text:
package org.elasticsearch.index.mapper.source;

import org.apache.lucene.index.IndexableField;
import org.elasticsearch.Version;
import org.elasticsearch.cluster.metadata.IndexMetaData;
import org.elasticsearch.common.bytes.BytesArray;
import org.elasticsearch.common.compress.CompressedXContent;
import org.elasticsearch.common.compress.CompressorFactory;
import org.elasticsearch.common.settings.Settings;
import org.elasticsearch.common.xcontent.XContentFactory;
import org.elasticsearch.common.xcontent.XContentParser;
import org.elasticsearch.common.xcontent.XContentType;
import org.elasticsearch.index.mapper.*;
import org.elasticsearch.test.ESSingleNodeTestCase;

import java.io.IOException;
import java.util.ArrayList;
import java.util.Arrays;
import java.util.List;
import java.util.Map;

import static org.hamcrest.Matchers.equalTo;

public class DefaultSourceMappingTests extends ESSingleNodeTestCase {

    public void testNoFormat() throws Exception {
        String mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
                .startObject("_source").endObject()
                .endObject().endObject().string();

        DocumentMapperParser parser = createIndex("test").mapperService().documentMapperParser();
        DocumentMapper documentMapper = parser.parse(mapping);
        ParsedDocument doc = documentMapper.parse("test", "type", "1", XContentFactory.jsonBuilder().startObject()
                .field("field", "value")
                .endObject().bytes());

        assertThat(XContentFactory.xContentType(doc.source()), equalTo(XContentType.JSON));

        documentMapper = parser.parse(mapping);
        doc = documentMapper.parse("test", "type", "1", XContentFactory.smileBuilder().startObject()
                .field("field", "value")
                .endObject().bytes());

        assertThat(XContentFactory.xContentType(doc.source()), equalTo(XContentType.SMILE));
    }

    public void testJsonFormat() throws Exception {
        String mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
                .startObject("_source").field("format", "json").endObject()
                .endObject().endObject().string();

        DocumentMapperParser parser = createIndex("test").mapperService().documentMapperParser();
        DocumentMapper documentMapper = parser.parse(mapping);
        ParsedDocument doc = documentMapper.parse("test", "type", "1", XContentFactory.jsonBuilder().startObject()
                .field("field", "value")
                .endObject().bytes());

        assertThat(XContentFactory.xContentType(doc.source()), equalTo(XContentType.JSON));

        documentMapper = parser.parse(mapping);
        doc = documentMapper.parse("test", "type", "1", XContentFactory.smileBuilder().startObject()
            .field("field", "value")
            .endObject().bytes());

        assertThat(XContentFactory.xContentType(doc.source()), equalTo(XContentType.JSON));
    }

    public void testJsonFormatCompressedBackcompat() throws Exception {
        String mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
                .startObject("_source").field("format", "json").field("compress", true).endObject()
                .endObject().endObject().string();

        Settings backcompatSettings = Settings.builder().put(IndexMetaData.SETTING_VERSION_CREATED, Version.V_1_4_2.id).build();
        DocumentMapperParser parser = createIndex("test", backcompatSettings).mapperService().documentMapperParser();
        DocumentMapper documentMapper = parser.parse(mapping);
        ParsedDocument doc = documentMapper.parse("test", "type", "1", XContentFactory.jsonBuilder().startObject()
                .field("field", "value")
                .endObject().bytes());

        assertThat(CompressorFactory.isCompressed(doc.source()), equalTo(true));
        byte[] uncompressed = CompressorFactory.uncompressIfNeeded(doc.source()).toBytes();
        assertThat(XContentFactory.xContentType(uncompressed), equalTo(XContentType.JSON));

        documentMapper = parser.parse(mapping);
        doc = documentMapper.parse("test", "type", "1", XContentFactory.smileBuilder().startObject()
                .field("field", "value")
                .endObject().bytes());

        assertThat(CompressorFactory.isCompressed(doc.source()), equalTo(true));
        uncompressed = CompressorFactory.uncompressIfNeeded(doc.source()).toBytes();
        assertThat(XContentFactory.xContentType(uncompressed), equalTo(XContentType.JSON));
    }

    public void testIncludes() throws Exception {
        String mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").field("includes", new String[]{"path1*"}).endObject()
            .endObject().endObject().string();

        DocumentMapper documentMapper = createIndex("test").mapperService().documentMapperParser().parse(mapping);

        ParsedDocument doc = documentMapper.parse("test", "type", "1", XContentFactory.jsonBuilder().startObject()
            .startObject("path1").field("field1", "value1").endObject()
            .startObject("path2").field("field2", "value2").endObject()
            .endObject().bytes());

        IndexableField sourceField = doc.rootDoc().getField("_source");
        Map<String, Object> sourceAsMap;
        try (XContentParser parser = XContentFactory.xContent(XContentType.JSON).createParser(new BytesArray(sourceField.binaryValue()))) {
            sourceAsMap = parser.map();
        }
        assertThat(sourceAsMap.containsKey("path1"), equalTo(true));
        assertThat(sourceAsMap.containsKey("path2"), equalTo(false));
    }

    public void testExcludes() throws Exception {
        String mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").field("excludes", new String[]{"path1*"}).endObject()
            .endObject().endObject().string();

        DocumentMapper documentMapper = createIndex("test").mapperService().documentMapperParser().parse(mapping);

        ParsedDocument doc = documentMapper.parse("test", "type", "1", XContentFactory.jsonBuilder().startObject()
            .startObject("path1").field("field1", "value1").endObject()
            .startObject("path2").field("field2", "value2").endObject()
            .endObject().bytes());

        IndexableField sourceField = doc.rootDoc().getField("_source");
        Map<String, Object> sourceAsMap;
        try (XContentParser parser = XContentFactory.xContent(XContentType.JSON).createParser(new BytesArray(sourceField.binaryValue()))) {
            sourceAsMap = parser.map();
        }
        assertThat(sourceAsMap.containsKey("path1"), equalTo(false));
        assertThat(sourceAsMap.containsKey("path2"), equalTo(true));
    }

    public void testDefaultMappingAndNoMapping() throws Exception {
        String defaultMapping = XContentFactory.jsonBuilder().startObject().startObject(MapperService.DEFAULT_MAPPING)
                .startObject("_source").field("enabled", false).endObject()
                .endObject().endObject().string();

        DocumentMapperParser parser = createIndex("test").mapperService().documentMapperParser();
        DocumentMapper mapper = parser.parse("my_type", null, defaultMapping);
        assertThat(mapper.type(), equalTo("my_type"));
        assertThat(mapper.sourceMapper().enabled(), equalTo(false));
        try {
            mapper = parser.parse(null, null, defaultMapping);
            assertThat(mapper.type(), equalTo("my_type"));
            assertThat(mapper.sourceMapper().enabled(), equalTo(false));
            fail();
        } catch (MapperParsingException e) {
            // all is well
        }
        try {
            mapper = parser.parse(null, "{}", defaultMapping);
            assertThat(mapper.type(), equalTo("my_type"));
            assertThat(mapper.sourceMapper().enabled(), equalTo(false));
            fail();
        } catch (MapperParsingException e) {
            assertThat(e.getMessage(), equalTo("malformed mapping no root object found"));
            // all is well
        }
    }

    public void testDefaultMappingAndWithMappingOverride() throws Exception {
        String defaultMapping = XContentFactory.jsonBuilder().startObject().startObject(MapperService.DEFAULT_MAPPING)
                .startObject("_source").field("enabled", false).endObject()
                .endObject().endObject().string();

        String mapping = XContentFactory.jsonBuilder().startObject().startObject("my_type")
                .startObject("_source").field("enabled", true).endObject()
                .endObject().endObject().string();

        DocumentMapper mapper = createIndex("test").mapperService().documentMapperParser().parse("my_type", mapping, defaultMapping);
        assertThat(mapper.type(), equalTo("my_type"));
        assertThat(mapper.sourceMapper().enabled(), equalTo(true));
    }

    public void testDefaultMappingAndNoMappingWithMapperService() throws Exception {
        String defaultMapping = XContentFactory.jsonBuilder().startObject().startObject(MapperService.DEFAULT_MAPPING)
                .startObject("_source").field("enabled", false).endObject()
                .endObject().endObject().string();

