Stratospheric influence on ECMWF sub‐seasonal forecast skill for energy‐industry‐relevant surface weather in European countries

Meteorologists in the energy industry increasingly draw upon the potential for enhanced sub‐seasonal predictability of European surface weather following anomalous states of the winter stratospheric polar vortex (SPV). How the link between the SPV and the large‐scale tropospheric flow translates into forecast skill for surface weather in individual countries – a spatial scale that is particularly relevant for the energy industry – remains an open question. Here we quantify the effect of anomalously strong and weak SPV states at forecast initial time on the probabilistic extended‐range reforecast skill of the European Centre for Medium‐Range Weather Forecasts (ECMWF) in predicting country‐ and month‐ahead‐averaged anomalies of 2 m temperature, 10 m wind speed, and precipitation. After anomalous SPV states, specific surface weather anomalies emerge, which resemble the opposing phases of the North Atlantic Oscillation. We find that forecast skill is, to first order, only enhanced for countries that are entirely affected by these anomalies. However, the model has a flow‐dependent bias for 2 m temperature (T2M): it predicts the warm conditions in Western, Central and Southern Europe following strong SPV states well, but is overconfident with respect to the warm anomaly in Scandinavia. Vice versa, it predicts the cold anomaly in Scandinavia following weak SPV states well, but struggles to capture the strongly varying extent of the cold air masses into Central and Southern Europe. This tends to reduce skill (in some cases significantly) for Scandinavian countries following strong SPV states, and most pronounced, for many Central, Southern European, and Balkan countries following weak SPV states. As most of the weak SPV states are associated with sudden stratospheric warmings (SSWs), our study thus advices particular caution when interpreting sub‐seasonal regional T2M forecasts following SSWs. In contrast, it suggests that the model benefits from enhanced predictability for a considerable part of Europe following strong SPV states

A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis

SummaryLymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P1), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P1 receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P1 antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P1 antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P1 receptor antagonism and to differentiate the effects from those of S1P1 agonists

A Monoselective Sphingosine-1-Phosphate Receptor-1 Agonist Prevents Allograft Rejection in a Stringent Rat Heart Transplantation Model

SummaryFTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P1) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P1 receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P1-dependent phenomena. Oral administration of AUY954 induces a profound and reversible reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P1 receptor is sufficient to achieve efficacy in an animal model of transplantation

Programmable Sequence-Specific Transcriptional Regulation of Mammalian Genome Using Designer TAL Effectors

The ability to direct functional proteins to specific DNA sequences is a long-sought goal in the study and engineering of biological processes. Transcription activator–like effectors (TALEs) from Xanthomonas sp. are site-specific DNA-binding proteins that can be readily designed to target new sequences. Because TALEs contain a large number of repeat domains, it can be difficult to synthesize new variants. Here we describe a method that overcomes this problem. We leverage codon degeneracy and type IIs restriction enzymes to generate orthogonal ligation linkers between individual repeat monomers, thus allowing full-length, customized, repeat domains to be constructed by hierarchical ligation. We synthesized 17 TALEs that are customized to recognize specific DNA-binding sites, and demonstrate that they can specifically modulate transcription of endogenous genes (SOX2 and KLF4) in human cells.Harvard University. Society of FellowsNational Human Genome Research Institute (U.S.) (Center for Excellence in Genomics Science P50 HG003170)United States. Dept. of Energy (Genomes to Life DE-FG02-02ER63445)United States. Defense Advanced Research Projects Agency (W911NF-08-1-0254, G.M.C.)Wyss Institute of Biologically Inspired EngineeringNational Institutes of Health (U.S.) (Transformative R01 (R01 NS073124-01))European School of Molecular Medicine (predoctoral fellowship

Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior

Applications of CRISPR–Cas systems in neuroscience

Genome-editing tools, and in particular those based on CRISPR-Cas (clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein) systems, are accelerating the pace of biological research and enabling targeted genetic interrogation in almost any organism and cell type. These tools have opened the door to the development of new model systems for studying the complexity of the nervous system, including animal models and stem cell-derived in vitro models. Precise and efficient gene editing using CRISPR-Cas systems has the potential to advance both basic and translational neuroscience research.National Institute of Mental Health (U.S.) (Grant 5DP1-MH100706)National Institute of Mental Health (U.S.) (Grant 1R01-MH110049)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant 5R01DK097768-03

Stratospheric modulation of the large-scale circulation in the Atlantic-European region and its implications for surface weather events

Extreme states of the stratospheric polar vortex can have long‐lasting impacts on extratropical circulation patterns, such as the North Atlantic Oscillation (NAO). This provides windows of subseasonal predictability beyond the typical weather forecast horizon of about 10 days. Subseasonal forecasts of surface weather are of significant interest in weather‐dependent socio‐economic sectors. For example, demand and supply for electricity and gas are weather dependent and therefore accurate forecasts are important for the energy industry and energy trading. Here we investigate the subseasonal impact of stratospheric conditions on surface weather events relevant to the energy industry in five subregions of Europe in winter. We use a definition of seven Atlantic–European weather regimes to describe the variability of the large‐scale circulation on subseasonal time scales. Results indicate that weather events are often associated with more than one preferred weather regime. In turn, some weather regimes project onto a specific NAO phase, while others are independent of the NAO. As expected, anomalous stratospheric polar vortex states predominantly modulate the occurrence of regimes related to the NAO and affect the likelihood of their associated weather events. In contrast, the occurrence of weather regimes which do not project well onto the NAO is not affected by anomalous stratospheric polar vortex states. These regimes provide pathways to unexpected weather events in extreme stratospheric polar vortex states. For example, weak stratospheric polar vortex states enhance the likelihood of negative NAO. High wind events in Central Europe predominantly occur during the zonal regime, strongly projecting onto positive NAO. However, these events also occur during the Atlantic trough regime, which is unaffected by anomalous stratospheric polar vortex states and thus provides a pathway to Central European high wind events during weak stratospheric polar vortex states. A correct NAO prediction alone is therefore not sufficient to correctly predict surface weather after extreme stratospheric polar vortex states. Moreover, weather regime life cycles independent of the NAO also need to be forecast accurately.ISSN:0035-9009ISSN:1477-870

Cellular assay for the characterization of sphingosine-1-phosphate lyase inhibitors

Sphingosine-1-phosphate (S1P) lyase represents a target for therapeutic intervention in immune regulation. Inhibitors of the lyase can be identified by established biochemical assays, but a cellular test system for such inhibitors has not been described so far. We found that silencing or inhibition of S1P lyase with siRNA or active-site directed inhibitors in cultured mammalian cells does not cause a relevant increase of S1P in the cells as measured by LC-MS/MS. However, addition of sphingosine to cultures of cell lines or primary cells provides a source of intracellular S1P that is susceptible to degradation by the lyase and hence increases upon inhibition or silencing of the enzyme. The assay was optimized with respect to sphingosine concentration, incubation time, and cell density, and was routinely established for use with HEK293 cells. The assay was found suitable for the testing of novel active-site directed S1P lyase inhibitors, providing important information on their relative potency in intact cells