The Open Global Glacier Model (OGGM) v1.1 Maussion, Fabien; Butenko, Anton; Champollion, Nicolas ...
Geoscientific Model Development,
03/2019, Letnik:
12, Številka:
3
Journal Article
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Despite their importance for sea-level rise, seasonal water availability, and
as a source of geohazards, mountain glaciers are one of the few remaining
subsystems of the global climate system for ...which no globally applicable,
open source, community-driven model exists. Here we present the Open Global
Glacier Model (OGGM), developed to provide a modular and open-source
numerical model framework for simulating past and future change of any
glacier in the world. The modeling chain comprises data downloading tools
(glacier outlines, topography, climate, validation data), a preprocessing
module, a mass-balance model, a distributed ice thickness estimation model,
and an ice-flow model. The monthly mass balance is obtained from gridded
climate data and a temperature index melt model. To our knowledge, OGGM is
the first global model to explicitly simulate glacier dynamics: the model
relies on the shallow-ice approximation to compute the depth-integrated flux
of ice along multiple connected flow lines. In this paper, we describe and
illustrate each processing step by applying the model to a selection of
glaciers before running global simulations under idealized climate forcings.
Even without an in-depth calibration, the model shows very realistic
behavior. We are able to reproduce earlier estimates of global glacier volume
by varying the ice dynamical parameters within a range of plausible values.
At the same time, the increased complexity of OGGM compared to other
prevalent global glacier models comes at a reasonable computational cost:
several dozen glaciers can be simulated on a personal computer, whereas
global simulations realized in a supercomputing environment take up to a few
hours per century. Thanks to the modular framework, modules of various
complexity can be added to the code base, which allows for new kinds of model
intercomparison studies in a controlled environment. Future developments will
add new physical processes to the model as well as automated calibration
tools. Extensions or alternative parameterizations can be easily added by the
community thanks to comprehensive documentation. OGGM spans a wide range of
applications, from ice–climate interaction studies at millennial timescales
to estimates of the contribution of glaciers to past and future sea-level
change. It has the potential to become a self-sustained community-driven
model for global and regional glacier evolution.
Estimations of global glacier mass changes over the course of the 20th century require automated initialization methods, allowing the reconstruction of past glacier states from limited information. ...In a previous study, we developed a method to initialize the Open Global Glacier Model (OGGM) from past climate information and present-day geometry alone. Tested in an idealized framework, this method aimed to quantify how much information present-day glacier geometry carries about past glacier states. The method was not applied to real-world cases, and therefore, the results were not comparable with observations. This study closes the gap to real-world cases by introducing a glacier-specific calibration of the mass balance model. This procedure ensures that the modeled present-day geometry matches the observed area and that the past glacier evolution is consistent with bias-corrected past climate time series. We apply the method to 517 glaciers, spread globally, for which either mass balance observations or length records are available, and compare the observations to the modeled reconstructed glacier changes. For the validation of the initialization method, we use multiple measures of reconstruction skill (e.g., MBE, RMSE, and correlation). We find that the modeled mass balances and glacier lengths are in good agreement with the observations, especially for glaciers with many observation years. These results open the door to a future global application.
To provide estimates of past glacier mass changes over the course of the 20th century, an adequate initial state is required. However, empirical evidence about past glacier states at regional or ...global scales is largely incomplete, both spatially and temporally, calling for the use of automated numerical methods.
This study presents a new way to initialize the Open Global Glacier Model from past climate information and present-day glacier states. We use synthetic experiments to show that even with these perfectly known but incomplete boundary conditions, the problem of model initialization is an ill-posed inverse problem leading to nonunique solutions, and we propose an ensemble approach as a way forward. The method works as follows: we generate a large set of physically plausible glacier candidates for a given year in the past (e.g., 1850 in the Alps), all of which are then modeled forward to the date of the observed glacier outline and evaluated by comparing the results of the forward runs to the present-day states. We test the approach on 2660 Alpine glaciers and determine error estimates of the method from the synthetic experiments. The results show that the solution is often nonunique, as many of the reconstructed initial states converge towards the observed state in the year of observation. We find that the median state of the best 5 % of all acceptable states is a reasonable best estimate. The accuracy of the method depends on the type of the considered observation for the evaluation (glacier length, area, or geometry). Trying to find past states from only present-day length instead of the full geometry leads to a sharp increase in uncertainty. Our study thus also provides quantitative information on how well the reconstructed initial glacier states are constrained through the limited information available to us. We analyze which glacier characteristics influence the reconstructability of a glacier, and we discuss ways to develop the method further for real-world applications.
The Open Global Glacier Model (Author abstract) Maussion, Fabien; Butenko, Anton; Champollion, Nicolas ...
Geoscientific model development,
03/2019, Letnik:
12, Številka:
3
Journal Article
Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to ...hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1, and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations.