        MapperService mapperService = createIndex("test").mapperService();
        mapperService.merge(MapperService.DEFAULT_MAPPING, new CompressedXContent(defaultMapping), true, false);

        DocumentMapper mapper = mapperService.documentMapperWithAutoCreate("my_type").getDocumentMapper();
        assertThat(mapper.type(), equalTo("my_type"));
        assertThat(mapper.sourceMapper().enabled(), equalTo(false));
    }

    public void testDefaultMappingAndWithMappingOverrideWithMapperService() throws Exception {
        String defaultMapping = XContentFactory.jsonBuilder().startObject().startObject(MapperService.DEFAULT_MAPPING)
                .startObject("_source").field("enabled", false).endObject()
                .endObject().endObject().string();

        MapperService mapperService = createIndex("test").mapperService();
        mapperService.merge(MapperService.DEFAULT_MAPPING, new CompressedXContent(defaultMapping), true, false);

        String mapping = XContentFactory.jsonBuilder().startObject().startObject("my_type")
                .startObject("_source").field("enabled", true).endObject()
                .endObject().endObject().string();
        mapperService.merge("my_type", new CompressedXContent(mapping), true, false);

        DocumentMapper mapper = mapperService.documentMapper("my_type");
        assertThat(mapper.type(), equalTo("my_type"));
        assertThat(mapper.sourceMapper().enabled(), equalTo(true));
    }

    void assertConflicts(String mapping1, String mapping2, DocumentMapperParser parser, String... conflicts) throws IOException {
        DocumentMapper docMapper = parser.parse(mapping1);
        docMapper = parser.parse(docMapper.mappingSource().string());
        MergeResult mergeResult = docMapper.merge(parser.parse(mapping2).mapping(), true, false);

        List<String> expectedConflicts = new ArrayList<>(Arrays.asList(conflicts));
        for (String conflict : mergeResult.buildConflicts()) {
            assertTrue("found unexpected conflict [" + conflict + "]", expectedConflicts.remove(conflict));
        }
        assertTrue("missing conflicts: " + Arrays.toString(expectedConflicts.toArray()), expectedConflicts.isEmpty());
    }

    public void testEnabledNotUpdateable() throws Exception {
        DocumentMapperParser parser = createIndex("test").mapperService().documentMapperParser();
        // using default of true
        String mapping1 = XContentFactory.jsonBuilder().startObject().startObject("type").endObject().endObject().string();
        String mapping2 = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").field("enabled", false).endObject()
            .endObject().endObject().string();
        assertConflicts(mapping1, mapping2, parser, "Cannot update enabled setting for [_source]");

        // not changing is ok
        String mapping3 = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").field("enabled", true).endObject()
            .endObject().endObject().string();
        assertConflicts(mapping1, mapping3, parser);
    }

    public void testIncludesNotUpdateable() throws Exception {
        DocumentMapperParser parser = createIndex("test").mapperService().documentMapperParser();
        String defaultMapping = XContentFactory.jsonBuilder().startObject().startObject("type").endObject().endObject().string();
        String mapping1 = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").array("includes", "foo.*").endObject()
            .endObject().endObject().string();
        assertConflicts(defaultMapping, mapping1, parser, "Cannot update includes setting for [_source]");
        assertConflicts(mapping1, defaultMapping, parser, "Cannot update includes setting for [_source]");

        String mapping2 = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").array("includes", "foo.*", "bar.*").endObject()
            .endObject().endObject().string();
        assertConflicts(mapping1, mapping2, parser, "Cannot update includes setting for [_source]");

        // not changing is ok
        assertConflicts(mapping1, mapping1, parser);
    }

    public void testExcludesNotUpdateable() throws Exception {
        DocumentMapperParser parser = createIndex("test").mapperService().documentMapperParser();
        String defaultMapping = XContentFactory.jsonBuilder().startObject().startObject("type").endObject().endObject().string();
        String mapping1 = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").array("excludes", "foo.*").endObject()
            .endObject().endObject().string();
        assertConflicts(defaultMapping, mapping1, parser, "Cannot update excludes setting for [_source]");
        assertConflicts(mapping1, defaultMapping, parser, "Cannot update excludes setting for [_source]");

        String mapping2 = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").array("excludes", "foo.*", "bar.*").endObject()
            .endObject().endObject().string();
        assertConflicts(mapping1, mapping2, parser, "Cannot update excludes setting for [_source]");

        // not changing is ok
        assertConflicts(mapping1, mapping1, parser);
    }

    public void testComplete() throws Exception {
        DocumentMapperParser parser = createIndex("test").mapperService().documentMapperParser();
        String mapping = XContentFactory.jsonBuilder().startObject().startObject("type").endObject().endObject().string();
        assertTrue(parser.parse(mapping).sourceMapper().isComplete());

        mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").field("enabled", false).endObject()
            .endObject().endObject().string();
        assertFalse(parser.parse(mapping).sourceMapper().isComplete());

        mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").array("includes", "foo.*").endObject()
            .endObject().endObject().string();
        assertFalse(parser.parse(mapping).sourceMapper().isComplete());

        mapping = XContentFactory.jsonBuilder().startObject().startObject("type")
            .startObject("_source").array("excludes", "foo.*").endObject()
            .endObject().endObject().string();
        assertFalse(parser.parse(mapping).sourceMapper().isComplete());
    }

    public void testSourceObjectContainsExtraTokens() throws Exception {
        String mapping = XContentFactory.jsonBuilder().startObject().startObject("type").endObject().endObject().string();
        DocumentMapper documentMapper = createIndex("test").mapperService().documentMapperParser().parse(mapping);

        try {
            documentMapper.parse("test", "type", "1", new BytesArray("{}}")); // extra end object (invalid JSON)
            fail("Expected parse exception");
        } catch (MapperParsingException e) {
            assertNotNull(e.getRootCause());
            String message = e.getRootCause().getMessage();
            assertTrue(message, message.contains("Unexpected close marker '}'"));
        }
    }
}

redpajama_set_name: RedPajamaGithub


text:
Q: How can i update a cordova lib for my app (2.1.0 to 5.1.1) How can i update a cordova lib for my Android Application from Version 2.1.0 to 5.1.1 i can't download the .jar file from the offical webpage

A: using bellow commands
npm install -g cordova

using this command latest version are installed this command fire in to your CMD
And if you want to down your cordova version 5.0 to 3.6.3 or any other cordova version then use bellow command
npm install -g cordova@3.6.3-0.2.13

redpajama_set_name: RedPajamaStackExchange


== Why these are useful == As a new contributor, you might prefer FLOSS communities where contributors pay attention to these sorts of social questions. Having a code of conduct is often an indicator that a project has a sizeable number of contributors and interested in growing. As a project maintainer, you might want to look these over as inspiration for your project. For more advice, see [http://adainitiative.org/2014/02/howto-design-a-code-of-conduct-for-your-community/ "HOWTO design a code of conduct for your community"] by the Ada Initiative. Feel free to add links to unlisted CoC. Please preserve alphabetical order on project name.


