10 research outputs found

    The Routledge handbook of second language acquisition and technology. Ziegler, N. & González-Lloret, M. (Eds.) (2022). Routledge, New York and London, 409 pages, ISBN: 978-1-351-11758-6

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    The COVID-19 pandemic has “thrusted both teachers and learners” (p. 16) into a new language learning environment where the relentlessly progressing technology is exerting an increasingly indispensable role, which has stimulated a reevaluation on the relationship between second language acquisition (SLA) and technology. Contributed by a pool of expertise with full scholarly apparatus, The Routledge Handbook of Second Language Acquisition and Technology offers enlightening insights into this reevaluation. FUNDING INFORMATION: This review was supported by Shanghai International Studies University (grant no. 2020114210).The COVID-19 pandemic has “thrusted both teachers and learners” (p. 16) into a new language learning environment where the relentlessly progressing technology is exerting an increasingly indispensable role, which has stimulated a reevaluation on the relationship between second language acquisition (SLA) and technology. Contributed by a pool of expertise with full scholarly apparatus, The Routledge Handbook of Second Language Acquisition and Technology offers enlightening insights into this reevaluation. FUNDING INFORMATION: This review was supported by Shanghai International Studies University (grant no. 2020114210)

    Creación y Simulación de Metodologías de Análisis, Clasificación e Integración de Nuevos Requerimientos a Software Propietario

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    La priorización de nuevos requerimientos a implementar en un software propietario es un punto fundamental para su mantenimiento, la conservación de la calidad, observación de las reglas de negocio y los estándares de la empresa. Aunque existen herramientas de priorización basadas en técnicas probadas y reconocidas, las mismas requieren una calificación previa de cada requerimiento. Si la empresa cuenta con solicitudes provenientes de varios clientes de un mismo producto, aumentan los factores que afectan a la empresa, las herramientas disponibles no contemplan estos aspectos y hacen mucho más compleja la tarea de calificación. Este trabajo de investigación abarca la realización de un relevamiento de los métodos de priorización y selección de nuevos requerimientos utilizados por empresas de la zona de Rosario, y la definición de una metodología para la selección un nuevo requerimiento, que implica el análisis y evaluación de todas las implicaciones sobre el producto de software y la empresa, respetando sus reglas de negocio. La metodología creada conduce a la definición de los procesos para la construcción de una herramienta de calificación y priorización de nuevos requerimientos en software propietario que tiene solicitudes de varios clientes al mismo tiempo, con instrumentos de calificación que consideran todos los aspectos relacionados, proveerá técnicas de priorización actuales y emitirá informes personalizados según diferentes perspectivas de la empresa.Eje: Ingeniería de SoftwareRed de Universidades con Carreras en Informática (RedUNCI

    JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation

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    <div><p>Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate– and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein <i>in vivo</i> and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G<sub>1</sub> phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis <i>in vivo</i>, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.</p></div

    Negative regulation of p53 transcriptional activity by JMJD6.

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    <p>(A) Measurement of mRNA (left panel) and protein (right panel) levels of p21 and PUMA by real-time RT PCR and Western blotting in HCT116 cells that were transfected with JMJD6 siRNAs and/or JMJD6 siRNA-1–resistant JMJD6 form (rJMJD6) followed by treatment with or without VP-16. Each bar represents the mean ± S.D. for triplicate measurements. *<i>p</i><0.05. (B) HCT116 cells were treated with control siRNA or JMJD6 siRNAs and challenged with or without VP-16. Real-time RT PCR was performed using exon–exon junction-specific or intron–exon junction-specific primers to measure spliced and unspliced mRNA levels of <i>p21</i> and <i>PUMA</i> by RT-qPCR analysis to determine splicing efficiency of <i>p21</i> (left panel) and <i>PUMA</i> mRNA (right panel). Each bar represents the mean ± S.D. for triplicate measurements. (C) Reporter assays in HCT116 cells that were transfected with JMJD6 siRNAs and/or rJMJD6 together with p21 promoter-driven luciferase reporter construct and challenged with or without VP-16. *<i>p</i><0.05. (D) qChIP was performed in HCT116 cells treated with control siRNA or JMJD6 siRNA with indicated antibodies. (E) HCT116 cells transfected with JMJD6 siRNAs and/or rJMJD6 were synchronized by double thymidine block and released into the cell cycle. Cells were collected for cell cycle analysis by flow cytometry. Experiments were repeated three times and the data from a representative experiment are shown. *<i>p</i><0.05. (F) HCT116 cells were transfected with control siRNA or JMJD6 siRNAs and challenged with or without VP-16 for 24 h. Annexin V/PI staining and flow cytometry were performed to assess the effect of JMJD6 on the apoptosis of HCT116 cells. Experiments were repeated three times, and the data from a representative experiment are shown. Each bar represents the mean ± S.D. for triplicate experiments. *<i>p</i><0.05.</p

    JMJD6 is physically associated with p53 <i>in vivo</i> and <i>in vitro</i>.