Background Since its emergence in December 2019, over 700 million people worldwide have been infected with SARS-CoV-2 up to May 2024. While early rollout of mRNA vaccines against COVID-19 has saved ...many lives, there was increasing immune escape of new virus variants. Longitudinal monitoring of population-wide SARS-CoV-2 antibody responses from regular sample collection irrespective of symptoms provides representative data on infection and seroconversion/seroreversion rates. Aim To examine adaptive and cellular immune responses of a German SARS-CoV-2 outbreak cohort through several waves of infection with different virus variants. Methods Utilising a 31-month longitudinal seroepidemiological study (n = 1,446; mean age: 50 years, range: 2–103) initiated during the first SARS-CoV-2 superspreading event (February 2020) in Heinsberg, Germany, we analysed acute infection, seroconversion and virus neutralisation at five follow-up visits between October 2020 and November 2022; cellular and cross-protective immunity against SARS-CoV-2 Omicron variants were also examined. Results SARS-CoV-2 spike (S)-specific IgAs decreased shortly after infection, while IgGs remained stable. Both increased significantly after vaccination. We predict an 18-month half-life of S IgGs upon infection. Nucleocapsid (N)-specific responses declined over 12 months post-infection but increased (p < 0.0001) during Omicron. Frequencies of SARS-CoV-2-specific TNF-alpha + /IFN-gamma + CD4 + T-cells declined over 12 months after infection (p < 0.01). SARS-CoV-2 S antibodies and neutralisation titres were highest in triple-vaccinated participants infected between April 2021 and November 2022 compared with infections between April 2020 and January 2021. Cross neutralisation against Omicron BQ.1.18 and XBB.1.5 was very low in all groups. Conclusion Infection and/or vaccination did not provide the population with cross-protection against Omicron variants.
Nonparenteral transmission might contribute to human parvovirus 4 (PARV4) infections in sub-Saharan Africa. PARV4 DNA was detected in 8 (0.83%) of 961 nasal samples and 5 (0.53%) of 943 fecal samples ...from 1,904 children in Ghana. Virus concentrations ≤ 6-7 log(10) copies/mL suggest respiratory or fecal-oral modes of PARV4 transmission.
This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A ...high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.
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•YAP1/TAZ pathway inhibitors identified by phenotypic high-throughput screen•Target deconvolution identifies GGTase-I as the direct target•GGTase-I inhibitors block Rho-GTPase signaling and downstream YAP1/TAZ•GGTase-I inhibitor BAY-593 demonstrates potent anti-tumor activity in vivo
Graham et al. describe the identification and characterization of small molecule inhibitors of oncogenic YAP1/TAZ activity using phenotypic screening. They perform target deconvolution studies to identify the direct target combined with in vitro and in vivo studies to describe the mode-of-action and therapeutic potential of the inhibitors.
Abstract YAP1/TAZ have been shown to be aberrantly activated oncogenes in several human solid tumors, resulting in enhanced cell proliferation, metastasis and provision of a pro-tumorigenic ...microenvironment, making YAP1/TAZ targets for novel cancer therapies. Yet, the development of effective inhibitors of these potent oncogenes has been challenging. In this work, we break new ground in this direction through the identification of novel inhibitors of YAP1/TAZ activity. This study describes the identification and target deconvolution of novel small molecule inhibitors of oncogenic YAP1/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. HTS hits that selectively inhibited TEAD-luciferase, but not TK-Renilla-luciferase (n = 3.994) were subsequently assessed regarding their ability to induce translocation of YAP1 from the nucleus to the cytoplasm in MDA-MB-231 cells, which is the physiological mechanism of inactivation. Out of these, 392 hits showed activity to induce translocation of YAP1. Finally, selected hits active in both assays (n = 96) were assessed regarding their effect on endogenous YAP1/TAZ target genes. The small molecule BAY-856 demonstrated the most consistent YAP1/TAZ inhibitory activity of all selected hits, which warranted further exploration of the unknown direct drug target. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex, as the direct target of YAP1/TAZ pathway inhibitor BAY-856. BAY-856 and close analogs with improved in vitro potency blocked the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in several tumor types in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties. BAY-593 demonstrated anti-tumor activity in solid tumor models and blockade of YAP1/TAZ signaling in vivo. BAY-593 is a novel tool compound to explore Rho-GTPase signaling and downstream YAP1/TAZ biology in vitro and in vivo. Citation Format: Keith Graham, Philip Lienau, Benjamin Bader, Stefan Prechtl, Jan Naujoks, Ralf Lesche, Barbara Nicke, Wilhelm Bone, Sven Golfier, Krzysztof Brzezinka, Stefan Kaulfuss, Charlotte Kopitz, Holger Steuber, Nico Braeuer, Katrin Nowak-Reppel, Carlo Stresemann, Patrick Steigemann, Julia Kuehnlenz, Lisette Potze, Francesca Zanconato, Anna Montebaur, Sabine Pilari, Sikander Hayat, Atanas Kamburov, Andreas Steffen, Andreas Schlicker, Philipp Buchgraber, Nuria Aiguabella Font, Tobias Heinrich, Lara Kuhnke, Annette O. Walter, Simona Blotta, Matthias Ocker, Ashley Lakner, Dominik Mumberg, Knut Eis, Stefano Piccolo, Martin Lange. Novel YAP1/TAZ pathway inhibitors identified through phenotypic screening with potent anti-tumor activity via blockade of GGTase-I and Rho-GTPase signaling abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4584.
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