The Space Weather Modeling Framework (SWMF) provides a high‐performance flexible framework for physics‐based space weather simulations, as well as for various space physics applications. The SWMF ...integrates numerical models of the Solar Corona, Eruptive Event Generator, Inner Heliosphere, Solar Energetic Particles, Global Magnetosphere, Inner Magnetosphere, Radiation Belt, Ionosphere Electrodynamics, and Upper Atmosphere into a high‐performance coupled model. The components can be represented with alternative physics models, and any physically meaningful subset of the components can be used. The components are coupled to the control module via standardized interfaces, and an efficient parallel coupling toolkit is used for the pairwise coupling of the components. The execution and parallel layout of the components is controlled by the SWMF. Both sequential and concurrent execution models are supported. The SWMF enables simulations that were not possible with the individual physics models. Using reasonably high spatial and temporal resolutions in all of the coupled components, the SWMF runs significantly faster than real time on massively parallel supercomputers. This paper presents the design and implementation of the SWMF and some demonstrative tests. Future papers will describe validation (comparison of model results with measurements) and applications to challenging space weather events. The SWMF is publicly available to the scientific community for doing geophysical research. We also intend to expand the SWMF in collaboration with other model developers.
Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, ...including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.
Superabsorbent polymers (SAP) are a new, promising class of chemical admixtures which offer new possibilities in respect of influencing the properties of cement-based materials in the fresh, ...hardening, and hardened states. Much research work has been done in the last two decades to set the stage for introducing this truly multipurpose agent into the practice of construction. In particular, three RILEM Technical Committees: 196-ICC, 225-SAP and 260-RSC contributed considerably to the related progress by coordinating and combining the efforts of international experts in the field. The major product of the RILEM TC 225-SAP work was the State-of-the-Art Report published in 2012. This comprehensive document covered all topics relevant to the application of SAP as a concrete admixture. Since then further important progress has been made in understanding the working mechanisms of SAP in concrete and the effects of SAP-addition on various concrete properties. The article at hand presents an update on the state-of-the-art and is the concluding document delivered by the RILEM TC 260-RSC.
Molecular control of the pluripotent state is thought to reside in a core circuitry of master transcription factors including the homeodomain-containing protein NANOG, which has an essential role in ...establishing ground state pluripotency during somatic cell reprogramming. Whereas the genomic occupancy of NANOG has been extensively investigated, comparatively little is known about NANOG-associated proteins and their contribution to the NANOG-mediated reprogramming process. Using enhanced purification techniques and a stringent computational algorithm, we identify 27 high-confidence protein interaction partners of NANOG in mouse embryonic stem cells. These consist of 19 previously unknown partners of NANOG that have not been reported before, including the ten-eleven translocation (TET) family methylcytosine hydroxylase TET1. We confirm physical association of NANOG with TET1, and demonstrate that TET1, in synergy with NANOG, enhances the efficiency of reprogramming. We also find physical association and reprogramming synergy of TET2 with NANOG, and demonstrate that knockdown of TET2 abolishes the reprogramming synergy of NANOG with a catalytically deficient mutant of TET1. These results indicate that the physical interaction between NANOG and TET1/TET2 proteins facilitates reprogramming in a manner that is dependent on the catalytic activity of TET1/TET2. TET1 and NANOG co-occupy genomic loci of genes associated with both maintenance of pluripotency and lineage commitment in embryonic stem cells, and TET1 binding is reduced upon NANOG depletion. Co-expression of NANOG and TET1 increases 5-hydroxymethylcytosine levels at the top-ranked common target loci Esrrb and Oct4 (also called Pou5f1), resulting in priming of their expression before reprogramming to naive pluripotency. We propose that TET1 is recruited by NANOG to enhance the expression of a subset of key reprogramming target genes. These results provide an insight into the reprogramming mechanism of NANOG and uncover a new role for 5-methylcytosine hydroxylases in the establishment of naive pluripotency.
In patients with major depressive disorder (MDD), functional neuroimaging studies have reported an increased activation of the dorsolateral prefrontal cortex (DLPFC) during executive performance and ...working memory (WM) processing, and also an increased activation of the anterior cingulate cortex (ACC) during baseline conditions. However, the functional coupling of these cortical networks during WM processing is less clear.
In this study, we used a verbal WM paradigm, event-related functional magnetic resonance imaging (fMRI) and multivariate statistical techniques to explore patterns of functional coupling of temporally dissociable dorsolateral prefrontal and cingulate networks. By means of independent component analyses (ICAs), two components of interest were identified that showed either a positive or a negative temporal correlation with the delay period of the cognitive activation task in both healthy controls and MDD patients.
