Differential positive control by Oct-1 and Oct-2: activation of a transcriptionally silent motif through Oct-1 and VP16 corecruitment

Transcriptional regulation by the ubiquitous human POU homeo domain protein Oct-1 and the related B-cell protein Oct-2 is a model for understanding how proteins that recognize the same regulatory site elicit different programs of gene transcription. Here, we describe a mechanism for differential promoter activation whereby only Oct-1, through selective corecruitment with the herpesvirus trans-activator VP16, acquires the ability to stimulate transcription from a TAATGARAT-containing site that responds to neither Oct-1 nor Oct-2 alone. To measure differential in vivo activation by human Oct-1 and Oct-2 in response to VP16, we have developed a transient assay in murine NIH-3T3 cells. Surprisingly, murine Oct-1 associates with VP16 much less effectively than its human counterpart, most likely because the murine Oct-1 homeo domain differs at four positions from the human Oct-1 homeo domain. The murine cell transient assay shows directly that human Oct-1, but not human Oct-2, can respond to VP16 in vivo. The Oct-1 DNA-binding POU domain is sufficient and the Oct-1 homeo domain is critical for this response, because an Oct-1 POU domain containing the Oct-2 homeo domain fails to respond to the VP16-induced positive control of transcription. Thus, by selective homeo domain interaction and corecruitment to an otherwise silent regulatory element, VP16 expands the repertoire of sites responsive to Oct-1 without affecting the activity of its close relative Oct-2

A single amino acid exchange transfers VP16-induced positive control from the Oct-1 to the Oct-2 homeo domain

The selective association of the herpesvirus trans-activator VP16 with the human Oct-1 homeo domain is a model for differential positive transcriptional control by homeo domains. VP16 discriminates between the closely related homeo domains of Oct-1 and Oct-2 by distinguishing among their seven amino-acid differences; these differences lie on the surface that is thought to be accessible when the homeo domain is bound to DNA. Only two of these seven differences are recognized by VP16, one in each of the first two alpha-helices of the tri-alpha-helical homeo domain. The major determinant for selective association with VP16 in vitro and VP16-induced positive control in vivo is a single glutamic acid residue at position 22 in the first alpha-helix of the Oct-1 homeo domain, but the acidic properties of this residue are not critical for association with VP16 in vitro or in vivo, because it can be replaced by glutamine with little or no deleterious effect. Mere replacement of the single corresponding alanine residue in the Oct-2 homeo domain with the key glutamic acid residue is sufficient to confer on the Oct-2 homeo domain the ability to associate with VP16 in vitro and respond to VP16-induced positive control in vivo. Thus, the specificity of homeo domain positive control can be conferred by a single amino acid difference

Cryogenic microstripline-on-Kapton microwave interconnects

Simple broadband microwave interconnects are needed for increasing the size of focal plane heterodyne radiometer arrays. We have measured loss and cross-talk for arrays of microstrip transmission lines in flex circuit technology at 297 and 77 K, finding good performance to at least 20 GHz. The dielectric constant of Kapton substrates changes very little from 297 to 77 K, and the electrical loss drops. The small cross-sectional area of metal in a printed circuit structure yields overall thermal conductivities similar to stainless steel coaxial cable. Operationally, the main performance tradeoffs are between crosstalk and thermal conductivity. We tested a patterned ground plane to reduce heat flux.Comment: 3 pages, 3 figures, submitted to The Review of Scientific Instrument

Practice-based simulation model: a curriculum innovation to enhance the critical thinking skills of nursing students

Objective: The purpose of this paper is to describe the Practice Based Simulation Model (PBSM) as a pedagogical framework that enables the integration of simulation in a way that ensures critical thinking skills are explicitly taught as part of the processes and outcomes of students' learning. Setting: The PBSM is an innovative pedagogical strategy that offers greater flexibility; one that can be applied to various types of educational contexts and delivery modes, while simultaneously ensuring desired learning outcomes. Primary argument: The use of simulation has been gaining popularity because of its capacity to provide effective experiential learning as a method of enhancing learners' critical thinking skills. Despite ample literature that highlights the need for the integration of simulation into nursing curricula, there are few papers demonstrating simulated learning experiences that are underpinned by sound pedagogy. This paper asserts that simulated learning experiences need to be integrated into a curriculum underpinned by sound pedagogy, such as the PBSM, in order to ensure that learning facilitates the development of the critical thinking abilities deemed essential for nursing. Conclusion: The PBSM demonstrates an example of effective integration of simulation into a curriculum, and highlights the importance of the integral relationship of simulation as a key component of curriculum

First report of Pleuroceras pseudoplatani on Acer rubrum, A. griseum, A. saccharinum, A. negundo, A. circinatum and A. macrophyllum in Scotland

Peer reviewedPublisher PD

First Season QUIET Observations: Measurements of Cosmic Microwave Background Polarization Power Spectra at 43 GHz in the Multipole Range 25 ≤ ℓ ≤ 475

