► Introduces the Agricultural Model Intercomparison and Improvement Project (AgMIP). ► Describes AgMIP Protocols for consistent research activities. ► Demonstrates AgMIP approaches using climate, ...crop, and economic model analyses. ► Wheat pilot results elucidate the relative uncertainties from crop and climate models. ► Outlines AgMIP crop-specific, regional, and global research activities.
The Agricultural Model Intercomparison and Improvement Project (AgMIP) is a major international effort linking the climate, crop, and economic modeling communities with cutting-edge information technology to produce improved crop and economic models and the next generation of climate impact projections for the agricultural sector. The goals of AgMIP are to improve substantially the characterization of world food security due to climate change and to enhance adaptation capacity in both developing and developed countries. Analyses of the agricultural impacts of climate variability and change require a transdisciplinary effort to consistently link state-of-the-art climate scenarios to crop and economic models. Crop model outputs are aggregated as inputs to regional and global economic models to determine regional vulnerabilities, changes in comparative advantage, price effects, and potential adaptation strategies in the agricultural sector. Climate, Crop Modeling, Economics, and Information Technology Team Protocols are presented to guide coordinated climate, crop modeling, economics, and information technology research activities around the world, along with AgMIP Cross-Cutting Themes that address uncertainty, aggregation and scaling, and the development of Representative Agricultural Pathways (RAPs) to enable testing of climate change adaptations in the context of other regional and global trends. The organization of research activities by geographic region and specific crops is described, along with project milestones.
Pilot results demonstrate AgMIP's role in assessing climate impacts with explicit representation of uncertainties in climate scenarios and simulations using crop and economic models. An intercomparison of wheat model simulations near Obregón, Mexico reveals inter-model differences in yield sensitivity to CO2 with model uncertainty holding approximately steady as concentrations rise, while uncertainty related to choice of crop model increases with rising temperatures. Wheat model simulations with mid-century climate scenarios project a slight decline in absolute yields that is more sensitive to selection of crop model than to global climate model, emissions scenario, or climate scenario downscaling method. A comparison of regional and national-scale economic simulations finds a large sensitivity of projected yield changes to the simulations’ resolved scales. Finally, a global economic model intercomparison example demonstrates that improvements in the understanding of agriculture futures arise from integration of the range of uncertainty in crop, climate, and economic modeling results in multi-model assessments.
This paper presents the first plasmid DNA irradiations carried out with Very High Energy Electrons (VHEE) over 100-200 MeV at the CLEAR user facility at CERN to determine the Relative Biological ...Effectiveness (RBE) of VHEE. DNA damage yields were measured in dry and aqueous environments to determine that ~ 99% of total DNA breaks were caused by indirect effects, consistent with other published measurements for protons and photons. Double-Strand Break (DSB) yield was used as the biological endpoint for RBE calculation, with values found to be consistent with established radiotherapy modalities. Similarities in physical damage between VHEE and conventional modalities gives confidence that biological effects of VHEE will also be similar-key for clinical implementation. Damage yields were used as a baseline for track structure simulations of VHEE plasmid irradiation using GEANT4-DNA. Current models for DSB yield have shown reasonable agreement with experimental values. The growing interest in FLASH radiotherapy motivated a study into DSB yield variation with dose rate following VHEE irradiation. No significant variations were observed between conventional and FLASH dose rate irradiations, indicating that no FLASH effect is seen under these conditions.
An intercentrosomal linker keeps a cell's two centrosomes joined together until it is dissolved at the onset of mitosis. A second connection keeps daughter centrioles engaged to their mothers until ...they lose their orthogonal arrangement at the end of mitosis. Centriole disengagement is required to license centrioles for duplication. We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP. We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. Cep68 and PCNT bind to different pools of Cep215. We propose that Cep68 degradation allows Cep215 removal from the peripheral PCM preventing centriole separation following disengagement, whereas PCNT cleavage mediates Cep215 removal from the core of the PCM to inhibit centriole disengagement and duplication.
