In recent years, several climate subsystems have been identified that may undergo a relatively rapid transition compared to the changes in their forcing. Such transitions are rare events in general, ...and simulating long-enough trajectories in order to gather sufficient data to determine transition statistics would be too expensive. Conversely, rare events algorithms like TAMS (trajectory-adaptive multilevel sampling) encourage the transition while keeping track of the model statistics. However, this algorithm relies on a score function whose choice is crucial to ensure its efficiency. The optimal score function, called the committor function, is in practice very difficult to compute. In this paper, we compare different data-based methods (analog Markov chains, neural networks, reservoir computing, dynamical Galerkin approximation) to estimate the committor from trajectory data. We apply these methods on two models of the Atlantic Ocean circulation featuring very different dynamical behavior. We compare these methods in terms of two measures, evaluating how close the estimate is from the true committor and in terms of the computational time. We find that all methods are able to extract information from the data in order to provide a good estimate of the committor. Analog Markov Chains provide a very reliable estimate of the true committor in simple models but prove not so robust when applied to systems with a more complex phase space. Neural network methods clearly stand out by their relatively low testing time, and their training time scales more favorably with the complexity of the model than the other methods. In particular, feedforward neural networks consistently achieve the best performance when trained with enough data, making this method promising for committor estimation in sophisticated climate models.
Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit ...cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 - was completed in just 11 years, with approval being received approximately 5 years after the initiation of the first Phase I trial.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Because of the impact of extreme heat waves and heat domes on society and biodiversity, their study is a key challenge. We specifically study long-lasting extreme heat waves, which are among the most ...important for climate impacts. Physics driven weather forecast systems or climate models can be used to forecast their occurrence or predict their probability. The present work explores the use of deep learning architectures, trained using outputs of a climate model, as an alternative strategy to forecast the occurrence of extreme long-lasting heatwave. This new approach will be useful for several key scientific goals which include the study of climate model statistics, building a quantitative proxy for resampling rare events in climate models, study the impact of climate change, and should eventually be useful for forecasting. Fulfilling these important goals implies addressing issues such as class-size imbalance that is intrinsically associated with rare event prediction, assessing the potential benefits of transfer learning to address the nested nature of extreme events (naturally included in less extreme ones). We train a Convolutional Neural Network, using 1,000 years of climate model outputs, with large-class undersampling and transfer learning. From the observed snapshots of the surface temperature and the 500 hPa geopotential height fields, the trained network achieves significant performance in forecasting the occurrence of long-lasting extreme heatwaves. We are able to predict them at three different levels of intensity, and as early as 15 days ahead of the start of the event (30 days ahead of the end of the event).
In Escherichia coli, penicillin-binding protein 3 (PBP3), also known as FtsI, is a central component of the divisome, catalyzing cross-linking of the cell wall peptidoglycan during cell division. ...PBP3 is mainly periplasmic, with a 23 residues cytoplasmic tail and a single transmembrane helix. We have solved the crystal structure of a soluble form of PBP3 (PBP3(57-577)) at 2.5 Å revealing the two modules of high molecular weight class B PBPs, a carboxy terminal module exhibiting transpeptidase activity and an amino terminal module of unknown function. To gain additional insight, the PBP3 Val88-Ser165 subdomain (PBP3(88-165)), for which the electron density is poorly defined in the PBP3 crystal, was produced and its structure solved by SAD phasing at 2.1 Å. The structure shows a three dimensional domain swapping with a β-strand of one molecule inserted between two strands of the paired molecule, suggesting a possible role in PBP3(57-577) dimerization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Proline
conformational isomerization is a mechanism that affects different types of protein functions and behaviors. Using analytical characterization, structural analysis, and molecular dynamics ...simulations, we studied the causes of an aberrant two-peak size-exclusion chromatography profile observed for a trispecific anti-HIV antibody. We found that proline isomerization in the tyrosine-proline-proline (YPP) motif in the heavy chain complementarity-determining region (CDR)3 domain of one of the antibody arms (10e8v4) was a component of this profile. The pH effect on the conformational equilibrium that led to these two populations was presumably caused by a histidine residue (H147) in the light chain that is in direct contact with the YPP motif. Finally, we demonstrated that, due to chemical equilibrium between the
and
proline conformers, the antigen-binding potency of the trispecific anti-HIV antibody was not significantly affected in spite of a potential structural clash of 10e8v4 YP
P
conformers with the membrane-proximal ectodomain region epitope in the GP41 antigen. Altogether, these results reveal at mechanistic and molecular levels the effect of proline isomerization in the CDR on the antibody binding and analytical profiles, and support further development of the trispecific anti-HIV antibody.
Summary
We studied the cytological and biochemical properties of the FtsA protein of Streptococcus pneumoniae. FtsA is a widespread bacterial cell division protein that belongs to the actin ...superfamily. In Escherichia coli and Bacillus subtilis, FtsA localizes to the septal ring after FtsZ, but its exact role in septation is not known. In S. pneumoniae, we found that, during exponential growth, the protein localizes to the nascent septa, at the equatorial zones of the dividing cells, where an average of 2200 FtsA molecules per cell are present. Likewise, FtsZ was found to localize with the same pattern and to be present at an average of 3000 molecules per cell. Consistent with the colocalization, FtsA was found to interact with FtsZ and with itself. Purified FtsA is able to bind several nucleotides, the affinity being highest for adenosine triphosphate (ATP), and lower for other triphosphates and diphosphates. The protein polymerizes in vitro, in a nucleotide‐dependent manner, forming long corkscrew‐like helixes, composed of 2 + 2 paired protofilaments. No nucleotide hydrolytic activity was detected. Consistent with the absence of an ATPase activity, the polymers are highly stable and not dynamic. These results suggest that the FtsA protein could also polymerize in vivo and the polymers participate in septation.
A collection of stomatopods assembled during the KUW 2009 expedition to Mayotte Island and deposited in the Muséum national d’Histoire naturelle Paris is studied with a review of previous records ...from Comoros and Mayotte Island. In total 14 species are recognized 3 of them being new records for this region. A brief comparison with other regions studied for stomatopods indicates that sampling is still insufficient in Comoros and Mayotte and that dozens of species remain to be inventoried in that region.
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. ...The initial 1-{3-H-imidazo4–5-cpyridin-2-yl}-3,4-dihydro-2H-pyrido2,1-aisoindole-6-one (1) compound showed moderate activity (IC50 = 7.6 μM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an “induced” hydrophobic pocket, 10–15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K d = 0.35 nM on Hsp90; IC50 = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.
Raf kinase, an enzyme which acts downstream in the Ras signaling pathway, is involved in cancerous cell proliferation. Thus, small molecule inhibitors of Raf kinase activity may be important agents ...for the treatment of cancer. A novel class of Raf-1 inhibitors was discovered, using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials. The present review summarizes the medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase.
The RAS-RAF-MEK-ERK signaling pathway (ERK pathway) plays a key role in tumorigenesis and cancer progression. Mutations of RAS or B-RAF lead to a constitutive activation of the ERK pathway, which ...ultimately results in increased cell division, and cell survival. This review article focuses on the recent literature related to ERK pathway inhibitors, with a particular emphasis on RAF kinase inhibitors. Preclinical and clinical data for the RAF kinase inhibitor sorafenib (BAY 43-9006 tosylate), that was recently approved in the US for the treatment of advanced renal cell carcinoma, are also outlined.
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