The Q/U Imaging ExperimenT (QUIET) employs coherent receivers at 43 GHz and 94 GHz, operating on the Chajnantor plateau in the Atacama Desert in Chile, to measure the anisotropy in the polarization of the cosmic microwave background (CMB). QUIET primarily targets the B modes from primordial gravitational waves. The combination of these frequencies gives sensitivity to foreground contributions from diffuse Galactic synchrotron radiation. Between 2008 October and 2010 December, over 10,000 hr of data were collected, first with the 19 element 43 GHz array (3458 hr) and then with the 90 element 94 GHz array. Each array observes the same four fields, selected for low foregrounds, together covering ≈1000 deg^2. This paper reports initial results from the 43 GHz receiver, which has an array sensitivity to CMB fluctuations of 69 μK√s. The data were extensively studied with a large suite of null tests before the power spectra, determined with two independent pipelines, were examined. Analysis choices, including data selection, were modified until the null tests passed. Cross-correlating maps with different telescope pointings is used to eliminate a bias. This paper reports the EE, BB, and EB power spectra in the multipole range ℓ = 25-475. With the exception of the lowest multipole bin for one of the fields, where a polarized foreground, consistent with Galactic synchrotron radiation, is detected with 3σ significance, the E-mode spectrum is consistent with the ΛCDM model, confirming the only previous detection of the first acoustic peak. The B-mode spectrum is consistent with zero, leading to a measurement of the tensor-to-scalar ratio of r = 0.35^(+1.06)_(–0.87). The combination of a new time-stream "double-demodulation" technique, side-fed Dragonian optics, natural sky rotation, and frequent boresight rotation leads to the lowest level of systematic contamination in the B-mode power so far reported, below the level of r = 0.1

Improving the evidence base of Markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings

<p>Abstract</p> <p>Background</p> <p>Despite concerns about affordability and sustainability, many models of the lifetime costs of antiretroviral therapy (ART) used in resource limited settings are based on data from small research cohorts, together with pragmatic assumptions about life-expectancy. This paper revisits these modelling assumptions in order to provide input to future attempts to model the lifetime costs and the costs of scaling up ART.</p> <p>Methods</p> <p>We analysed the determinants of costs and outcomes in patients receiving ART in line with standard World Health Organization (WHO) guidelines for resource poor settings in a private sector managed ART programme in South Africa. The cohort included over 5,000 patients with up to 4 years (median 19 months) on ART. Generalized linear and Cox proportional hazards regression models were used to establish cost and outcome determinants respectively.</p> <p>Results</p> <p>The key variables associated with changes in mean monthly costs were: being on the second line regimen; receiving ART from 4 months prior to 4 months post treatment initiation; having a recent or current CD4 count <50 cells/µL or 50-199 cells/µl; having mean ART adherence <75% as determined by monthly pharmacy refill data; and having a current or recent viral load >100,000 copies/mL. In terms of the likelihood of dying, the key variables were: baseline CD4 count<50 cells/µl (particularly during the first 4 months on treatment); current CD4 count <50 cells/µl and 50-199 cells/µl (particularly during later periods on treatment); and being on the second line regimen. Being poorly adherent and having an unsuppressed viral load was also associated with a higher likelihood of dying.</p> <p>Conclusions</p> <p>While there are many unknowns associated with modelling the resources needed to scale-up ART, our analysis has suggested a number of key variables which can be used to improve the state of the art of modelling ART. While the magnitude of the effects associated with these variables would be likely to differ in other settings, the variables influencing costs and survival are likely to be generalizable. This is of direct relevance to those concerned about assessing the long-term costs and sustainability of expanded access to ART.</p

A systematic review of behavioral outcomes for leadership interventions among health professionals

Background: Healthcare requires effective leadership to improve patient outcomes, manage change, and achieve organizational goals. Purpose: The purpose of this study was to evaluate interventions aimed at improving leadership behavior in health professionals. Methods: A systematic literature review of key databases (PubMed, CINAHL, Embase, and Scopus) was performed in September 2018. Data were extracted and synthesized. Results: Thirty-three articles from 31 studies met the inclusion criteria. Self-reported leadership behavior showed a significant postprogram improvement. Objective observations were more likely to show improved leadership behavior than subjective observations. Face-to-face delivery of leadership development was more effective than online delivery. Interventions incorporating the elements of personal development planning, self-directed learning, workplace-based learning, and reflection were more likely to develop leadership behavior. Conclusions/implications for practice: Leadership interventions had a beneficial effect on the leadership behaviors of participants based on both subjective and objective changes in behavior. In addition to focusing on individual skill development, interventions that aim to develop leadership should consider the organizational, social, cultural, and political contexts in which behavioral change is expected. Workplace-based learning should be included in program development

Elementary amenable subgroups of R. Thompson's group F

The subgroup structure of Thompson's group F is not yet fully understood. The group F is a subgroup of the group PL(I) of orientation preserving, piecewise linear self homeomorphisms of the unit interval and this larger group thus also has a poorly understood subgroup structure. It is reasonable to guess that F is the "only" subgroup of PL(I) that is not elementary amenable. In this paper, we explore the complexity of the elementary amenable subgroups of F in an attempt to understand the boundary between the elementary amenable subgroups and the non-elementary amenable. We construct an example of an elementary amenable subgroup up to class (height) omega squared, where omega is the first infinite ordinal.Comment: 20 page