The Remote Observatories of the Southeastern Association for Research in Astronomy (SARA)

We describe the remote facilities operated by the Southeastern Association for Research in Astronomy (SARA) , a consortium of colleges and universities in the US partnered with Lowell Observatory, the Chilean National Telescope Allocation Committee, and the Instituto de Astrofísica de Canarias. SARA observatories comprise a 0.96 m telescope at Kitt Peak, Arizona; one of 0.6 m aperture on Cerro Tololo, Chile; and the 1 m Jacobus Kapteyn Telescope at the Roque de los Muchachos, La Palma, Spain. All are operated using standard VNC or Radmin protocols communicating with on-site PCs. Remote operation offers considerable flexibility in scheduling, allowing long-term observational cadences difficult to achieve with classical observing at remote facilities, as well as obvious travel savings. Multiple observers at different locations can share a telescope for training, educational use, or collaborative research programs. Each telescope has a CCD system for optical imaging, using thermoelectric cooling to avoid the need for frequent local service, and a second CCD for offset guiding. The Arizona and Chile telescopes also have fiber-fed echelle spectrographs. Switching between imaging and spectroscopy is very rapid, so a night can easily accommodate mixed observing modes. We present some sample observational programs. For the benefit of other groups organizing similar consortia, we describe the operating structure and principles of SARA, as well as some lessons learned from almost 20 years of remote operations

Homo-PROTACs:bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation

United States Acculturation and Cancer Patients' End-of-Life Care

Background: Culture shapes how people understand illness and death, but few studies examine whether acculturation influences patients' end-of-life treatment preferences and medical care. Methods and Findings: In this multi-site, prospective, longitudinal cohort study of terminally-ill cancer patients and their caregivers (n = 171 dyads), trained interviewers administered the United States Acculturation Scale (USAS). The USAS is a 19-item scale developed to assess the degree of "Americanization" in first generation or non-US born caregivers of terminally-ill cancer patients. We evaluated the internal consistency, concurrent, criterion, and content validity of the USAS. We also examined whether caregivers' USAS scores predicted patients' communication, treatment preferences, and end-of-life medical care in multivariable models that corrected for significant confounding influences (e.g. education, country of origin, English proficiency). The USAS measure was internally consistent (Cronbach α = 0.98); and significantly associated with US birthplace (r = 0.66, P<0.0001). USAS scores were predictive of patients' preferences for prognostic information (AOR = 1.31, 95% CI:1.00-1.72), but not comfort asking physicians' questions about care (AOR 1.23, 95% CI:0.87-1.73). They predicted patients' preferences for feeding tubes (AOR = 0.68, 95% CI:0.49-0.99) and wish to avoid dying in an intensive care unit (AOR = 1.36, 95% CI:1.05-1.76). Scores indicating greater acculturation were also associated with increased odds of patient participation in clinical trials (AOR = 2.20, 95% CI:1.28-3.78), compared with lower USAS scores, and greater odds of patients receiving chemotherapy (AOR = 1.59, 95% CI:1.20-2.12). Conclusion: The USAS is a reliable and valid measure of "Americanization" associated with advanced cancer patients' end-of-life preferences and care. USAS scores indicating greater caregiver acculturation were associated with increased odds of patient participation in cancer treatment (chemotherapy, clinical trials) compared with lower scores. Future studies should examine the effects of acculturation on end-of-life care to identify patient and provider factors that explain these effects and targets for future interventions to improve care (e.g., by designing more culturally-competent health education materials). © 2013 Wright et al

Core Outcome Set for IgE-mediated food allergy clinical trials and observational studies of interventions: International Delphi consensus study 'COMFA'

