Dynamics and Dilemmas of Women Leading Women

Through examination of transcripts of the first five leadership succession discussions that occurred in a work group designed to empower teachers we explored dynamics and dilemmas associated with women leading a women\u27s group based on feminist principles. We addressed three research questions: How is leadership, as reflected in leadership succession processes, experienced in such a group? What dynamics are associated with leadership succession in this type of group? What are outcomes of the process for members? Results indicated that the experience of leadership shifted considerably during the first six years of the group, with reflective images of leadership moving from the mythical to the pragmatic, from the powerful to the less powerful. Dynamics evolved in ways that were partially consistent and partially inconsistent with organizational life-cycle literature. The group experienced ambivalence and tension surrounding the type of authority given to designated leaders. Members dealt with discomfort by shifting the focus of the group coordinator\u27s attention to external relations and by rotating internal leadership responsibilities. This approach resolved tensions associated with authority and increased members\u27 senses of their own power, even as it decreased the range of initiative-taking that was implicitly allowable within the group. This analysis of leadership succession in a women\u27s group with an empowerment agenda offers a salient case for the study of dilemmas likely to be present in many change efforts. Its results suggest that attempting to resolve contradiction and tensions is less helpful than acknowledging them and working within them

European Paediatric Formulation Initiative (EuPFI)-Formulating Ideas for Better Medicines for Children.

© American Association of Pharmaceutical Scientists 2016, published by Springer US, available online at doi: https://doi.org/10.1208/s12249-016-0584-1The European Paediatric Formulation Initiative (EuPFI), founded in 2007, aims to promote and facilitate the preparation of better and safe medicines for children through linking research and information dissemination. It brings together the capabilities of the industry, academics, hospitals, and regulators within a common platform in order to scope the solid understanding of the major issues, which will underpin the progress towards the future of paediatric medicines we want.The EuPFI was formed in parallel to the adoption of regulations within the EU and USA and has served as a community that drives research and dissemination through publications and the organisation of annual conferences. The membership and reach of this group have grown since its inception in 2007 and continue to develop and evolve to meet the continuing needs and ambitions of research into and development of age appropriate medicines. Five diverse workstreams (age-appropriate medicines, Biopharmaceutics, Administration Devices, Excipients and Taste Assessment & Taste Masking (TATM)) direct specific workpackages on behalf of the EuPFI. Furthermore, EuPFI interacts with multiple diverse professional groups across the globe to ensure efficient working in the area of paediatric medicines. Strong commitment and active involvement of all EuPFI stakeholders have proved to be vital to effectively address knowledge gaps related to paediatric medicines, discuss potential areas for further research and identify issues that need more attention and analysis in the future.Peer reviewedFinal Accepted Versio

Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches

The gas-phase reaction of NH2 with formaldehyde (CH2O) is not a source of formamide (NH2CHO) in interstellar environments

The first experimental study of the low-temperature kinetics of the gas-phase reaction of NH2 with formaldehyde (CH2O) has been performed. This reaction has previously been suggested as a source of formamide (NH2CHO) in interstellar environments. A pulsed Laval nozzle equipped with laser-flash photolysis and laser-induced fluorescence spectroscopy was used to create and monitor the temporal decay of NH2 in the presence of CH2O. No loss of NH2 could be observed via reaction with CH2O and we place an upper-limit on the rate coefficient of <6x10-12 cm3 molecule-1 s-1 at 34K. Ab initio calculations of the potential energy surface were combined with RRKM calculations to predict a rate coefficient of 6.2x10-14 cm3 molecule-1 s-1 at 35K, consistent with the experimental results. The presence of a significant barrier, 18 kJ mol-1, for the formation of formamide as a product, means that only the H-abstraction channel producing NH3 + CHO, in which the transfer of an H-atom can occur by quantum mechanical tunnelling through a 23 kJ mol-1 barrier, is open at low temperatures. These results are in contrast with a recent theoretical study which suggested that the reaction could proceed without a barrier and was therefore a viable route to gas-phase formamide formation. The calculated rate coefficients were used in an astrochemical model which demonstrated that this reaction produces only negligible amounts of gas-phase formamide under interstellar and circumstellar conditions. The reaction of NH2 with CH2O is therefore not an important source of formamide at low temperatures in interstellar environments.Comment: Manuscript, 14 pages, 4 figures. Supporting Information, 8 pages, 2 figures. Accepted for publication in The Astrophysical Journal Letter

Identification of key residues that confer Rhodobacter sphaeroides LPS activity at horse TLR4/MD-2.

The molecular determinants underpinning how hexaacylated lipid A and tetraacylated precursor lipid IVa activate Toll-like receptor 4 (TLR4) are well understood, but how activation is induced by other lipid A species is less clear. Species specificity studies have clarified how TLR4/MD-2 recognises different lipid A structures, for example tetraacylated lipid IVa requires direct electrostatic interactions for agonism. In this study, we examine how pentaacylated lipopolysaccharide from Rhodobacter sphaeroides (RSLPS) antagonises human TLR4/MD-2 and activates the horse receptor complex using a computational approach and cross-species mutagenesis. At a functional level, we show that RSLPS is a partial agonist at horse TLR4/MD-2 with greater efficacy than lipid IVa. These data suggest the importance of the additional acyl chain in RSLPS signalling. Based on docking analysis, we propose a model for positioning of the RSLPS lipid A moiety (RSLA) within the MD-2 cavity at the TLR4 dimer interface, which allows activity at the horse receptor complex. As for lipid IVa, RSLPS agonism requires species-specific contacts with MD-2 and TLR4, but the R2 chain of RSLA protrudes from the MD-2 pocket to contact the TLR4 dimer in the vicinity of proline 442. Our model explains why RSLPS is only partially dependent on horse TLR4 residue R385, unlike lipid IVa. Mutagenesis of proline 442 into a serine residue, as found in human TLR4, uncovers the importance of this site in RSLPS signalling; horse TLR4 R385G/P442S double mutation completely abolishes RSLPS activity without its counterpart, human TLR4 G384R/S441P, being able to restore it. Our data highlight the importance of subtle changes in ligand positioning, and suggest that TLR4 and MD-2 residues that may not participate directly in ligand binding can determine the signalling outcome of a given ligand. This indicates a cooperative binding mechanism within the receptor complex, which is becoming increasingly important in TLR signalling.This work was supported by a project grant from the Horserace Betting Levy Board to CEB and a Horserace Betting Levy Board Veterinary Research Training Scholarship to KLI. This work was also supported by a Wellcome Trust program grant to NJG and CEB. CEB is a BBSRC Research Development Fellow.This is the final version of the article. It first appeared from PLOS at http://dx.doi.org/10.1371/journal.pone.0098776

Detecting weak spectral lines in interferometric data through matched filtering

Funding: R.A.L. and J.H. gratefully acknowledge funding from National Science Foundation Graduate Research Fellowships (Grant No. DGE-1144152). R.A.L. also acknowledges funding from the NRAO Student Observing Support Program. K.I.Ö. acknowledges funding from the Alfred P. Sloan Foundation and the David and Lucile Packard Foundation. C.W. acknowledges financial support from the Netherlands Organisation for Scientific Research (NWO, grant 639.041.335) and start-up funds from the University of Leeds, UK.Modern radio interferometers enable observations of spectral lines with unprecedented spatial resolution and sensitivity. In spite of these technical advances, many lines of interest are still at best weakly detected and therefore necessitate detection and analysis techniques specialized for the low signal-to-noise ratio (S/N) regime. Matched filters can leverage knowledge of the source structure and kinematics to increase sensitivity of spectral line observations. Application of the filter in the native Fourier domain improves S/N while simultaneously avoiding the computational cost and ambiguities associated with imaging, making matched filtering a fast and robust method for weak spectral line detection. We demonstrate how an approximate matched filter can be constructed from a previously observed line or from a model of the source, and we show how this filter can be used to robustly infer a detection significance for weak spectral lines. When applied to ALMA Cycle 2 observations of CH3OH in the protoplanetary disk around TW Hya, the technique yields a ≈53% S/N boost over aperture-based spectral extraction methods, and we show that an even higher boost will be achieved for observations at higher spatial resolution. A Python-based open-source implementation of this technique is available under the MIT license at http://github.com/AstroChem/VISIBLE.Publisher PDFPeer reviewe