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Ependymoma is the second most common malignant pediatric tumor of the CNS, accounting for approximately 10% of all brain tumors in children . Prognosis remains relatively poor and little progress has been made in recent decades to develop new treatments.
Epigenetic modifications can be defined as stable and heritable changes in gene expression resulting from modifications to the DNA molecule without alterations in the DNA sequence. Epigenetic alterations play a role in the development and progression of many cancers. The most common types of modification altered include DNA methylation, histone acetylation and histone methylation [2–5].
In cancer, increased DNA methylation at promoters of tumor suppressor genes, resulting in their silencing, is often seen. Therefore, de-methylating agents have been investigated for therapeutic use. One of the most advanced is decitabine, which targets DNA methyltransferase enzymes. It has been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome as well as being investigated in clinical trials for other cancers [6, 7].
Histone acetylation plays a key role in the regulation of gene expression and levels are often altered in cancer. Histone de-acetylase inhibitors (HDACi) are the most clinically advanced agents targeting epigenetic modifications. A number of agents targeting this modification are FDA approved, including vorinostat, for the treatment of cutaneous T-cell lymphoma, and panobinostat, for the treatment of multiple myeloma [8, 9].
Histone methylation also plays an important role in cancer development and progression . In particular, the repressive tri-methylation mark on lysine 27 of histone H3 (H3K27) has been shown to be important for pediatric brain tumors including ependymoma [11, 12]. H3K27 is methylated by the polycomb repressor complex 2 (PRC2). Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, is commonly mutated or overexpressed in cancer . Inhibitors targeting EZH2 have been developed including GSK343 and EPZ-6438 [14–16].
Recent studies have highlighted the importance of epigenetic modifications in ependymoma [11, 17–19]. DNA methylation profiling has demonstrated this epigenetic mark can define ependymoma sub-groups based on demographic and clinical features, including age at diagnosis and tumor location [11, 17]. For pediatric patients, DNA methylation defined two posterior fossa (PF) groups, EPN_PFA and EPN_PFB, and two supratentorial (ST) groups, EPN_RELPOS and EPN_YAP1. EPN_PFA tumors were shown to occur in young children and displayed a hyper-methylated phenotype. EPN_PFB tumors occurred in older children and displayed a hypo-methylated phenotype . EPN_RELPOS and EPN_YAP1 ependymomas were characterized by recently discovered fusion genes involving RELA and YAP1 respectively .
Initial pre-clinical evidence supports the potential therapeutic targeting of epigenetic modifications in ependymoma. Mack et al demonstrated decitabine and GSK343 inhibited the growth of primary ependymoma cultures in vitro. Studies also support the clinical potential of HDAC inhibitors in ependymoma [18, 21].
Pre-clinical analysis of agents targeting epigenetic modifications in ependymoma has so far been undertaken using a small set of in vitro cultured cells. However, the epigenetic profile of these models was not investigated. The clinical relevance of in vitro models has long been questioned and studies have shown that epigenetic modifications can alter during cell culture [22–24].
In this study, we have expanded the pre-clinical investigation of agents targeting DNA methylation, histone acetylation and H3K27 methylation using a panel of ependymoma cell lines. Alongside this, we used DNA methylation profiling to measure how closely the cultured cells retained their original profiles. We show that epigenetic agents inhibited the growth and induced the death of ependymoma cells with variable efficacy, but was often outside clinically achievable ranges. Importantly, DNA methylation profiling of the cultured ependymoma cells indicated their profiles were altered from that seen in primary ependymoma tumor tissue for the majority of the lines tested, questioning the validity of in vitro cultured cells for analysis of epigenetic agents.
Cultured cells derived from six ependymomas (3 ST, 3 PF) were used in the study. Analysis of C11orf95-RELA fusion status and DNA methylation profiling was used to characterize the cells.
C11orf95-RELA fusion status was determined using western blot to wild-type RELA. Fusions (seen as larger proteins than wild-type rela) were detected in all cells derived from ST ependymomas (BXD-1425EPN, DKFZ-EP1, EPN1) but none of the PF cells (EPN8, EPN9, EPN10) (Figure 1A).
Figure 1: Cell line subgroup characterization. C11orf95-RELA fusion status was determined using western blot for wild-type rela (A). A larger protein than the wild-type (WT), representing the fusion gene, was seen in all three ST cell lines but not in the PF cells. t-SNE dimension reduction demonstrated that cultured ependymoma cells mainly grouped together with cell lines derived from other brain tumors rather than primary ependymoma samples, with the exception of DKFZ-EP1, which clustered with EPN_RELPOS cells (B).
All cells underwent DNA methylation profiling using Infinium HumanMethylation450 BeadChip arrays (Illumina). Supervised class prediction by the previously published classifier  (http://www.molecularneuropathology.org) was used to assign cell line profiles to tumor subgroups. The only cell line that could be confidently assigned to an ependymoma molecular subgroup was DKFZ-EP1, which was classified as EPN_RELPOS. EPN10 was classified as EPN_PFA. However, this was with a low level of confidence. All other ependymoma cells were misclassified with very low confidence scores (Table 1). DNA methylation has been shown to alter during in vitro cell culture, which may explain these discrepancies [22–24]. Clustering of the cultured ependymoma cells alongside ependymoma tumors, plus cell lines from other brain tumor types, demonstrated that all the cultured cells formed one group, with the exception of the DKFZ-EP1 cell line which correctly grouped with the EPN_RELPOS ependymomas (Figure 1B). This suggested that in vitro culture induced DNA methylation changes in the cells, resulting in a common culture induced profile.
*0 = 0% confidence, 1 = 100% confidence.
To assess the clinical potential of agents targeting epigenetic modifications, ependymoma cells were incubated with selected agents and the effects on cell viability investigated (Figure 2). For each agent there was no clear difference between the more representative model, DKFZ-EP1, and the other ependymoma cells. There was also no clear difference between cells with (BXD-1425EPN, DKFZ-EP1, EPN1) or without (EPN8, EPN9, EPN10) the C11orf95-RELA fusion.
Figure 2: Effect of epigenetic agents on ependymoma cell line viability. Epigenetic agents reduced the viability of ependymoma cells. Ependymoma cells were treated with vorinostat (A) and panobinostat (B), or vehicle control, for 72 hrs. Both agents reduced cell viability, relative to vehicle control, in the majority of ependymoma cells, including the DKFZ-EP1 cells. Ependymoma cells were incubated with decitabine (C) for 144 hrs. A decrease in viability was seen in only a minority of ependymoma cells, which did not include DKFZ-EP1 cells. Cells were incubated with GSK343 (D) for 120 hrs. GKS343 did not induce a decrease in viability in the majority of ependymoma cells tested. Cell viability was measured using a MTT assay.
The HDAC inhibitors vorinostat and panobinostat were most effective, causing a significant decrease in viability in most cells tested (Figure 2A, 2B). IC50 concentrations for vorinostat ranged from 5 μM to greater than 20 μM, and panobinostat from 90–510 nM (Supplementary Table 1).
The de-methylating agent decitabine caused a significant reduction in viability in BXD-1425EPN and EPN8 cells (Figure 2C), which was only seen after 144 hrs. Only a modest effect on viability was seen in all other ependymoma cells tested. IC50 concentrations ranged from 50 nM to greater than 5 μM (Supplementary Table 1).
The EZH2 inhibitor GSK343 did not induce a significant reduction in viability for the majority of ependymoma cells tested (Figure 2D). The largest effect was seen for BXD-1425EPN and EPN8 cells. IC50 concentrations ranged from 16 μM to greater than 20 μM (Supplementary Table 1). The decrease in viability was only observed after 120 hrs.
Cell death was analyzed to determine whether the epigenetic agents induced a cytotoxic response. One drug was selected targeting each epigenetic mechanism. Cell death was measured using a LDH assay following vorinostat, decitabine and GSK343 treatment (Figure 3). There was again no clear difference in the level of cell death induced between the more representative DKFZ-EP1 cells and the other ependymoma cells, or between cells with or without the C11orf95-RELA fusion.
Figure 3: Effect of epigenetic agents on ependymoma cell death. A LDH assay was used to measure whether cell death was induced by epigenetic agents. Vorinostat induced cell death in all ependymoma cells tested following 72 hrs treatment (A). Decitabine did not induce cell death in any ependymoma cells following treatment for 144 hrs (B). GSKS343 induced cell death following 120 hrs treatment (C).
Vorinostat and GSK343 both induced cell death in ependymoma cells (Figure 3), suggesting this was the significant cause of decreased viability induced by both these agents. However, significant cell death was not induced by decitabine (Figure 3), suggesting a growth arrest was induced instead.
The effect of targeting multiple epigenetic modifications was investigated to determine if a combinatorial approach enhanced their effects (Supplementary Figure 1). For combinations involving decitabine, cells were treated with decitabine alone before addition of the second drug. HDAC and EZH2 inhibitors can block the progression of G1 cells into S phase, which interferes with the action of decitabine [26, 27].
In general, no significant enhanced effects were seen between treatment with combinations or each drug alone (Supplementary Figure 1). No clear difference was seen in response to drug combinations between DKFZ-EP1 and other ependymoma cells tested.
Decitabine plus vorinostat showed some enhancement of effects in some cells tested. However, this was only seen at higher drug concentrations and was not seen in the DKFZ-EP1 cells. The combination of decitabine with GSK343 did not enhance their inhibitory effects and for some combinations were antagonistic. Vorinostat combined with GSK343 enhanced the effects on cell viability in BXD-1425 and EPN1 cell lines, although in general only at higher concentrations.
Fetal neural stem cells (fNSC) grown as multicellular spheroids were used to assess toxicity to normal cells. fNSCs were incubated with each drug using the same concentrations as ependymoma cells. The effect on cell viability was measured using an alamar blue assay.
All drugs reduced fNSC viability (Figure 4). The fNSCs were more sensitive to HDAC inhibitors and GSK343 than all ependymoma cells tested. However, they were less sensitive to decitabine than the most sensitive ependymoma cells (BXD-1425EPN, EPN8) (Supplementary Table 2).
Figure 4: Toxicity of epigenetic agents to fNSCs. Epigenetic agents displayed toxicity to fNSCs. Cells were incubated with each drug at the same concentrations and incubation times as ependymoma cells. Viability was measured using an alamar blue assay.
Recent research suggests epigenetic modifications play an important role in ependymoma pathology and are therefore a potential therapeutic target, which now needs testing using pre-clinical models. We have shown that agents targeting epigenetic modifications inhibited the growth of cultured ependymoma cells with variable efficiency, suggesting clinical potential in some instances. However, we also demonstrated a lack of similarity between the DNA methylation profiles of the majority of cultured ependymoma cell lines tested and primary ependymoma tumors, with cultured cells appearing closer to cell lines from other brain tumor types. This suggests alterations were induced during culture, resulting in a common DNA methylation profile that overrides the differences normally seen between these tumor types. DNA methylation has been shown to alter during cell culture [22–24] which may explain why the profiles of these cells did not match ependymoma tumors.
These findings highlight the importance of profiling cell lines to measure their validity as a pre-clinical model, and questions the use of 2D cultured cells for pre-clinical testing of epigenetic agents, suggesting more representative models are needed. This might include 3D in vitro models. A number of 3D culture systems have been developed, including spheroids, organoids and growth on hydrogels or scaffolds, which allow cells to grow in a system that better reflects tissue architecture and physiological conditions [28, 29]. 3D models of various cancers, including brain tumors, have been shown to have biological profiles closer to the primary tumor than cells cultured in 2D on a flat plastic surface [30–34].
No clear difference was seen in response to epigenetic agents between the one cell line, which retained an ependymoma-like DNA methylation profile (DFKZ-EP1), and those that did not. However, as only one cell line was confidently assigned to an ependymoma subgroup, limited conclusions could be made about how much the alterations in DNA methylation seen during in vitro culture altered the response to the agents tested.
The most effective agents against ependymoma cells in this study were the HDAC inhibitors which induced cytotoxicity in the majority of ependymoma cells tested, including DKFZ-EP1, agreeing with previous reports [18, 21]. Milde et al also treated the DKFZ-EP1 cell line with vorinostat and panobinostat, identifying IC50 concentrations of 776 nM and 2.9 nM respectively, which were lower than our calculated IC50 concentrations (5 μM and 360 nM). However, Milde et al treated the cells when grown as neurospheres instead of a monolayer in serum-supplemented media, which could explain the difference in sensitivity.
Although both vorinostat and panobinostat induced growth inhibition, it was not at clinically achievable concentrations. Reported peak plasma concentrations for vorinostat and panobinostat were 4.5 μM and 40 nM respectively [35, 36], with phase I trials of vorinostat in pediatric solid tumors suggesting this may be lower in pediatric patients (1.4–1.6 μM) [37, 38]. This suggests HDAC inhibitors would not be effective as single agents in patients and agrees with analysis of two HDAC inhibitors in an in vivo ependymoma mouse model where low activity was seen [39, 40]. Additionally, although vorinostat was well tolerated in phase I trials of pediatric solid tumors, including ependymoma, limited clinical responses were observed [37, 38]. A combination approach to lower doses needed for an effective response, or a local drug delivery system to enable effective concentrations to reach the tumor while avoiding high systematic doses, could improve the clinical potential of these agents.
Previous research suggested DNA methylation plays an important role in ependymoma [11, 17, 19]. Growth inhibition was only achieved in two cell lines tested, which did not include DKFZ-EP1, questioning the clinical potential of this agent. Mack et al previously demonstrated growth inhibition of short-term cultures of cells derived from EPN_PFA tumors . However, profiling was not undertaken to determine if the cells tested retained their original DNA methylation profile.