Chromothripsis: Chromosomes in Crisis Jones, Mathew J.K.; Jallepalli, Prasad V.
Developmental cell,
11/2012, Letnik:
23, Številka:
5
Journal Article
Recenzirano
Odprti dostop
During oncogenesis, cells acquire multiple genetic alterations that confer essential tumor-specific traits, including immortalization, escape from antimitogenic signaling, neovascularization, ...invasiveness, and metastatic potential. In most instances, these alterations are thought to arise incrementally over years, if not decades. However, recent progress in sequencing cancer genomes has begun to challenge this paradigm, because a radically different phenomenon, termed chromothripsis, has been suggested to cause complex intra- and interchromosomal rearrangements on short timescales. In this Review, we review established pathways crucial for genome integrity and discuss how their dysfunction could precipitate widespread chromosome breakage and rearrangement in the course of malignancy.
Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows ...RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and, consequently, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint and confers specific sensitization of mutant K-Ras cancer cells to DNA damage chemotherapeutic agents in vitro and in vivo.
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•Mutant K-Ras cancer cells require WT-H/N-Ras for G2 DNA damage checkpoint activation•The activation of ATR/Chk1 in mutant K-Ras cancer cells is dependent on WT-H/N-Ras•WT-H-Ras suppression leads to regression of K-Ras tumors in response to DNA damage
Grabocka et al. report that cancer cells expressing mutant K-Ras require wild-type H-Ras and N-Ras to activate the ATR-Chk1-mediated DNA damage checkpoint. This dependence on wild-type H- and N-Ras can be exploited to sensitize K-Ras-driven cancers to DNA damage-inducing chemotherapeutic agents.
Summary
Jasmonic acid (JA) and its biologically active derivatives (bioactive JAs) perform a critical role in regulating plant responses to wound stress. The perception of bioactive JAs by the F‐box ...protein COI1 triggers the SCFCOI1/ubiquitin‐dependent degradation of JASMONATE ZIM‐DOMAIN (JAZ) proteins that repress the expression of JA‐response genes. JA is required for many wound‐inducible systemic defense responses, but little is known about the role of the hormone in long‐distance signal relay between damaged and undamaged leaves. Here, we show that the wounding of Arabidopsis thaliana leaves results in the rapid (<5 min) accumulation of jasmonoyl‐l‐isoleucine (JA‐Ile), the bioactive form of JA, in leaves distal to the wound site. The rapid systemic increase in JA‐Ile preceded the onset of early transcriptional responses, and was associated with JAZ degradation. Wound‐induced systemic production of JA‐Ile required the JA biosynthetic enzyme 12‐oxo‐phytodienoic acid (OPDA) reductase 3 (OPR3) in undamaged responding leaves, but not in wounded leaves, and was largely dependent on the JA‐conjugating enzyme JAR1. Interestingly, the wound‐induced synthesis of JA/JA‐Ile in systemic leaves was correlated with a rapid decline in OPDA levels. These results are consistent with a model in which a rapidly transmitted wound signal triggers the systemic synthesis of JA, which, upon conversion to JA‐Ile, activates the expression of early response genes by the SCFCOI1/JAZ pathway.
Diabet. Med. 28, 1144–1153 (2011)
Aim To quantify global variation in the incidence of lower extremity amputations in light of the rising prevalence of diabetes mellitus.
Methods An electronic ...search was performed using the EMBASE and MEDLINE databases from 1989 until 2010 for incidence of lower extremity amputation. The literature review conformed to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement standards.
Results Incidence of all forms of lower extremity amputation ranges from 46.1 to 9600 per 105 in the population with diabetes compared with 5.8–31 per 105 in the total population. Major amputation ranges from 5.6 to 600 per 105 in the population with diabetes and from 3.6 to 68.4 per 105 in the total population. Significant reductions in incidence of lower extremity amputation have been shown in specific at‐risk populations after the introduction of specialist diabetic foot clinics.