BACKGROUND IgE-mediated food allergy (FA) is a global health concern with substantial individual and societal implications. While diverse intervention strategies have been researched, inconsistencies in reported outcomes limit evaluations of FA treatments. To streamline evaluations and promote consistent reporting, the Core Outcome Measures for Food Allergy (COMFA) initiative aimed to establish a Core Outcome Set (COS) for FA clinical trials and observational studies of interventions. METHODS The project involved a review of published clinical trials, trial protocols and qualitative literature. Outcomes found as a result of review were categorized and classified, informing a two-round online-modified Delphi process followed by hybrid consensus meeting to finalize the COS. RESULTS The literature review, taxonomy mapping and iterative discussions with diverse COMFA group yielded an initial list of 39 outcomes. The iterative online and in-person meetings reduced the list to 13 outcomes for voting in the formal Delphi process. One more outcome was added based on participant suggestions after the first Delphi round. A total of 778 participants from 52 countries participated, with 442 participating in both Delphi rounds. No outcome met a priori criteria for inclusion, and one was excluded as a result of the Delphi. Thirteen outcomes were brought to the hybrid consensus meeting as a result of Delphi and two outcomes, 'allergic symptoms' and 'quality of life' achieved consensus for inclusion as 'core' outcomes. CONCLUSION In addition to the mandatory reporting of adverse events for FA clinical trials or observational studies of interventions, allergic symptoms and quality of life should be measured as core outcomes. Future work by COMFA will define how best to measure these core outcomes

Centriole movements in mammalian epithelial cells during cytokinesis

<p>Abstract</p> <p>Background</p> <p>In cytokinesis, when the cleavage furrow has been formed, the two centrioles in each daughter cell separate. It has been suggested that the centrioles facilitate and regulate cytokinesis to some extent. It has been postulated that termination of cytokinesis (abscission) depends on the migration of a centriole to the intercellular bridge and then back to the cell center. To investigate the involvement of centrioles in cytokinesis, we monitored the movements of centrioles in three mammalian epithelial cell lines, HeLa, MCF 10A, and the p53-deficient mouse mammary tumor cell line KP-7.7, by time-lapse imaging. Centrin1-EGFP and α-Tubulin-mCherry were co-expressed in the cells to visualize respectively the centrioles and microtubules.</p> <p>Results</p> <p>Here we report that separated centrioles that migrate from the cell pole are very mobile during cytokinesis and their movements can be characterized as 1) along the nuclear envelope, 2) irregular, and 3) along microtubules forming the spindle axis. Centriole movement towards the intercellular bridge was only seen occasionally and was highly cell-line dependent.</p> <p>Conclusions</p> <p>These findings show that centrioles are highly mobile during cytokinesis and suggest that the repositioning of a centriole to the intercellular bridge is not essential for controlling abscission. We suggest that centriole movements are microtubule dependent and that abscission is more dependent on other mechanisms than positioning of centrioles.</p

A General Strategy to Endow Natural Fusion-protein-Derived Peptides with Potent Antiviral Activity

Fusion between the viral and target cell membranes is an obligatory step for the infectivity of all enveloped virus, and blocking this process is a clinically validated therapeutic strategy

Differential Function of Lip Residues in the Mechanism and Biology of an Anthrax Hemophore

To replicate in mammalian hosts, bacterial pathogens must acquire iron. The majority of iron is coordinated to the protoporphyrin ring of heme, which is further bound to hemoglobin. Pathogenic bacteria utilize secreted hemophores to acquire heme from heme sources such as hemoglobin. Bacillus anthracis, the causative agent of anthrax disease, secretes two hemophores, IsdX1 and IsdX2, to acquire heme from host hemoglobin and enhance bacterial replication in iron-starved environments. Both proteins contain NEAr-iron Transporter (NEAT) domains, a conserved protein module that functions in heme acquisition in Gram-positive pathogens. Here, we report the structure of IsdX1, the first of a Gram-positive hemophore, with and without bound heme. Overall, IsdX1 forms an immunoglobin-like fold that contains, similar to other NEAT proteins, a 310-helix near the heme-binding site. Because the mechanistic function of this helix in NEAT proteins is not yet defined, we focused on the contribution of this region to hemophore and NEAT protein activity, both biochemically and biologically in cultured cells. Site-directed mutagenesis of amino acids in and adjacent to the helix identified residues important for heme and hemoglobin association, with some mutations affecting both properties and other mutations affecting only heme stabilization. IsdX1 with mutations that reduced the ability to associate with hemoglobin and bind heme failed to restore the growth of a hemophore-deficient strain of B. anthracis on hemoglobin as the sole iron source. These data indicate that not only is the 310-helix important for NEAT protein biology, but also that the processes of hemoglobin and heme binding can be both separate as well as coupled, the latter function being necessary for maximal heme-scavenging activity. These studies enhance our understanding of NEAT domain and hemophore function and set the stage for structure-based inhibitor design to block NEAT domain interaction with upstream ligands