Where inhibition was achieved IC50 concentrations were within clinical ranges, with reported plasma concentrations up to 5 μM . Decitabine has been shown to cross the blood brain barrier where CSF concentrations were reported at up to 50% of plasma concentrations . Our results demonstrated the effects seen upon treatment with decitabine were cytostatic, suggesting it would need to be used in combination to induce cell death.
The EZH2 inhibitor GSK343 was the least effective of all agents tested. Inhibition was achieved at relatively high concentrations compared to those identified previously in sensitive ependymomas . However, it was closer to IC50 concentrations reported for other cancer types [16, 43]. Pharmacokinetic studies in rat models demonstrated GSK343 displayed high clearance suggesting it is only useful as an in vitro experimental tool and not suitable for in vivo studies . Alternative EZH2 inhibitors with good pharmacokinetic properties and clinical potential have now been developed, including EPZ-6438, which is currently being investigated in clinical trials with promising preliminary results [13–15]. However, initial pre-clinical testing suggested this drug also displayed low activity in ependymoma .
Multiple epigenetic mechanisms can be de-regulated in cancer and studies have shown benefit of targeting multiple mechanisms in combination [45, 46]. However, the combinations tested against ependymoma cells did not show a significant increase in the effects on cell viability.
Epigenetic modifications play a key role in normal brain development [47, 48]. Therefore, caution must be taken when considering targeting these processes for ependymoma therapy. Our analysis suggested the drugs we tested do show toxicity to normal neural stem cells at similar or lower concentrations than those required to inhibit ependymoma cell growth. However, the fetal brain has been shown to have the capacity to respond and repair damage induced by the de-methylating agent 5-azacytidine . Studies investigating toxicity to normal astrocytes and neuronal cells suggest decitabine was not toxic to these cells at concentrations that inhibited growth in sensitive ependymoma cell lines [50, 51]. In contrast, vorinostat and panobinostat have been shown to induce cytotoxicity to normal astrocytes and neurons at similar concentrations to those needed to inhibit ependymoma cell growth [52–54]. However, no neurotoxicity was seen following systematic administration of vorinostat to mice , or in a recent human trial of vorinostat in recurrent glioblastoma . Additionally, in clinical trials of pediatric patients, epigenetic drugs have been well tolerated [37, 38, 57, 58]. Further analysis is needed to determine the long-term consequences of any toxicity induced.
In conclusion, we have presented pre-clinical evidence demonstrating epigenetic agents could inhibit the growth of ependymoma cells. However, our results suggest caution is needed in the clinical progression of these agents as inhibitory effects were not always at clinically achievable concentrations and toxicity to normal cells was also seen. Importantly, the alteration of DNA methylation profiles in the majority of cells tested questions the validity of using 2D in vitro cultured cell lines as a model and suggests we need more accurate and biologically relevant models for pre-clinical testing to identify successful drug combinations before translation into the clinical setting.
The ependymoma cell line BXD-1425EPN was provided by Dr Xiao-Nan Li, Baylor College of Medicine and has previously been characterized . Cells were derived from a 9-year-old male with a recurrent ST anaplastic ependymoma. The DKFZ-EP1 cell line was provided by Dr T Milde and Dr O Witt, DKFZ and has previously been characterized . Cells were derived from the malignant ascites of an 18-year-old female with a primary grade III classic ST ependymoma. The EPN1 cell line was generated and characterized in house . Cells were derived from a 13-year-old male with a recurrent ST ependymoma. Short term cultures of three PF ependymomas were established as previously described . EPN8 was derived from a 1.5-year-old male with a primary grade III anaplastic PF ependymoma. EPN9 was derived from a 16-month female with a primary grade II PF ependymoma. EPN10 was derived from a 2-year-old female with a PF primary anaplastic ependymoma.
Cells were cultured in standard humidified incubators at 5% CO2. BXD-1425EPN and DKFZ-EP1 cells were cultured in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (FBS) (PAA Laboratories) plus antibiotics. EPN1, EPN8, EPN9 and EPN10 were cultured in DMEM supplemented with 15% FBS plus antibiotics.
Doubling times for the cell lines were calculated as BXD-1425EPN; 23 hrs, DKFZ-EP1; 116 hrs, EPN1; 203 hrs, EPN8; 48 hrs, EPN9; 34 hrs, EPN10; 48 hrs. The passage range for the cell lines used were BXD-1425EPN; P66-75, DKFZ-EP1; P10-25, EPN8; p6-15, EPN9; p6-15, EPN10 p6-15.
STR DNA profiling analysis was used for cell line authentication by Eurofins Genomics (Ebersberg, Germany). STR genotypes were generated for two different passages of each line and, where available, the DNA extracted from the tumor tissue the cell line was derived from. Genotypes for all passages of each line matched each other. The genotypes of the primary lines EPN1, EPN8 and EPN10 matched the primary tissue they were derived from, confirming the cultured cells originated from the tumor. No cell line matched any profile in the ATCC and DSMZ databases.
Ependymoma cells were analyzed for the presence of the C11orf95-RELA fusion using western blot of wild-type RELA . Western blots were run as previously described . Membranes were incubated with primary antibodies to RELA (1/10,000, Cell Signalling Technology) and GAPDH (1/50,000, Abcam).
DNA was extracted from cells as previously described . Profiling was performed on bisulphite modified DNA using Infinium HumanMethylation450 BeadChip arrays (Illumina) at UCL Genomics (London, UK). All computational analyses were performed in R version 3.4.1 . Raw signal intensities were obtained from IDAT files using the minfi Bioconductor package . Each sample was normalized by performing a background correction (shifting 5% percentile of negative control probes to 0) and a dye-bias correction for both color channels. A correction for the type of material used (FFPE/frozen) was performed by fitting univariate, linear models to the log2-transformed intensity values (removeBatchEffect function, limma package v3.34.5 ). Methylated and un-methylated signals were corrected individually. Beta values were calculated from the re-transformed intensities using an offset of 100.
Prior to clustering probes targeting the X and Y chromosomes, probes containing a single nucleotide polymorphism within five base pairs of, and including, the target CpG and probes not mapping uniquely to the human reference genome (hg19) were removed. To perform unsupervised dimension reduction the remaining probes were used to calculate the 1-variance weighted pearson correlation between samples. The resulting matrix was used for input for t-SNE analysis (t-Distributed Stochastic Neighbor Embedding , Rtsne package version 0.13 ) with the default parameters: theta = 0, pca = F, max_iter = 2500, perplexity = 30.
To predict tumor subgroups a methylation based classifier was used  (http://www.molecularneuropathology.org) which assigns methylation profiles to 91 different tumor subgroups including all ependymoma subgroups previously described  and gives a confidences score for the prediction.
Ependymoma cell line methylation profiles have been deposited in NCBI's Gene Expression Omnibus (GEO http://www.ncbi.nlm.nih.gov/geo) and are accessible through GEO Series accession number GSE111428. Methylation data of ependymomas used for the t-SNE analysis are available in GEO series GSE65362. Methylation data for medulloblastoma and high grade glioma cell lines used for the t-SNE analysis area available in GEO series GSE112067. The medulloblastoma cell lines used were DAOY, UW228-2, ONS-76, D425 MED, D458 MED and D487 MED. The high grade glioma cell lines used were SJ-G2 and SF188. All were cultured under standard conditions prior to DNA extraction and methylation profiling.
All drugs were reconstituted in DMSO. Decitabine (Sigma-Aldrich) at a concentration of 200 mM, vorinostat (Sigma-Aldrich) 250 mM, panobinostat (Selleck Chemicals) 50 mM and GSK343 (Sigma-Aldrich) 28 mM.
Cells were seeded in 96 well plates and incubated overnight. Subsequently, cells were treated with indicated drug or vehicle control (DMSO). For vorinostat, viability was measured after 72 hrs exposure to the drug. For GSK343, drug was replenished after 72 hrs and viability measured 120 hrs after drug treatment started. Cells were treated with decitabine using similar methods to published studies [67–70]. Transient low doses that induce de-methylation but no cytotoxicity, that was unrelated to DNA methylation, were used. Decitabine was replenished 24 and 48 hrs after initial treatment. Viability was measured 144 hrs after drug treatment started.
For combination experiments targeting multiple epigenetic modifications, drugs were used at a fixed ratio based on single agent IC50 concentrations. Cells were treated with 0.125, 0.25, 0.5, 1, 2 and 4 times the IC50 concentration. For combinations involving decitabine, cells were pre-treated for 48 hrs with decitabine before addition of the second drug after which cells were incubated for a further 96 hrs. Cells were incubated with vorinostat in combination with GSK343 for 72 hrs.
Cell viability was measured using the Cell proliferation kit I (MTT) (Roche), following manufacturer's instructions. Each condition was performed in triplicate, in three independent repeats. The percentage of viable cells relative to vehicle control was calculated based on averaged triplicates for each condition. IC50 concentrations were estimated from dose response curves.
Cells were seeded in 96 well plates and incubated overnight. Subsequently, cells were treated with indicated drug or vehicle control. Cells were incubated for 72 hrs with vorinostat, 120 hrs with GSK343 and 144 hrs with decitabine before analysis. GSK343 was replenished after 72 hrs and decitabine after 24 and 48 hrs. Cell death was measured using the Cytotoxicity Detection KitPLUS (LDH) (Roche), following manufacturer's instructions. Each condition was performed in triplicate, in three independent repeats.
Fetal neural stem cells (fNSC) were derived and cultured as previously described . 10,000 cells per well were seeded into Ultra low attachment 96-well round bottom plates and incubated for 48 hrs, allowing time for formation of a single uniformly sized spheroid. Subsequently, indicated drug or vehicle control was added and incubated for indicated time period. Decitabine was replenished after 24 and 48 hrs. Cell viability was measured using an alamar blue assay (ThermoFisher Scientific), following manufacturer's instructions. Each condition was performed in triplicate, in three independent repeats.
H3K27: lysine 27 of histone H3; PRC2: polycomb repressor complex 2; EZH2: enhancer of zeste homolog 2; PF: posterior fossa; ST: supratentorial; fNSC: fetal neural stem cell.
Concept and design: Hazel Anne Rogers, Richard Guy Grundy; Provision of study material: Hazel Anne Rogers, Rebecca Chapman, Holly Kings, Julie Allard, Jodie Barron-Hastings; Data analysis and interpretation: Hazel Anne Rogers, Kristian Pajtler, Martin Sill, Stefan Pfister; Manuscript writing: Hazel Anne Rogers; Final approval of manuscript: All authors.
We thank Dr Tracey Bradshaw, Jasper Estranero, Dr Delyan Ivanov and Dr Tim Ritzmann for technical support. The authors thank Dr Xiao-Nan Li, Baylor College of Medicine, for providing the BXD-1425EPN cell line and Dr T Milde and Dr O Witt for providing the DKFZ-EP1 cell line.
This research was funded by the University of Nottingham, Joseph Foote Foundation, Olivia's Journey, Figurehting Ependymoma and the Sam White Legacy.
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56. Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS, Reilly JF, Loboda A, Nebozhyn M, Fantin VR, Richon VM, Scheithauer B, Giannini C, et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol. 2009; 27:2052–8. https://doi.org/10.1200/JCO.2008.19.0694.
57. Phillips CL, Davies SM, McMasters R, Absalon M, O'Brien M, Mo J, Broun R, Moscow JA, Smolarek T, Garzon R, Blum W, Schwind S, Marcucci G, Perentesis JP. Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults. Br J Haematol. 2013; 161:406–10. https://doi.org/10.1111/bjh.12268.
58. George RE, Lahti JM, Adamson PC, Zhu K, Finkelstein D, Ingle AM, Reid JM, Krailo M, Neuberg D, Blaney SM, Diller L. Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children's Oncology Group study. Pediatr Blood Cancer. 2010; 55:629–38. https://doi.org/10.1002/pbc.22607.
59. Yu L, Baxter PA, Voicu H, Gurusiddappa S, Zhao Y, Adesina A, Man TK, Shu Q, Zhang YJ, Zhao XM, Su JM, Perlaky L, Dauser R, et al. A clinically relevant orthotopic xenograft model of ependymoma that maintains the genomic signature of the primary tumor and preserves cancer stem cells in vivo. Neuro Oncol. 2010; 12:580–94.
60. Hussein D, Punjaruk W, Storer LC, Shaw L, Othman R, Peet A, Miller S, Bandopadhyay G, Heath R, Kumari R, Bowman KJ, Braker P, Rahman R, et al. Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion. Neuro Oncol. 2011; 13:70–83. https://doi.org/10.1093/neuonc/noq144.
61. Levesley J, Lusher ME, Lindsey JC, Clifford SC, Grundy R, Coyle B. RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines. Neuro Oncol. 2011; 13:1265–76. https://doi.org/10.1093/neuonc/nor129.
62. Team RC. R: A language and environment for statistical computing. R Foundation fo r Statistical Computing, Vienna, Austria. https://www.r-project.org/.
63. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014; 30:1363–9. https://doi.org/10.1093/bioinformatics/btu049.
64. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43:e47. https://doi.org/10.1093/nar/gkv007.
65. van der Maaten L, Hinton G. Visualising data using t-SNE. J Mach Learn Res. 2008; 9.
66. Krijthe JH. Rtsne: T-Distributed stochastic neighbor emebedding using a Barnes-Hut implementation. https://github.com/jkrijthe/Rtsne.
67. Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, Harris J, Yen RW, Ahuja N, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. 2012; 21:430–46. https://doi.org/10.1016/j.ccr.2011.12.029.
68. Turcan S, Fabius AW, Borodovsky A, Pedraza A, Brennan C, Huse J, Viale A, Riggins GJ, Chan TA. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine. Oncotarget. 2013; 4:1729–36. https://doi.org/10.18632/oncotarget.1412.
69. Foulks JM, Parnell KM, Nix RN, Chau S, Swierczek K, Saunders M, Wright K, Hendrickson TF, Ho KK, McCullar MV, Kanner SB. Epigenetic drug discovery: targeting DNA methyltransferases. J Biomol Screen. 2012; 17:2–17. https://doi.org/10.1177/1087057111421212.
70. Karakoula K, Jacques TS, Phipps KP, Harkness W, Thompson D, Harding BN, Darling JL, Warr TJ. Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma. Cancer Lett. 2014; 346:34–44. https://doi.org/10.1016/j.canlet.2013.12.005.
71. Ivanov DP, Parker TL, Walker DA, Alexander C, Ashford MB, Gellert PR, Garnett MC. Multiplexing spheroid volume, resazurin and acid phosphatase viability assays for high-throughput screening of tumour spheroids and stem cell neurospheres. PLoS One. 2014; 9:e103817. https://doi.org/10.1371/journal.pone.0103817.