Conclusion Significant global variation exists in the incidence of lower extremity amputation. Ethnicity and social deprivation play a significant role but it is the role of diabetes and its complications that is most profound. Lower extremity amputation reporting methods demonstrate significant variation with no single standard upon which to benchmark care. Effective standardized reporting methods of major, minor and at‐risk populations are needed in order to quantify and monitor the growing multidisciplinary team effect on lower extremity amputation rates globally.
This paper presents the first demonstration of deeply penetrating dose delivery using focused very high energy electron (VHEE) beams using quadrupole magnets in Monte Carlo simulations. We show that ...the focal point is readily modified by linearly changing the quadrupole magnet strength only. We also present a weighted sum of focused electron beams to form a spread-out electron peak (SOEP) over a target region. This has a significantly reduced entrance dose compared to a proton-based spread-out Bragg peak (SOBP). Very high energy electron (VHEE) beams are an exciting prospect in external beam radiotherapy. VHEEs are less sensitive to inhomogeneities than proton and photon beams, have a deep dose reach and could potentially be used to deliver FLASH radiotherapy. The dose distributions of unfocused VHEE produce high entrance and exit doses compared to other radiotherapy modalities unless focusing is employed, and in this case the entrance dose is considerably improved over existing radiations. We have investigated both symmetric and asymmetric focusing as well as focusing with a range of beam energies.
Aluminium–air cells are high-energy density (<400 W h kg−1) primary batteries developed in the 1960s. This review shows the influence of the materials, including: aluminium alloy, oxygen reduction ...catalyst and electrolyte type, in the battery performance. Two issues are considered: (a) the parasitic corrosion of aluminium at open-circuit potential and under discharge, due to the reduction of water on the anode and (b) the formation of a passive hydroxide layer on aluminium, which inhibits dissolution and shifts its potential to positive values. To overcome these two issues, super-pure (99.999 wt%) aluminium alloyed with traces of Mg, Sn, In and Ga are used to inhibit corrosion or to break down the passive hydroxide layer. Since high-purity aluminium alloys are expensive, an alternative approach is to add inhibitors or additives directly into the electrolyte. The effectiveness of binary and ternary alloys and the addition of different electrolyte additives are evaluated. Novel methods to overcome the self-corrosion problem include using anionic membranes and gel electrolytes or alternative solvents, such as alcohols or ionic liquids, to replace aqueous solutions. The air cathode is also considered and future opportunities and directions for the development of aluminium–air cells are highlighted.
► Discussion of the rationale to choose a suitable alloy for Al–air battery. ► Effect of the properties and preparation route to enhance the oxidation of Al. ► Effect of the inhibitors on the anode oxidation in the alkaline electrolyte. ► Comparison of the performance of high-activity oxygen reduction electrodes.
Delivery of vaccine antigens to the dermis and/or epidermis of human skin (i.e. intradermal delivery) might be more efficient than injection into the muscle or subcutaneous tissue, thereby reducing ...the volumes of antigen. This is known as dose-sparing and has been demonstrated in clinical trials with some, but not all, vaccines. Dose-sparing could be beneficial to immunization programmes by potentially reducing the costs of purchase, distribution and storage of vaccines; increasing vaccine availability and effectiveness. The data obtained with intradermal delivery of some vaccines are encouraging and warrant further study and development; however significant gaps in knowledge and operational challenges such as reformulation, optimizing vaccine presentation and development of novel devices to aid intradermal vaccine delivery need to be addressed. Modelling of the costs and potential savings resulting from intradermal delivery should be done to provide realistic expectations of the potential benefits and to support cases for investment. Implementation and uptake of intradermal vaccine delivery requires further research and development, which depends upon collaboration between multiple stakeholders in the field of vaccination.
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