61 research outputs found

    Beta-peptides with improved affinity for hDM2 and hDMX

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    We previously described a series of 314-helical β-peptides that bind the hDM2 protein and inhibit its interaction with a p53-derived peptide in vitro. Here we present a detailed characterization of the interaction of these peptides with hDM2 and report two new β-peptides in which non-natural side chains have been substituted into the hDM2-recognition epitope. These peptides feature both improved affinity and inhibitory potency in fluorescence polarization and ELISA assays. Additionally, one of the new β-peptides also binds the hDM2-related protein, hDMX, which has been identified as another key therapeutic target for activation of the p53 pathway in tumors

    Examining intersections between violence against women and violence against children:Perspectives of adolescents and adults in displaced Colombian communities

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    BackgroundResearch examining the interrelated drivers of household violence against women and violence against children is nascent, particularly in humanitarian settings. Gaps remain in understanding how relocation, displacement and ongoing insecurity affect families and may exacerbate household violence.MethodsEmploying purposive sampling, we used photo elicitation methods to facilitate semi-structured, in-depth interviews with female and male adolescents and adults aged 13–75 (n = 73) in two districts in Colombia from May to August of 2017. Participants were displaced and/or residing in neighborhoods characterized by high levels of insecurity from armed groups.ResultsUsing inductive thematic analysis and situating the analysis within a feminist socioecological framework, we found several shared drivers of household violence. Intersections among drivers at all socioecological levels occurred among societal gender norms, substance use, attempts to regulate women’s and children’s behavior with violence, and daily stressors associated with numerous community problems. A central theme of relocation was of family compositions that were in continual flux and of family members confronted by economic insecurity and increased access to substances.ConclusionsFindings suggest interventions that systemically consider families’ struggles with relocation and violence with multifaceted attention to socioecological intersections

    Empowering Students in Higher-Education to Teach and Learn

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    We explored opportunities, advantages and barriers to enabling students to establish student-led learning events at a New Zealand university. We used an action-research approach to explore if students felt empowered to use the infrastructure of this university to realise something that they themselves set out to achieve. We discovered that, in achieving a series of open discussions about sustainability, students adopted a democratic, distributed form of decision-making, not unlike a typical academic model, with leaders taking temporary roles that included passing on responsibility to those who followed. Students were proud of the events they created and identified the discussion format as something different from their experience as undergraduate students in our institution. This article, co-authored by staff and students, considers whether higher education processes that do empower students do so adequately and the extent to which students are prepared by higher education to take on powerful roles after they graduate

    Constraining the epoch of reionization with the variance statistic: simulations of the LOFAR case

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    Several experiments are underway to detect the cosmic redshifted 21-cm signal from neutral hydrogen from the Epoch of Reionization (EoR). Due to their very low signal-to-noise ratio, these observations aim for a statistical detection of the signal by measuring its power spectrum. We investigate the extraction of the variance of the signal as a first step towards detecting and constraining the global history of the EoR. Signal variance is the integral of the signal's power spectrum, and it is expected to be measured with a high significance. We demonstrate this through results from a simulation and parameter estimation pipeline developed for the Low Frequency Array (LOFAR)-EoR experiment. We show that LOFAR should be able to detect the EoR in 600 hours of integration using the variance statistic. Additionally, the redshift (zrz_r) and duration (Δz\Delta z) of reionization can be constrained assuming a parametrization. We use an EoR simulation of zr=7.68z_r = 7.68 and Δz=0.43\Delta z = 0.43 to test the pipeline. We are able to detect the simulated signal with a significance of 4 standard deviations and extract the EoR parameters as zr=7.72−0.18+0.37z_r = 7.72^{+0.37}_{-0.18} and Δz=0.53−0.23+0.12\Delta z = 0.53^{+0.12}_{-0.23} in 600 hours, assuming that systematic errors can be adequately controlled. We further show that the significance of detection and constraints on EoR parameters can be improved by measuring the cross-variance of the signal by cross-correlating consecutive redshift bins.Comment: 13 pages, 14 figures, Accepted for publication in MNRA

    Predictions for the 21 cm-galaxy cross-power spectrum observable with LOFAR and Subaru

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    The 21 cm-galaxy cross-power spectrum is expected to be one of the promising probes of the Epoch of Reionization (EoR), as it could offer information about the progress of reionization and the typical scale of ionized regions at different redshifts. With upcoming observations of 21 cm emission from the EoR with the Low Frequency Array (LOFAR), and of high-redshift Ly α emitters with Subaru's Hyper Suprime-Cam (HSC), we investigate the observability of such cross-power spectrum with these two instruments, which are both planning to observe the ELAIS-N1 field at z = 6.6. In this paper, we use N-body + radiative transfer (both for continuum and Ly α photons) simulations at redshift 6.68, 7.06 and 7.3 to compute the 3D theoretical 21 cm-galaxy cross-power spectrum and cross-correlation function, as well as to predict the 2D 21 cm-galaxy cross-power spectrum and cross-correlation function expected to be observed by LOFAR and HSC. Once noise and projection effects are accounted for, our predictions of the 21 cm-galaxy cross-power spectrum show clear anti-correlation on scales larger than ∼60 h−1 Mpc (corresponding to k ∼ 0.1 h Mpc−1), with levels of significance p = 0.003 at z = 6.6 and p = 0.08 at z = 7.3. On smaller scales, instead, the signal is completely contaminated. On the other hand, our 21 cm-galaxy cross-correlation function is strongly contaminated by noise on all scales, since the noise is no longer being separated by its k modes

    Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist

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    Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production
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