Métis Child and Family Services Society is pleased to welcome you to our new comprehensive online resource which will encompass our objectives, and provide you with the information needed to strengthen and support our children, families and communities.
We aim to improve the quality and effectiveness of social services to Métis children and families in need. To develop and provide programs which will preserve and strengthen the Métis family. To develop community awareness of and responsibility for the well-being of Métis Children and families.
It is important to understand the underlying beliefs and convictions of Métis Local 1885 in establishing Métis Child and Family Services. We believe children, with the secure and caring guidance of family and culture, grow into healthy adults wanting to make a meaningful contribution to the families, communities and societies that they are a part of. We are also aware of the wreckage that can and does occur when these systems of family and community support break down. It is our belief that the lives of Métis children who come into care, or who appear "at risk" within the Alberta Children Services system are the responsibility of the Métis community. We believe the involvement of family and community is essential when working with children who are "at risk" of entering the Alberta Children Services system. The hope and convictions of Métis LOCAL 1885 is that mutual goals can be realized through the combined cooperative efforts between the various levels of government and the Métis community.
The Métis Jiggers were originally formed in 2003 by the late Georgina Donald. Métis Jiggers are committed to the cultural preservation of Métis traditional music and dance. They promote the Métis traditions of music and dance by performing at various functions and events across Alberta.