In a prefronto-parietal network, a decreased functional connectivity pattern was identified in depressed patients comprising inferior parietal, superior prefrontal and frontopolar regions. Within this cortical network, MDD patients additionally revealed a pattern of increased functional connectivity in the left DLPFC and the cerebellum compared to healthy controls. In a second, temporally anti-correlated network, healthy controls exhibited higher connectivity in the ACC, the ventrolateral and the superior prefrontal cortex compared to MDD patients.
These results complement and expand previous functional neuroimaging findings by demonstrating a dysconnectivity of dissociable prefrontal and cingulate regions in MDD patients. A disturbance of these dynamic networks is characterized by a simultaneously increased connectivity of the DLPFC during task-induced activation and increased connectivity of the ACC during task-induced deactivation.
Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS ...mutations with disease progression and reduced survival in colorectal cancer patients.
We used TaqMan low-density array (TLDA) qRT-PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion.
MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells.
We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers.
Current organ-preservation regimens for upper aerodigestive tract squamous cell carcinoma (SCCA) require endoscopic procedures under general anesthesia to evaluate the tumor response. The purpose of ...our study was to determine whether CT perfusion (CTP) parameters correlate with response to induction chemotherapy as assessed by endoscopy under general anesthesia.
Nine patients with advanced (stage 3 or 4) SCCA of the oropharynx were enrolled in a nested phase 2 prospective trial in which induction chemotherapy was used to assess the tumor response. Patients underwent direct laryngoscopy and CTP before and 3 weeks after one cycle of induction chemotherapy. The outcome variables were the surgeon's estimate of tumor volume during endoscopy with biopsy under anesthesia and CTP parameters (capillary permeability (CP), blood volume (BV), blood flow (BF), and mean transit time (MTT)). Wilcoxon rank sum analysis was used to correlate the baseline values of BF and BV with response to induction chemotherapy. Comparison of agreement between the reduction in tumor volume and change in CTP parameters was performed by using kappa estimates.
Seven of 9 patients demonstrated > or =50% tumor volume reduction, representing positive response to induction chemotherapy. In the responder group, the following changes in mean pre- and postinduction chemotherapy values were noted: mean BF, 114.2 mL/100 g /min (preinduction) to 45.1 mL/100 g/min (postinduction); mean BV, 5.11 mL/100 g to 3.1 mL/100 g; mean CP, 25.6 mL/100 g /min (preinduction) to 18.3 mL/100 g / min (postinduction); mean MTT, 4.9 seconds (preinduction) to 8.0 seconds (postinduction). In the nonresponder group, the following changes were noted: mean BF, 56.9 mL/100 g/min to 75.9 mL/100 g/min; mean, BV 2.7 mL/100 g to 4.71 mL/100 g; mean CP, 24.1 mL/100 g/min to 23.7 mL/100 g/min; mean MTT, 4.3 seconds to 5.34 seconds. Higher baseline (pretherapy) values of BV showed significant correlation with endoscopic tumor response (P < .05). Reduction in the BV (by >/=20%) on follow-up studies also showed substantial agreement with clinical response as assessed with endoscopy (kappa = 0.73). The agreement between decreased BF, decreased CP, and increased MTT and clinical response was fair (kappa = 0.37).
These preliminary results show that deconvolution-based CTP technique offers potential for noninvasive monitoring of response to induction chemotherapy in patients with oropharyngeal cancers. Percentage reduction of BV is significantly correlated to endoscopic response to induction chemotherapy, though we acknowledge that the data correspond to short-term outcomes and long-term durability of response cannot be established. Nevertheless, validation of the use of deconvolution CTP parameters as predictors of tumor response may permit replacement of an invasive diagnostic procedure conducted under anesthesia currently used to assess response with noninvasive perfusion CT imaging.
Rap1GAP is a critical tumor suppressor gene that is downregulated in multiple aggressive cancers, such as head and neck squamous cell carcinoma, melanoma and pancreatic cancer. However, the ...mechanistic basis of rap1GAP downregulation in cancers is poorly understood. By employing an integrative approach, we demonstrate polycomb-mediated repression of rap1GAP that involves Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase in head and neck cancers. We further demonstrate that the loss of miR-101 expression correlates with EZH2 upregulation, and the concomitant downregulation of rap1GAP in head and neck cancers. EZH2 represses rap1GAP by facilitating the trimethylation of histone 3 at lysine 27, a mark of gene repression, and also hypermethylation of rap1GAP promoter. These results provide a conceptual framework involving a microRNA-oncogene-tumor suppressor axis to understand head and neck cancer progression.
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