Different Asian monsoon rainfall responses to idealised orography sensitivity experiments in the HadGEM3-GA6 and FGOALS-FAMIL global climate models

Recent work has shown the dominance of the Himalayas in supporting the Indian summer monsoon (ISM), perhaps by surface sensible heating along its southern slope and by mechanical blocking acting to separate moist tropical flow from drier mid-latitude air. Previous studies have also shown that Indian summer rainfall is largely unaffected in sensitivity experiments that remove only the Tibetan Plateau. However, given the large biases in simulating the monsoon in CMIP5 models, such results may be model dependent. This study investigates the impact of orographic forcing from the Tibetan Plateau, Himalayas and Iranian Plateau on the ISM and East Asian summer monsoons (EASM) in the UK Met Office HadGEM3-GA6 and China’s Institute of Atmospheric Physics FGOALS-FAMIL GCMs. The models chosen feature opposite-signed biases in their simulation of the ISM rainfall and circulation climatology. The changes to ISM and EASM circulation across the sensitivity experiments are similar in both models and consistent with previous studies. However, considerable differences exist in the rainfall responses over India and China, and in the detailed aspects such as onset and retreat dates. In particular, the models show opposing changes in Indian monsoon rainfall when the Himalaya and Tibetan Plateau orography are removed. Our results show that a multi-model approach, as suggested in the forthcoming Global Monsoon Model Intercomparison Project (GMMIP) associated with CMIP6, is needed to clarify the impact of orographic forcing on the Asian monsoon and to fully understand the implications of model systematic error

Options to Reform the European Union Legislation on GMOs: Scope and Definitions

We discuss options to reform the EU genetically modified organisms (GMO) regulatory framework, make risk assessment and decision-making more consistent with scientific principles, and lay the groundwork for international coherence. The first in a three-part series, this article focuses on reform options related to the scope of the legislation and the GMO definition.</p

Options to Reform the European Union Legislation on GMOs: Scope and Definitions

We discuss options to reform the EU genetically modified organisms (GMO) regulatory framework, make risk assessment and decision-making more consistent with scientific principles, and lay the groundwork for international coherence. The first in a three-part series, this article focuses on reform options related to the scope of the legislation and the GMO definition

Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screening

The mediator complex-associated cyclin dependent kinase CDK8 regulates beta-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies

2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1SER727 phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing

The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain

Peer reviewe

Comparison of a manual and an automated tracking method for Tibetan Plateau vortices

Tibetan Plateau vortices (TPVs) are mesoscale cyclones originating over the Tibetan Plateau (TP) during the extended summer season (April-September). Most TPVs stay on the TP while a small number can move off the TP to the east. TPVs are known to be one of the main precipitation-bearing systems on the TP and moving-off TPVs have been associated with heavy precipitation and flooding downstream of the TP (e.g. Sichuan province, Yangtze River Valley). Identifying and tracking TPVs is difficult both due to their comparatively small horizontal extent (400 – 800 km) and the limited availability of soundings over the TP, which, in turn, constitutes a challenge for short-term predictions of TPV-related impacts and for the climatological study of TPVs. In this study, (i) manual tracking (MT) results using radiosonde data from a network over and downstream of the TP are compared with (ii) results obtained by an automated tracking (AT) algorithm applied to ERA-Interim reanalysis. Ten MT-TPV cases are selected based on method (i) and matched to and compared with the corresponding AT-TPVs identified with method (ii). Conversely, ten AT-TPVs are selected and compared with the corresponding MT-TPVs. In general, the comparison shows good results in cases where the underlying data are in good agreement, but considerable differences are also seen in some cases and explained in terms of differences in the tracking methods, data availability/coverage and disagreement between sounding and ERA-Interim data. Recommendations are given for future efforts in TPV detection and tracking, including in an operational weather forecasting context

Meteorological input data requirements to predict cross-pollination of GMO Maize with Lagrangian approaches

Modeling pollen dispersal to predict cross-pollination is of great importance for the ongoing discussion of adventitious presence of genetically modified material in food and feed. Two different modeling approaches for pollen dispersal were used to simulate two years of data for the rate of cross-pollination of non-GM maize (Zea mays (L.)) fields by pollen from a central 1 ha transgenic field. The models combine the processes of wind pollen dispersal (transport) and pollen competition. Both models used for the simulation of pollen dispersal were Lagrangian approaches: a stochastic particle Lagrange model and a Lagrangian transfer function model. Both modeling approaches proved to be appropriate for the simulation of the cross-pollination rates. However, model performance differed significantly between years. We considered different complexity in meteorological input data. Predictions compare well with experimental results for all simplification steps, except that systematic deviations occurred when only main wind direction was used. Concluding, it can be pointed out that both models might be adapted to other pollen dispersal experiments of different crops and plot sizes, when wind direction statistics are available. However, calibration of certain model parameters is necessary