-central basins between 82° to 89°N and 30° to 130°E in summer 2012, when Arctic sea ice declined to a record minimum. During this cruise, we observed a widespread deposition of ice algal biomass of on average 9 grams of carbon per square meter to the deep-sea floor of the central Arctic basins. Data from this cruise will contribute to assessing the effect of current climate change on Arctic productivity, biodiversity, and ecological function.

Prediction of mechanisms of action of antibacterial compounds by gene expression profiling.

We have generated a database of expression profiles carrying the transcriptional responses of the model organism Bacillus subtilis following treatment with 37 well-characterized antibacterial compounds of different classes. The database was used to build a predictor for the assignment of the mechanisms of action (MoAs) of antibacterial compounds by the use of support vector machines. This predictor was able to correctly classify the MoA class for most compounds tested. Furthermore, we provide evidence that the in vivo MoA of hexachlorophene does not match the MoA predicted from in vitro data, a situation frequently faced in drug discovery. A database of this kind may facilitate the prioritization of novel antibacterial entities in drug discovery programs. Potential applications and limitations are discussed.