text:
package net.techreadiness.persistence.domain;

import javax.persistence.metamodel.SingularAttribute;
import javax.persistence.metamodel.StaticMetamodel;

@StaticMetamodel(ViewDefFieldDO.class)
public abstract class ViewDefFieldDO_ {

	public static volatile SingularAttribute<ViewDefFieldDO, Long> viewDefFieldId;
	public static volatile SingularAttribute<ViewDefFieldDO, Boolean> readOnly;
	public static volatile SingularAttribute<ViewDefFieldDO, ViewDefDO> viewDef;
	public static volatile SingularAttribute<ViewDefFieldDO, String> inputType;
	public static volatile SingularAttribute<ViewDefFieldDO, String> inputStyle;
	public static volatile SingularAttribute<ViewDefFieldDO, String> labelStyle;
	public static volatile SingularAttribute<ViewDefFieldDO, Integer> displayOrder;
	public static volatile SingularAttribute<ViewDefFieldDO, String> overrideName;
	public static volatile SingularAttribute<ViewDefFieldDO, EntityFieldDO> entityField;
	public static volatile SingularAttribute<ViewDefFieldDO, String> labelPosition;
	public static volatile SingularAttribute<ViewDefFieldDO, EntityRuleDO> editRule;
	public static volatile SingularAttribute<ViewDefFieldDO, EntityRuleDO> displayRule;
	public static volatile SingularAttribute<ViewDefFieldDO, String> displayWidth;
	public static volatile SingularAttribute<ViewDefFieldDO, Integer> columnNumber;

}


text:
Harry Melvin Rose (born May 30, 1906 in Niles, Ohio; died November 4, 1986 in Meredith, New Hampshire) was a microbiologist whose lab developed an accurate diagnostic test for rheumatoid arthritis in 1948 after Erik Waaler. He was among the first recipients of the Gairdner Foundation International Award for the test. He lived in Sandwich, New Hampshire.

References

Columbia University faculty
Members of the United States National Academy of Sciences
People from Niles, Ohio
American microbiologists
1906 births
1986 deaths
People from Sandwich, New Hampshire
Weill Cornell Medical College alumni

redpajama_set_name: RedPajamaWikipedia


Please note at this stage we are fairly picky about what we put in here and are trying to minimise duplicate stories even if they have different authors and also focusing a bit more on Greg Inglis stories and only adding a few articles about the Rabbitohs.
When Greg Inglis finishes his career in the NRL, he wants to have something to show for it – both on and off the field.
Inglis, who is in the first season of a five-year contract, believes South Sydney can win a premiership in that time. But he also wants to complete a university degree before he retires from the game.
South Sydney coach Michael Maguire insists Friday's NRL clash against Manly is not a defining match, but concedes his side will need to lift their game if they're to break their two-year hoodoo against the Sea Eagles.
Like the waves at nearby Manly Beach, the big games just keep coming in 2013 and Friday night's clash between the Sea Eagles and Rabbitohs looms as one of the best of the season.
Manly coach Geoff Toovey says South Sydney's lack lustre form against top-four sides will give them increased motivation ahead of Friday night's NRL showdown.
SOUTH Sydney star Greg Inglis says he is carrying a hip injury that he will have to manage for the rest of the season, but he won't let it stop him from taking the field in Friday night's showdown with fellow NRL heavyweights Manly.
South Sydney know they can match it with the NRL's big guns – but at Brookvale Oval on Friday night the Rabbitohs need to start proving they can beat them too.
Greg Inglis put a scare through South Sydney on Friday night when he aggravated an old hip problem during the Test in Canberra, but South Sydney officials believe he is unlikely to miss any football as a result.
(+ video highlights of game) GREG Inglis will lock horns with NSW Origin fullback Brett Stewart on Friday night with the Rabbitohs No.1 given the all-clear to take on the Sea Eagles after sustaining a minor injury in Friday night's ANZAC Test.
GREG Inglis will lock horns with NSW Origin fullback Brett Stewart on Friday night with the Rabbitohs No.1 given the all-clear to take on the Sea Eagles after sustaining a minor injury in Friday night's ANZAC Test.
COFFS HARBOUR, NSW, April 18 AAP – Greg Inglis has called for it, South Sydney coach Michael Maguire can't understand it and Nathan Merritt has given up worrying about it.
NRL action takes a backseat this weekend as the first of the representative matches get underway.
Slipping back into the centres for an Australian team, you will be comforted to hear, is as easy as "riding a bicycle". So says Greg Inglis – who admittedly would still be cool and calm and perhaps just a little bored in an emergency landing – on the job of switching from full-back to centre in Friday night's Test match against New Zealand.
Kangaroos superstar Greg Inglis has rubbished suggestions Friday's Anzac Test in Canberra against an under-strength New Zealand will be a one-sided walkover.
YOU run an eye over how Greg Inglis has performed at fullback for Souths in the last season or so, and wonder if he's ever played poorly.
Greg Inglis has scoffed at suggestions Friday's rugby league test against a weakened New Zealand will be a meaningless walkover.
GREG Inglis is arguably in the best form of his career since making the switch to fullback, but the South Sydney superstar believes he is no chance of stealing a representative No 1 jumper off the back of Billy Slater.
Small section with Greg in it.
Kenny-Dowall is more concerned about nullifying the offensive threats posed by Kangaroos and Queensland centre Greg Inglis.
2013 Member Appreciation Day a Hit!
The South Sydney Rabbitohs Member Appreciation Day, proudly brought to you the Capital Training Institute, was a huge success today (Sunday) with over 2000 Members coming to the Suttons South Sydney High Performance Centre at Redfern Oval to meet their favourite Rabbitohs.
Rabbitohs superstar Greg Inglis has been chosen in his customary international position of centre for Friday's ANZAC Test against New Zealand to be played in Canberra.
Rabbitohs TV catches up with Michael Maguire after the loss to the Storm.
Post Match Press Conference with John Sutton and Michael Maguire.
The South Sydney Rabbitohs' unbeaten run to start the season has been broken, but Rabbitohs Members and supporters can be very proud of the performance turned in by their side in their 17-10 loss to the Melbourne Storm tonight (Saturday) in front of 32,671 Members and fans.
Souths fullback Greg Inglis remains on eight points after not featuring in the Dally M scoring in the Rabbitohs' loss to the Storm.
THE NRL's heavyweights fought a colossal battle in front of more than 30,000 fans at ANZ Stadium last night. Here are the key points to emerge from the game.
South Sydney believe their NRL loss to Melbourne may prove to be good lesson for future battles.
Member Appreciation Day is locked in early this year!
All South Sydney Rabbitohs Members are encouraged to mark Sunday the 14th of April in their calendars for our 2013 Member Appreciation Day at Suttons South Sydney High Performance Centre, Redfern Oval.
This is a great opportunity for all Rabbitohs Members to get up close and personal with the Rabbitohs NRL squad the day after their big clash with the Storm at ANZ Stadium, which celebrates Junior Appreciation Round. So why not make an enjoyable weekend of it and come along to Member Appreciation Day and meet your favourite players and support your team as they continue their promising start to the season.
What a clash this will be! First meets second and there are fascinating matchups galore in what should be a brilliant Heritage Round.
SOUTH Sydney coach Michael Maguire believes the Rabbitohs' get-out-of-jail win over the Warriors was a huge step towards becoming a genuine NRL premiership contender.
Rabbitohs Head Coach Michael Maguire spoke to the Rugby League media today (Thursday), in the lead up to Saturday night's blockbuster match up with the Melbourne Storm.
Slater is in a moon boot after sustaining a foot injury in his side's win over Wests Tigers on Monday night, and he is in some doubt. But officials hope he will recover in time.
Inglis v Slater – possibly the greatest fullback showdown of the modern era. And footy fans can see the battle unfold on Saturday night with Inglis' Rabbitohs play Slater's Storm at ANZ Stadium. Both sides remain unbeaten after five rounds.
NRL premiership favouritism will be up for grabs when South Sydney host the Melbourne Storm at ANZ Stadium on Saturday night in the battle of the competition's only two unbeaten teams after five rounds.
Round 6 kicks off on Friday night with a long awaited grudge match between Sonny Bill Williams and the club he walked out on.
However, the game between Sydney and Canterbury will not be the only blockbuster this weekend, as the Rabbitohs and the Storm will go head to head to try and end each others' unbeaten run.
MONDAY night's performance by Melbourne Storm was good enough to beat Wests Tigers 26-12, but a repeat of the slow-starting, fast-finishing effort won't get it past South Sydney.
Souths are keen to enter negotiations with coach Michael Maguire to extend his contract. His current deal goes until the end of next season but CEO Shane Richardson wants to lock him in for five years.
Rabbitohs fullback Greg Inglis caught up with Rabbitohs TV after the victory over the Warriors in New Zealand.
Inglis talks about the performance, where the team needs to improve for next Saturday's clash with the Melbourne Storm, and reflects on scoring his 100th career try.
The South Sydney Rabbitohs have maintained their undefeated start to the season, getting over the top of the Warriors at Mt Smart Stadium today (Sunday), 24 points to 22 in front of 13,512 supporters.
The Rabbitohs have defeated a fast finishing New Zealand Warriors 24-22 to win across the Tasman for the first time since 2009.
South Sydney coach Michael Maguire admitted to heart flutters at times as the Rabbitohs tuned up for Saturday's NRL heavyweight showdown with premiers Melbourne by edging out the Warriors 24-22 in Auckland.
Watching on a Sydney television set, Hollywood actor Russell Crowe got the best birthday present he could hope for from his beloved Rabbitohs on Sunday.
Yet despite the obvious class of the South Sydney co-owner's team in their 24-22 victory over the Warriors in Auckland, it was very nearly a case of a well-wrapped present being taken right out of his hands.
South Sydney star Greg Inglis' improvement since his switch to fullback is reflected in his rise from seventh to third, with Cowboys halfback Johnathan Thurston down two places to fourth and Cooper Cronk rounding out the top five.
THERE is no change at the top of the Dally M rankings after the weekend's rounds but Cooper Cronk could overtake Greg Inglis after the Storm play the Tigers tonight.
THE last time South Sydney started the season with five straight wins, they won the comp. The year was 1971 (with Video).
Souths legend Mario Fenech said there was no doubt where coach Michael Maguire already ranked in the club's tradition-steeped history – even though he has entered only his second season at Redfern.
Having broken their long losing streak, some of the Warriors' depleted playing stocks are being replenished before they face NRL co-leaders South Sydney.
Canterbury-Bankstown will be without goalkicking centre Krisnan Inu for five matches after the NRL club opted to accept the early guilty plea for his spear tackle on South Sydney's Greg Inglis on Good Friday.
Canterbury centre Krisnan Inu has pleaded guilty to a grade-four dangerous throw charge and accepted a five-match ban for his ugly spear tackle on Greg Inglis.
Canterbury centre Krisnan Inu is expected to plead guilty to a grade-four dangerous throw charge and accept a five-match ban for his ugly spear tackle on Greg Inglis.
KRISNAN Inu faces a seven-week suspension for his sickening spear tackle on Greg Inglis – but the match officials who allowed him to stay on the field will today get off scot-free.
Krisnan Inu could serve as many as seven weeks on the sidelines after his spear tackle on Greg Inglis was deemed worthy of a grade four dangerous throw charge by the match review committee.
Referees boss Daniel Anderson will examine footage of Krisnan Inu's spear tackle on Greg Inglis on Monday morning to deem whether the Bulldogs centre should have been sent off.
ANOTHER strong performance from Souths fullback Greg Inglis has helped him to reach equal top of the Dally M leaderboard after NRL round four.
South Sydney have made their best start to an Australian National Rugby League season since 1971 with their fourth successive victory over Easter to be share the competition lead with Melbourne Storm.
The South Sydney Rabbitohs vs Canterbury-Bankstown Bulldogs Good Friday match set a new NRL regular season attendance record with 51,686 people coming through the turnstiles for the fixture at ANZ Stadium.
Rabbitohs Head Coach Michael Maguire and today's captain John Sutton spoke at the post match press conference following the Rabbitohs outstanding 17-12 victory over the Bulldogs on Good Friday.
Rabbitohs Head Coach Michael Maguire spoke to Rabbitohs TV after today's (Friday's) fantastic victory over the Bulldogs at ANZ Stadium.
Highlights from the 17-12 win over the Bulldogs at ANZ Stadium.
The South Sydney Rabbitohs have maintained their undefeated start to the 2013 Telstra Premiership with a gutsy 17 points to 12 victory over the Canterbury-Bankstown Bulldogs, away from home at ANZ Stadium, in front of a massive crowd of 51,686, a new NRL record for a regular season game.


