The art and science of climate model tuning

PublishedThis is the final version of the article. Available from American Meteorological Society via the DOI in this record.We survey the rationale and diversity of approaches for tuning, a fundamental aspect of climate modeling which should be more systematically documented and taken into account in multi-model analysis. The process of parameter estimation targeting a chosen set of observations is an essential aspect of numerical modeling. This process is usually named tuning in the climate modeling community. In climate models, the variety and complexity of physical processes involved, and their interplay through a wide range of spatial and temporal scales, must be summarized in a series of approximate sub-models. Most sub-models depend on uncertain parameters. Tuning consists of adjusting the values of these parameters to bring the solution as a whole into line with aspects of the observed climate. Tuning is an essential aspect of climate modeling with its own scientific issues, which is probably not advertised enough outside the community of model developers. Optimization of climate models raises important questions about whether tuning methods a priori constrain the model results in unintended ways that would affect our confidence in climate projections. Here we present the definition and rationale behind model tuning, review specific methodological aspects, and survey the diversity of tuning approaches used in current climate models. We also discuss the challenges and opportunities in applying so-called ‘objective‘ methods in climate model tuning. We discuss how tuning methodologies may affect fundamental results of climate models, such as climate sensitivity. The article concludes with a series of recommendations to make the process of climate model tuning more transparent.The authors would like to thank the World Climate Research Program and its Working Group on Coupled Modeling for initiating and helping organize the workshop on model tuning in October 2014 in Garmisch-Partenkirchen, Germany. Work at LLNL was performed under the auspices the U.S. Department of Energy by Lawrence Livermore National Laboratory under contract No. DE-AC52-07NA27344. The National Center for Atmospheric Research is sup- ported by the U.S. National Science Foundation. The contribution of Yun Qian was supported by the U.S. Department of Energy’s Office of Science as part of the Earth System Modeling Program. The Pacific Northwest National Laboratory is operated for DOE by Battelle Memorial Institute under contract DE-AC05-76RL0183

Earth system science frontiers - an early career perspective

The exigencies of the global community toward Earth system science will increase in the future as the human population, economies, and the human footprint on the planet continue to grow. This growth, combined with intensifying urbanization, will inevitably exert increasing pressure on all ecosystem services. A unified interdisciplinary approach to Earth system science is required that can address this challenge, integrate technical demands and long-term visions, and reconcile user demands with scientific feasibility. Together with the research arms of the World Meteorological Organization, the Young Earth System Scientists community has gathered early-career scientists from around the world to initiate a discussion about frontiers of Earth system science. To provide optimal information for society, Earth system science has to provide a comprehensive understanding of the physical processes that drive the Earth system and anthropogenic influences. This understanding will be reflected in seamless prediction systems for environmental processes that are robust and instructive to local users on all scales. Such prediction systems require improved physical process understanding, more high-resolution global observations, and advanced modeling capability, as well as high-performance computing on unprecedented scales. At the same time, the robustness and usability of such prediction systems also depend on deepening our understanding of the entire Earth system and improved communication between end users and researchers. Earth system science is the fundamental baseline for understanding the Earth’s capacity to accommodate humanity, and it provides a means to have a rational discussion about the consequences and limits of anthropogenic influence on Earth. Without its progress, truly sustainable development will be impossible. © 2017 American Meteorological Society. For information regarding reuse of this content and general copyright information, consult the AMS Copyright Policy (www.ametsoc.org/PUBSReuseLicenses)

Pharmacogenomic and structural analysis of constitutive G-protein coupled receptor activity

Premi a l'excel·lència investigadora. Àmbit de les Ciències de la Salut. 2008G-protein coupled receptors (GPCRs) respond to a chemically diverse plethora of signal transduction molecules. The notion that GPCRs also signal without an external chemical trigger, i.e. in a constitutive or spontaneous manner, resulted in a paradigm shift in the field of GPCR pharmacology. With the recognition of constitutive GPCR activity and the fact that GPCR binding and signaling can be strongly affected by a single point mutation, GPCR pharmacogenomics obtained a lot of attention. For a variety of GPCRs, point mutations have been convincingly linked to human disease. Mutations within conserved motifs, known to be involved in GPCR activation, might explain the properties of some naturally occurring constitutively active GPCR variants linked to disease. A brief history historical introduction to the present concept of constitutive receptor activity is given and the pharmacogenomic and the structural aspects of constitutive receptor activity are described

Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

<p>Abstract</p> <p>Background</p> <p>The activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX) was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ) cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of <it>KRAS </it>(3%). The aim of the correlative tumour tissue studies was to investigate the relationship between <it>EGFR </it>gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX.</p> <p>Methods</p> <p>Patients included in this correlative study (<it>n </it>= 39) were a subset of patients from the clinical phase II study. The association between <it>EGFR </it>gene copy number, activation of the EGFR pathway, abundance and mutation of E-cadherin which plays an important role in these disorders, BRAF mutation and clinical outcome of patients was studied. <it>EGFR </it>gene copy number was assessed by FISH. Expression of the phosphorylated forms of EGFR and its downstream effectors Akt and MAPK, in addition to E-cadherin was analysed by immunohistochemistry. The frequency of mutant V600E BRAF was evaluated by allele-specific PCR and the mutation profile of the E-cadherin gene <it>CDH1 </it>was examined by DHPLC followed by direct sequence analysis. Correlations with overall survival (OS), time to progression (TTP) and overall response rate (ORR) were assessed.</p> <p>Results</p> <p>Our study showed a significant association between increased <it>EGFR </it>gene copy number (≥ 4.0) and OS in gastric and OGJ cancer, indicating the possibility that patients may be selected for treatment on a genetic basis. Furthermore, a significant correlation was shown between activated EGFR and shorter TTP and ORR, but not between activated EGFR and OS. No V600E BRAF mutations were identified. On the other hand, an interesting trend between high E-cadherin expression levels and better OS was observed and two <it>CDH1 </it>exon 9 missense mutations (A408V and D402H) were detected.</p> <p>Conclusion</p> <p>Our finding that increased <it>EGFR </it>gene copy numbers, activated EGFR and the E-cadherin status are potentially interesting biomarkers needs to be confirmed in larger randomized clinical trials.</p> <p>Trial registration</p> <p>Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.</p

Discovery of a novel member of the histamine receptor family

We report the discovery, tissue distribution and pharmacological characterization of a novel receptor, which we have named H4. Like the three histamine receptors reported previously (H1, H2, and H3), the H4 receptor is a G protein-coupled receptor and is most closely related to the H3 receptor, sharing 58% identity in the transmembrane regions. The gene encoding the H4 receptor was discovered initially in a search of the GenBank databases as sequence fragments retrieved in a partially sequenced human genomic contig mapped to chromosome 18. These sequences were used to retrieve a partial cDNA clone and, in combination with genomic fragments, were used to determine the full-length open reading frame of 390 amino acids. Northern analysis revealed a 3.0-kb transcript in rat testis and intestine. Radioligand binding studies indicated that the H4 receptor has a unique pharmacology and binds [3H]histamine (K d = 44 nM) and [3H]pyrilamine (K d = 32 nM) and several psychoactive compounds (amitriptyline, chlorpromazine, cyproheptadine, mianserin) with moderate affinity (K i range of 33–750 nM). Additionally, histamine induced a rapid internalization of HA-tagged H4 receptors in transfected human embryonic kidney 293 cells

Strategies and performance of the CMS silicon tracker alignment during LHC Run 2

The strategies for and the performance of the CMS silicon tracking system alignment during the 2015–2018 data-taking period of the LHC are described. The alignment procedures during and after data taking are explained. Alignment scenarios are also derived for use in the simulation of the detector response. Systematic effects, related to intrinsic symmetries of the alignment task or to external constraints, are discussed and illustrated for different scenarios

Protein and lipid MALDI profiles classify breast cancers according to the intrinsic subtype

<p>Abstract</p> <p>Background</p> <p>Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) has been demonstrated to be useful for molecular profiling of common solid tumors. Using recently developed MALDI matrices for lipid profiling, we evaluated whether direct tissue MALDI MS analysis on proteins and lipids may classify human breast cancer samples according to the intrinsic subtype.</p> <p>Methods</p> <p>Thirty-four pairs of frozen, resected breast cancer and adjacent normal tissue samples were analyzed using histology-directed, MALDI MS analysis. Sinapinic acid and 2,5-dihydroxybenzoic acid/α-cyano-4-hydroxycinnamic acid were manually deposited on areas of each tissue section enriched in epithelial cells to identify lipid profiles, and mass spectra were acquired using a MALDI-time of flight instrument.</p> <p>Results</p> <p>Protein and lipid profiles distinguish cancer from adjacent normal tissue samples with the median prediction accuracy of 94.1%. Luminal, HER2+, and triple-negative tumors demonstrated different protein and lipid profiles, as evidenced by permutation <it>P </it>values less than 0.01 for 0.632+ bootstrap cross-validated misclassification rates with all classifiers tested. Discriminatory proteins and lipids were useful for classifying tumors according to the intrinsic subtype with median prediction accuracies of 80.0-81.3% in random test sets.</p> <p>Conclusions</p> <p>Protein and lipid profiles accurately distinguish tumor from adjacent normal tissue and classify breast cancers according to the intrinsic subtype.</p

MALDI imaging mass spectrometry for direct tissue analysis: a new frontier for molecular histology

Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating the distribution of proteins and small molecules within biological systems through the in situ analysis of tissue sections. MALDI-IMS can determine the distribution of hundreds of unknown compounds in a single measurement and enables the acquisition of cellular expression profiles while maintaining the cellular and molecular integrity. In recent years, a great many advances in the practice of imaging mass spectrometry have taken place, making the technique more sensitive, robust, and ultimately useful. In this review, we focus on the current state of the art of MALDI-IMS, describe basic technological developments for MALDI-IMS of animal and human tissues, and discuss some recent applications in basic research and in clinical settings