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    <p>(A) Cellular extracts from HCT116 cells stably expressing vector or FLAG-JMJD6 were immunopurified with anti-FLAG affinity columns and eluted with FLAG peptide. The eluates were resolved by SDS-PAGE and silver-stained. The proteins bands were retrieved and analyzed by mass spectrometry. (B) HCT116 cell lysates were immunoprecipitated with antibodies against JMJD6 followed by immunoblotting with antibodies against p53 (FL-393), or they were immunoprecipitated with antibodies against p53 (FL-393) followed by immunoblotting with antibodies against JMJD6. (C) Immunofluorescence-stained endogenous JMJD6 (red) and p53 (green) were visualized by confocal microscopy. DAPI staining was included to visualize the cell nucleus (blue). Scale bar, 25 µm. (D) Mapping the domain of p53 that is required for its interaction with JMJD6. GST pull-down experiments were performed with GST-fused JMJD6 and <i>in vitro</i> transcribed/translated Myc-tagged full-length p53 or deletions of p53.</p

    The negative effect of JMJD6 on p53 pathway depends on its hydroxylase activity.

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    <p>(A) HCT116 cells were transfected with vector, FLAG-JMJD6, or FLAG-JMJD6(H187A/D189A) (mut-JMJD6). The levels of the indicated proteins were detected by Western blotting. The mRNA levels of p21 and PUMA were detected by real-time RT PCR. (B) HCT116 cells were transfected with p21 promoter-driven luciferase construct together with vector, FLAG-JMJD6, or FLAG-JMJD6(H187A/D189A) (mut-JMJD6) plasmids. Cells were then harvested and luciferase activity was measured and normalized to that of renilla. Each bar represents the mean ± S.D. for triplicate experiments. (C) HCT116 cells transfected with vector or FLAG-JMJD6, or FLAG-JMJD6(H187A/D189A) (mut-JMJD6) were synchronized by double thymidine block and released into the cell cycle. Cells were collected for cell cycle analysis by flow cytometry. Experiments were repeated three times and the data from a representative experiment are shown. (D) HCT116 cells were transfected with vector, FLAG-JMJD6, or FLAG-JMJD6(H187A/D189A) (mut-JMJD6), and challenged with VP-16. Annexin V/PI staining and flow cytometry were performed to assess the effect of JMJD6 on the apoptosis of HCT116 cells.</p

    JMJD6 is a potential biomarker for colon cancer aggressiveness.

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    <p>(A) Immunohistochemical staining of JMJD6 in paired samples of breast ductal carcinoma (1), hepatocellular carcinoma (2), lung adenocarcinoma (3), lung squamous carcinoma (4), suprarenal epithelioma (5), pancreatic ductal carcinoma (6), colon adenocarcinoma (7), esophageal squamous carcinoma (8), rectal adenocarcinoma (9), and gastric adenocarcinoma (10) versus adjacent normal tissues. Representative tumor and adjacent normal sections stained with JMJD6 antibody are shown (magnification, ×25; scale bar, 200 µm). Each type of carcinoma included at least six paired samples and the scores were determined by evaluating the extent and intensity of immunopositivity. (B) Immunohistochemical staining of JMJD6 in 90 samples of colon adenocarcinomas paired with adjacent normal tissues. Representative sections from colon cancer (upper, tubular adenocarcinoma; lower, poorly differentiated adenocarcinoma) or adjacent normal tissue stained with JMJD6 antibody are shown (magnification, ×100; scale bar, 100 µm). The scores were determined by evaluating the extent and intensity of immunopositivity and were analyzed by paired-samples <i>t</i> test (***<i>p</i><0.001). (C) Representative sections of histological grade I, II, and III of colon adenocarcinomas that were stained with JMJD6 antibody are presented (magnification, ×100; scale bar, 100 µm). The scores were determined by evaluating the extent and intensity of immunopositivity and were analyzed by two-tailed unpaired <i>t</i> test (***<i>p</i><0.001). (D) Time-to-event data were plotted using Kaplan–Meier curves, and the 5-year survival rate of different groups was compared using the Mantel–Cox log-rank test (***<i>p</i> = 0.001). The <i>y</i>-axis represents the percentage of patients, and the <i>x</i>-axis represents the survival in months. (E) High expression of JMJD6 protein is found only in the base of intestinal glands (crypt of Lieberkuhn). Representative images of immunohistochemical staining of JMJD6 in normal intestinal glands are shown. Upper—magnification, ×25; scale bar, 200 µm. Lower—magnification, ×400; scale bar, 50 µm.</p

    JMJD6 hydroxylates p53 <i>in vivo</i> and <i>in vitro</i>.

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    <p>(A) Recombinant p53 was incubated with or without recombinant JMJD6 in the presence or absence of α-ketoglutarate (2-OG) and Fe(II). The mixture was then separated on SDS-PAGE, and the band corresponding to the molecular weight of p53 was excised and digested with trypsin and analyzed by LC-MS/MS. Inserts show the doubly charged peptide precursor ions that were fragmented. The relevant ion fragments are labeled, and the corresponding peptide positions are illustrated. K, lysine; K(OH), hydroxylated lysine; the expected increase in mass by hydroxylation modification is 16 Dalton. M, methionine; m, randomly oxidized methionine, which results in a +16 Dalton shift in mass. (I) Experimental group with 2-OG, Fe(II), and JMJD6; (II) negative control group without JMJD6; (III) negative control group without Fe(II); (IV) negative control group without 2-OG. (B) Wild-type JMJD6 hydroxylates p53<sup>381–393</sup> at K382 of p53 in the presence of 2-OG and Fe(II) <i>in vitro</i>. The peptides corresponding to amino acids 381–393 of p53 (wild-type p53, p53K382R, or p53K382A) were incubated with or without recombinant JMJD6 or JMJD6(H187A/D189A) in the presence or absence of 2-OG and Fe(II) for 2 h at 37°C. The mixture was then analyzed by MALDI/TOF. (C) Hydroxylation of p53 at K382 <i>in vivo</i>. Lysates from HCT116 cells were immunoprecipitated with anti-p53 monoclonal antibody-conjugated agarose. Bound proteins were eluted with p53 peptide, separated on SDS-PAGE, and analyzed by LC-MS/MS. Inserts show the doubly charged peptide precursor ions that were fragmented. The relevant ion fragments are labeled and the corresponding peptide positions are illustrated. Analysis by LC-MS/MS revealed the presence of modified p53<sup>382–393</sup> peptide (M+2H)<sup>2+</sup> containing hydroxylation of K382. (D) Extracted ion chromatogram (XIC) of nonmodified (upper panel) and hydroxylated p53K382 (lower panel) extracted from vector (black) or JMJD6 (red) transfected HCT116 cells.</p

    PARSEME corpora annotated for verbal multiword expressions (version 1.3)

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    This multilingual resource contains corpora in which verbal MWEs have been manually annotated. VMWEs include idioms (let the cat out of the bag), light-verb constructions (make a decision), verb-particle constructions (give up), inherently reflexive verbs (help oneself), and multi-verb constructions (make do). This is the first release of the corpora without an associated shared task. Previous version (1.2) was associated with the PARSEME Shared Task on semi-supervised Identification of Verbal MWEs (2020). The data covers 26 languages corresponding to the combination of the corpora for all previous three editions (1.0, 1.1 and 1.2) of the corpora. VMWEs were annotated according to the universal guidelines. The corpora are provided in the cupt format, inspired by the CONLL-U format. Morphological and syntactic information, ­­­­including parts of speech, lemmas, morphological features and/or syntactic dependencies, are also provided. Depending on the language, the information comes from treebanks (e.g., Universal Dependencies) or from automatic parsers trained on treebanks (e.g., UDPipe). All corpora are split into training, development and test data, following the splitting strategy adopted for the PARSEME Shared Task 1.2. The annotation guidelines are available online: https://parsemefr.lis-lab.fr/parseme-st-guidelines/1.3 The .cupt format is detailed here: https://multiword.sourceforge.net/cupt-format
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