text:
Trump should not lead GOP ticket in 2024, retiring Sen. Pat Toomey says
Last updated Sep 3, 2021
Senator Pat Toomey speaks to CNBC at the Ambrosetti forum in Italy on Sept. 3, 2021.
Mike Green | CNBC
Sen. Pat Toomey has urged his party not to nominate former President Donald Trump as its presidential candidate in 2024, calling his conduct in the aftermath of the 2020 election "completely unacceptable."
The Pennsylvania Republican voted to convict Trump in the impeachment trial over his role in stoking the Jan. 6 attack on the Capitol by his supporters, fueled by the former president's misinformation about the election being "stolen" due to widespread voter fraud.
Speaking to CNBC at the Ambrosetti Forum in Italy on Friday, Toomey, who is not seeking reelection in 2022, suggested his party consider other presidential nominees in 2024.
"I think that the future of our party is to be a party of ideas, and not to be a party about any one individual, and I think we will learn a lot from the next set of primaries," he said.
"I think after what happened post-2020 election, I think the president's behavior was completely unacceptable, so I don't think he should be the nominee to lead the party in 2024."
Despite his staunch conservative record over a two-decade congressional career, Toomey has broken away from the unwavering fealty to the former president that now serves as a litmus test in the GOP. Pennsylvania's Republican Party in March narrowly voted against formally censuring Toomey for his vote to convict Trump, instead issuing a "strong rebuke."
"I'm a conservative Republican by any objective measure, by looking at the voting record, by looking at my views compared to that of a traditional conservative Republican," Toomey told CNBC's Steve Sedgwick.
"It is President Trump who departed from Republican orthodoxy and conservative orthodoxy in a variety of ways. I stuck to the conservative views that I've had for a long time, he had a different point of view on matters such as trade and sometimes immigration and other things."
Trump loyalism, and a dispute over the investigation into the deadly storming of the Capitol, have become focal points of a battle for the soul of the Republican Party in recent months.
The right-wing House Freedom Caucus has mounted a pressure campaign urging House Minority Leader Kevin McCarthy to expel Reps. Liz Cheney and Adam Kinzinger from the Republican conference for agreeing to serve on the Jan. 6 select committee investigating the Capitol riot.
The former president still holds significant power over the GOP, with candidates loyal to him aiming to oust incumbent and mainstream Republicans in regional primary votes across the country, while Trump continues to push lies about the 2020 election being stolen.
Toomey also criticized Trump's deal with the Taliban to withdraw U.S. forces entirely from Afghanistan, a move he said was compounded by the imposition of a symbolic date by the administration of current President Joe Biden for the evacuation of American forces.
"My view is we had gotten to a point, and we could have sustained a very modest presence on the ground, extremely low rate of casualties, and we hadn't had a death in Afghanistan in well over a year, a modest cost monetarily," he said.
"For that price, we would have supported the Afghans who were actually the tip of the spear, the ones fighting, and could have prevented the reemergence of terrorists from a Taliban-controlled state."
Read More: Trump should not lead GOP ticket in 2024, retiring Sen. Pat Toomey says
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redpajama_set_name: RedPajamaCommonCrawl


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The Philippine President
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Philippine Embassy Exchanges Views With...
Philippine Embassy Exchanges Views With Tohoku University Professors, Students
Posted on 18 Nov 2021 • Categorized as News and Events
Minister and Consul Leah Victoria Rodriguez (middle) with Tohoku University professors and students
18 November 2021 – To promote awareness on the Philippines' disaster risk reduction efforts, the Philippine Embassy in Tokyo engaged with Tohoku University professors and students through their Graduate School of Law, School of Public Policy program.
Minister and Consul Rodriguez discusses the Philippines' disaster risk reduction efforts with Tohoku University professors and students.
The discussions will form part of the students' project, under their post-graduate degree course, to provide recommendations to the Japanese government in furthering bilateral, regional and international cooperation on building a disaster resilient society.
The Embassy, through Minister and Consul Leah Victoria C. Rodriguez, underscored the strong commitment of the Philippines to the Sendai Framework for Disaster Risk Reduction 2015-2030, and provided information on how the country has adopted measures to lessen the country's vulnerabilities and mitigate the effects of disasters, and build resilience of its people.
The Embassy supports efforts in the Philippines' goal of transforming towards equity and resiliency, under the Philippine Development Plan 2017-2022, which consists of strategies to expand economic opportunities, accelerate human capital development, reduce vulnerability and build safe and secure communities. END
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Gilas Men downs Indonesia to make it to the 2019 SEA Games Gold Medal Match
By SLAM PH | December 10, 2019
It wasn't as big a blow out as in their previous games but the Gilas Pilipinas Men still ended up with a big win in the Semifinals against Indonesia. They once again used a strong run to get the 97-70 win and advance to the Gold Medal Round.
It was a balanced effort for Gilas with Christian Standhardinger leading the way. He dropped 14 points to set the tone in the game. He was followed by Matthew Wright who put up an all-around line of 13 points, four rebounds and eight assists. Vic Manuel had 12 points while June Mar Fajardo and Stanley Pringle added nine points each. Laurent Kokodeputra had 20 points for Indonesia.
Indonesia, coached by former National Team head coach Rajko Toroman gave Gilas a run for their money as they were within striking distance midway through the game. Back-to-back triples from the Indonesians cut the Gilas lead from a 12-point double-digit lead, down to just six.
That's when Ross and Wright came alive for Gilas in the third. Ross drilled back-to-back threes to answer the Indonesia run. That sparked a 35-8 blast that turned the game into a blowout. Ross scored nine of his 11 in the third period alone. He was joined by Wright in the shooting display as the two powered a 39-point third quarter barrage. Gilas took a 78-45 lead after the third period and never looked back.
Gilas is now assured of at least a silver medal in the 5×5 Basketball Tournament. But they're looking for their 13th straight gold medal in this category when they face Thailand in their final game.


text:
import sys, os
sys.path.append(os.pardir)  # 부모 디렉터리의 파일을 가져올 수 있도록 설정
import numpy as np
import matplotlib.pyplot as plt
from deep_convnet import DeepConvNet
from dataset.mnist import load_mnist

(x_train, t_train), (x_test, t_test) = load_mnist(flatten=False)

network = DeepConvNet()
network.load_params("deep_convnet_params.pkl")

sampled = 10000 # 고속화를 위한 표본추출
x_test = x_test[:sampled]
t_test = t_test[:sampled]

print("caluculate accuracy (float64) ... ")
print(network.accuracy(x_test, t_test))

# float16(반정밀도)로 형변환
x_test = x_test.astype(np.float16)
for param in network.params.values():
    param[...] = param.astype(np.float16)

print("caluculate accuracy (float16) ... ")
print(network.accuracy(x_test, t_test))


I chased this storm as it quickly passed over me heading southwest. I got to the outskirts of town and started driving through the hills before coming to an opening in the canopy that looked out across the sky. I used a tripod and remote switch to open the shutter for 37 seconds and set the aperture to 16 in order to use hyperfocal distance to focus the bolt, since I could not focus on dark sky. Less than five minutes later the spring storm had passed. I began to have an asthma attack and left.


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