20 research outputs found
Organizational-pedagogical conditions to form the foreign competence in students with the features of linguistic giftedness
No full text© by The Author(s). The study of foreign competence at the present stage of the higher education development becomes more relevant. The article emphasizes the organizational-pedagogical conditions, providing the formation of foreign competence in students with the features of linguistic giftedness. The way to reveal the students, who have the features of linguistic giftedness, is presented. Experimental teaching showed the increased level of independent behavior in the process of foreign language study; the work in small groups on solution of linguistic tasks to the fullest extent actualizes potential linguistic abilities of students; the satisfaction with the learning process of subject "Foreign Language" has also increased
Organizational-pedagogical conditions to form the foreign competence in students with the features of linguistic giftedness
No full text© by The Author(s). The study of foreign competence at the present stage of the higher education development becomes more relevant. The article emphasizes the organizational-pedagogical conditions, providing the formation of foreign competence in students with the features of linguistic giftedness. The way to reveal the students, who have the features of linguistic giftedness, is presented. Experimental teaching showed the increased level of independent behavior in the process of foreign language study; the work in small groups on solution of linguistic tasks to the fullest extent actualizes potential linguistic abilities of students; the satisfaction with the learning process of subject "Foreign Language" has also increased
Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study
No full textAbstract 1583: Proteasome inhibition as a strategy for non-small cell lung carcinoma via inhibition of DNA double strand break repair.
No full textReal-world goal-directed behavior reveals aberrant functional brain connectivity in children with ADHD
No full textAbstract
Functional connectomics is a popular approach to investigate the neural underpinnings of developmental disorders of which attention deficit hyperactivity disorder (ADHD) is one of the most prevalent. Nonetheless, neuronal mechanisms driving the aberrant functional connectivity resulting in ADHD symptoms remain largely unclear. Whereas resting state activity reflecting intrinsic tonic background activity is only vaguely connected to behavioral effects, naturalistic neuroscience has provided means to measure phasic brain dynamics associated with overt manifestation of the symptoms. Here we collected functional magnetic resonance imaging (fMRI) data in three experimental conditions, an active virtual reality (VR) task where the participants execute goal-directed behaviors, a passive naturalistic Video Viewing task, and a standard Resting State condition. Thirty-nine children with ADHD and thirty-seven typically developing (TD) children participated in this preregistered study. Functional connectivity was examined with network-based statistics (NBS) and graph theoretical metrics. During the naturalistic VR task, the ADHD group showed weaker task performance and stronger functional connectivity than the TD group. Group differences in functional connectivity were observed in widespread brain networks: particularly subcortical areas showed hyperconnectivity in ADHD. More restricted group differences in functional connectivity were observed during the Video Viewing, and there were no group differences in functional connectivity in the Resting State condition. These observations were consistent across NBS and graph theoretical analyses, although NBS revealed more pronounced group differences. Furthermore, during the VR task and Video Viewing, functional connectivity in TD controls was associated with task performance during the measurement, while Resting State activity in TD controls was correlated with ADHD symptoms rated over six months. We conclude that overt expression of the symptoms is correlated with aberrant brain connectivity in ADHD. Furthermore, naturalistic paradigms where clinical markers can be coupled with simultaneously occurring brain activity may further increase the interpretability of psychiatric neuroimaging findings.Abstract
Functional connectomics is a popular approach to investigate the neural underpinnings of developmental disorders of which attention deficit hyperactivity disorder (ADHD) is one of the most prevalent. Nonetheless, neuronal mechanisms driving the aberrant functional connectivity resulting in ADHD symptoms remain largely unclear. Whereas resting state activity reflecting intrinsic tonic background activity is only vaguely connected to behavioral effects, naturalistic neuroscience has provided means to measure phasic brain dynamics associated with overt manifestation of the symptoms. Here we collected functional magnetic resonance imaging (fMRI) data in three experimental conditions, an active virtual reality (VR) task where the participants execute goal-directed behaviors, a passive naturalistic Video Viewing task, and a standard Resting State condition. Thirty-nine children with ADHD and thirty-seven typically developing (TD) children participated in this preregistered study. Functional connectivity was examined with network-based statistics (NBS) and graph theoretical metrics. During the naturalistic VR task, the ADHD group showed weaker task performance and stronger functional connectivity than the TD group. Group differences in functional connectivity were observed in widespread brain networks: particularly subcortical areas showed hyperconnectivity in ADHD. More restricted group differences in functional connectivity were observed during the Video Viewing, and there were no group differences in functional connectivity in the Resting State condition. These observations were consistent across NBS and graph theoretical analyses, although NBS revealed more pronounced group differences. Furthermore, during the VR task and Video Viewing, functional connectivity in TD controls was associated with task performance during the measurement, while Resting State activity in TD controls was correlated with ADHD symptoms rated over six months. We conclude that overt expression of the symptoms is correlated with aberrant brain connectivity in ADHD. Furthermore, naturalistic paradigms where clinical markers can be coupled with simultaneously occurring brain activity may further increase the interpretability of psychiatric neuroimaging findings
Proteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer
No full textDespite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80–90% decrease in homologous recombination (HR), a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.American Society for Radiation Oncology (Junior Faculty Career Research Training Award)Harvard University. Joint Center for Radiation Therapy (Foundation Grant)Dana-Farber/Harvard Cancer Center (SPORE Developmental Research Project Award in Lung Cancer Research)National Cancer Institute (U.S.) (Award K08CA172354
Abstract 1448: Whole genome RNAi screen identifies proteasome inhibition as a strategy for NSCLC radiosensitization
No full textAbstract 1318: Proteasome and Fanconi Anemia/BRCA pathways as prognostic determinants of glioblastoma response to radiation and temozolomide: a proposed clinical trial
No full textAbstract
OBJECTIVE: Despite the standard regimen of maximal resection followed by concurrent ionizing radiation (IR) and temozolomide (TMZ), long-term survivors of patients afflicted with glioblastoma (GBM) remain rare. We sought to identify molecular determinants of resistance to these agents using a combined functional genomic and bioinformatic approach.
METHODS: Parallel RNAi screens were performed to identify gene silencings that modulate IR and TMZ resistance. A viability-based screen was performed in multiple glioma lines with the Hannon-Elledge library of 74,705 short hairpin RNAs targeting nearly all human genes. A focused screen was also performed to identify modulators of the Fanconi Anemia (FA)/BRCA pathway, a pathway we previously identified as a determinant of IR and TMZ resistance. The most promising candidates were confirmed by independent RNAi and pharmacologic inhibition in vitro and in vivo xenografts. Correlations between relative expression levels of the candidate genes and patient survival were made using data from seven series of clinically annotated GBM gene expression profiles.
RESULTS: PSMA1, a core subunit of the 20S proteasome, was a top hit in both screens. Proteasome inhibition by either RNAi or pharmacologic inhibition sensitized GBM cell lines to IR and TMZ in both in vitro and in vivo xenograft models. This inhibition also resulted in decreased FANCD2 monoubiquitination, a marker for FA pathway activation.
Using our collated set of 531 patients, we observed that patients with low (< mean) PSMA1 showed higher OS vs. those with high expression, median OS = 14.8 vs. 12.2 months (log-rank P = 0.017). This correlation was recapitulated with several other proteasome genes. Since recent studies revealed distinct GBM subtypes, we tested whether the prognostic value of proteasome gene expression was subtype-specific. We found that the difference was only significant in the proneural subtype, median OS = 16.5 vs. 9.4 mo. (P = 0.012). Realizing that proteasome inhibition exerts phenotypes beyond FA pathway inhibition, we determined the extent to which FA/BRCA expression impacts prognosis. High FA/BRCA expression correlated with lower OS only for proneural tumors (P = 0.015); this observation suggested that proteasome function impacts tumor survival, in large part, by modulating the FA/BRCA pathway.
CONCLUSION: Proteasome inhibition sensitizes GBM cells to IR and TMZ and results in impaired FA pathway activation. Our combined functional genomic and bioinformatic analysis suggests a clinical trial: patients with proneural gliomas with high FA/BRCA expression should be treated with proteasome inhibitors such as bortezomib to augment standard therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1318.</jats:p
Abstract 3301: c-Myc modulates the dynamic transition between tumor initiating states in glioblastoma
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