NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Preliminary study on the utilization of Ca2+ and HCO3 − in karst water by different sources of Chlorella vulgaris

This article aims to present a picture of how a university discipline has been created in Lithuania, given the background of changes caused by the Lithuania’s emancipation from the Soviet Union. The theoretical frame of reference is provided by a modified model of Bronfenbrenners developmental ecology. Data collection has primarily been in the form of interviews with university staff from Lithuanian institutions for higher education. In addition to the interviews, literature lists, course schedules and other key documents have been collected and analysed. The analysis focuses on individual’s conceptualisation of three main areas. The study demonstrates how the creation of management and economics as a university discipline in Lithuania has been formed by a combination of political/ideological, economic, institutional and individual factors. One of the study’s main contributions is to highlight the significance of the concept of academic freedom and to focus on the paradox, where constraint under the old system is replaced by another form of constraint. In this case, where the rigidity of the old Soviet doctrine is replaced by a new freedom; but instead of being given greater opportunities to influence and change the subject, the academic staff are forced into a position where, once again they are subjugated to the influences of international sources

Regulation of thymocyte positive selection and motility by GIT2

Thymocytes are highly motile cells that migrate under the influence of chemokines in distinct thymic compartments as they mature. The motility of thymocytes is tightly regulated; however, the molecular mechanisms that control thymocyte motility are not well understood. Here we report that G protein–coupled receptor kinase-interactor 2 (GIT2) was required for efficient positive selection. Notably, Git2−/− double-positive thymocytes showed greater activation of the small GTPase Rac, actin polymerization and migration toward the chemokines CXCL12 (SDF-1) and CCL25 in vitro. By two-photon laser-scanning microscopy, we found that the scanning activity of Git2−/− thymocytes was compromised in the thymic cortex, which suggests GIT2 has a key role in regulating the chemokine-mediated motility of double-positive thymocytes.National Institutes of Health (U.S.) (R01AI064227)Leukemia & Lymphoma Society of Americ

CD4+ T Cell Depletion, Immune Activation and Increased Production of Regulatory T Cells in the Thymus of HIV-Infected Individuals

Mechanisms by which HIV affects the thymus are multiple and only partially known, and the role of thymic dysfunction in HIV/AIDS immunopathogenesis remains poorly understood. To evaluate the effects of HIV infection on intra-thymic precursors of T cells in HIV-infected adults, we conducted a detailed immunophenotypic study of thymic tissue isolated from 7 HIV-infected and 10 HIV-negative adults who were to undergo heart surgery. We found that thymuses of HIV-infected individuals were characterized by a relative depletion of CD4+ single positive T cells and a corresponding enrichment of CD8+ single positive T cells. In addition, thymocytes derived from HIV-infected subjects showed increased levels of activated and proliferating cells. Our analysis also revealed a decreased expression of interleukin-7 receptor in early thymocytes from HIV-infected individuals, along with an increase in this same expression in mature double- and single-positive cells. Frequency of regulatory T cells (CD25+FoxP3+) was significantly increased in HIV-infected thymuses, particularly in priorly-committed CD4 single positive cells. Our data suggest that HIV infection is associated with a complex set of changes in the immunophenotype of thymocytes, including a reduction of intrathymic CD4+ T cell precursors, increased expression of activation markers, changes in the expression pattern of IL-7R and enrichment of T regulatory cells generation

Deciphering the sophomore slump: changes to student perceptions during the undergraduate journey

The second year of university is little-researched, despite being a focal point for declining performance, persistence, and satisfaction. It is important to establish appropriate methods for studying this ‘sophomore slump’ and to pinpoint specific antecedents from broad domains noted in literature (e.g. students’ social integration, perceptions of the curriculum). Using a novel methodology, 166 undergraduates were surveyed in successive years of study to derive a gold standard ‘within-subjects’ data sample. Under a replicated design, a ‘between-subjects’ sample of over 1000 students completed the same e-survey just once, in year one, two, or three. Quantitative comparison of the responses across years showed over 85% agreement between samples. This endorses between-subject approaches (i.e. simultaneously surveying students from different years) to facilitate rapid interventions that benefit students before they graduate. In terms of detailed findings, year two saw positive trends in students’ academic engagement (e.g. self-reported independent study time), social integration (e.g. feeling accepted, involvement in extra-curricular activities), and views on teaching staff (e.g. approachability). Although appraisals remained broadly favourable, there was, in contrast, significant deterioration in global perceptions of the learning atmosphere (e.g. course enjoyment), as well as specific elements of the teaching provision (e.g. contact hours, feedback). Notably, there appeared to be little progression in students’ academic self-perceptions (e.g. confidence to make presentations, enter class debates). Year two also saw increased thoughts of drop-out. These results highlight the unique character of the second year at university and indicate potential target areas for enhancing this phase of the undergraduate journey

HIV-1 co-receptor usage:influence on mother-to-child transmission and pediatric infection

Viral CCR5 usage is not a predictive marker of mother to child transmission (MTCT) of HIV-1. CXCR4-using viral variants are little represented in pregnant women, have an increased although not significant risk of transmission and can be eventually also detected in the neonates. Genetic polymorphisms are more frequently of relevance in the child than in the mother. However, specific tissues as the placenta or the intestine, which are involved in the prevalent routes of infection in MTCT, may play an important role of selective barriers

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion