The effectiveness of polder systems on peak discharge capping of floods along the middle reaches of the Elbe River in Germany

International audienceIn flood modelling, many one-dimensional (1-D) hydrodynamic models are too restricted in capturing the spatial differentiation of processes within a polder or system of polders and two-dimensional (2-D) models are very demanding in data requirements and computational resources. The latter is an important consideration when uncertainty analyses using the Monte Carlo techniques are to complement the modelling exercises. This paper describes the development of a quasi-2-D modeling approach, which still calculates the dynamic wave in 1-D but the discretisation of the computational units are in 2-D, allowing a better spatial representation of the flow in polders and avoiding large additional expenditure on data pre-processing and computational time. The model DYNHYD (1-D hydrodynamics) from the WASP5 modeling package was used as a basis for the simulations and extended to incorporate the quasi-2-D approach. A local sensitivity analysis shows the sensitivity of parameters and boundary conditions on the filling volume of polders and capping of the peak discharge in the main river system. Two flood events on the Elbe River, Germany were used to calibrate and test the model. The results show a good capping effect on the flood peak by the proposed systems. The effect of capping reduces as the flood wave propagates down stream from the polders (up to 0.5 cm of capping is decreased for each additional kilometer from the polder)

Apraclonidine—An eye opener

Pharmacological testing with apraclonidine eye drops induces a typical reversal of anisocoria in patients with Horner’s syndrome. Moreover, apraclonidine was observed to have an elevating effect on the upper eyelid in Horner’s syndrome as well as in healthy subjects, which is thought to be mediated by alpha-1 adrenergic receptors present in the Muller’s muscle. We aim to quantitatively investigate the effect of apraclonidine on eyelid position in patients with Horner’s syndrome compared to physiological anisocoria based on infrared video recordings from pupillometry. We included 36 patients for analysis who underwent binocular pupillometry before and after apraclonidine 1% testing for the evaluation of anisocoria. Vertical eyelid measurements were taken from infrared videos and averaged from multiple pupillometry cycles. Receiver operating characteristic curves were calculated to determine the optimal cutoff value for change in eyelid aperture pre- and post-apraclonidine. A decrease of inter-eye difference in the aperture of >0.42 mm was discriminative of Horner’s syndrome compared to physiological anisocoria with a sensitivity of 80% and a specificity of 75%. Our data confirm an eyelid- elevating effect of the apraclonidine test, more pronounced in eyes with a sympathetic denervation deficit. Measuring eyelid aperture on pupillometry recordings may improve the diagnostic accuracy of apraclonidine testing in Horner’s syndrome

Drought cascades across multiple systems in Central Asia identified based on the dynamic space–time motion approach

Drought is typically induced by the extreme water deficit stress that cascades through the atmosphere, hydrosphere, and biosphere. Cascading drought events could cause severe damage in multiple systems. However, identifying cascading drought connections considering the dynamic space–time progression remains challenging, which hinders further exploring the emergent patterns of drought cascades. This study proposes a novel framework for tracking drought cascades across multiple systems by utilizing dynamic space–time motion similarities. Our investigation focuses on the four primary drought types in Central Asia from 1980 to 2007, namely precipitation (PCP), evapotranspiration (ET), runoff, and root zone soil moisture (SM), representing the four systems of atmosphere, hydrosphere, biosphere, and soil layer respectively. A total of 503 cascading drought events are identified in this study, including the 261 four-system cascading drought events. Our results show a significant prevalence of the four-system cascading drought pattern in Central Asia with high systematic drought risk, mainly when seasonal PCP droughts with high severity/intensity and sizeable spatial extent are observed. As for the temporal order in the cascading drought events, ET droughts are likely to occur earlier than runoff droughts after PCP droughts, and SM droughts are more likely to occur at last, implying the integrated driven effect of the energy-limited and water-limited phases on the drought progression in Central Asia. Our proposed framework could attain precise internal spatial trajectories within each cascading drought event and enable the capture of space–time cascading connections across diverse drought systems and associated hazards. The identification of cascading drought patterns could provide a systematic understanding of the drought evolution across multiple systems under exacerbated global warming.</p

A fully automated high-throughput workflow for 3D-based chemical screening in human midbrain organoids

Three-dimensional (3D) culture systems have fueled hopes to bring about the next generation of more physiologically relevant high-throughput screens (HTS). However, current protocols yield either complex but highly heterogeneous aggregates ('organoids') or 3D structures with less physiological relevance ('spheroids'). Here, we present a scalable, HTS-compatible workflow for the automated generation, maintenance, and optical analysis of human midbrain organoids in standard 96-well-plates. The resulting organoids possess a highly homogeneous morphology, size, global gene expression, cellular composition, and structure. They present significant features of the human midbrain and display spontaneous aggregate-wide synchronized neural activity. By automating the entire workflow from generation to analysis, we enhance the intra- and inter-batch reproducibility as demonstrated via RNA sequencing and quantitative whole mount high-content imaging. This allows assessing drug effects at the single-cell level within a complex 3D cell environment in a fully automated HTS workflow

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

The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis.

Weibel-Palade body (WPB) exocytosis underlies hormone-evoked VWF secretion from endothelial cells (ECs). We identify new endogenous components of the WPB: Rab3B, Rab3D, and the Rab27A/Rab3 effector Slp4-a (granuphilin), and determine their role in WPB exocytosis. We show that Rab3B, Rab3D, and Rab27A contribute to Slp4-a localization to WPBs. siRNA knockdown of Slp4-a, MyRIP, Rab3B, Rab3D, Rab27A, or Rab3B/Rab27A, or overexpression of EGFP-Slp4-a or EGFP-MyRIP showed that Slp4-a is a positive and MyRIP a negative regulator of WPB exocytosis and that Rab27A alone mediates these effects. We found that ECs maintain a constant amount of cellular Rab27A irrespective of the WPB pool size and that Rab27A (and Rab3s) cycle between WPBs and a cytosolic pool. The dynamic redistribution of Rab proteins markedly decreased the Rab27A concentration on individual WPBs with increasing WPB number per cell. Despite this, the probability of WPB release was independent of WPB pool size showing that WPB exocytosis is not determined simply by the absolute amount of Rab27A and its effectors on WPBs. Instead, we propose that the probability of release is determined by the fractional occupancy of WPB-Rab27A by Slp4-a and MyRIP, with the balance favoring exocytosis

Inhibition of resistance-refractory P. falciparum kinase PKG delivers prophylactic, blood stage, and transmission-blocking antiplasmodial activity

The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084. PKG is known to play essential roles in Plasmodium invasion of and egress from host cells, matching MMV030084's activity profile. Resistance selections and gene editing identified tyrosine kinase-like protein 3 as a low-level resistance mediator for PKG inhibitors, while PKG itself never mutated under pressure. These studies highlight PKG as a resistance-refractory antimalarial target throughout the Plasmodium life cycle and promote MMV030084 as a promising Plasmodium PKG-targeting chemotype

New Measure of Insulin Sensitivity Predicts Cardiovascular Disease Better than HOMA Estimated Insulin Resistance

10.1371/journal.pone.0074410PLoS ONE89-POLN