Astrophage of neutron stars from supersymmetric dark matter Q-balls

The gauge-mediated model of supersymmetry breaking implies that stable non-topological solitons, Q-balls, could form in the early universe and comprise the dark matter. It is shown that the inclusion of the effects from gravity-mediation set an upper limit on the size of Q-balls. When in a dense baryonic environment Q-balls grow until reaching this limiting size at which point they fragment into two equal-sized Q-balls. This Q-splitting process will rapidly destroy a neutron star that absorbs even one Q-ball. The new limits on Q-ball dark matter require an ultralight gravitino m_3/2 < keV, naturally avoiding the gravitino overclosure problem, and providing the MSSM with a dark matter candidate where gravitino dark matter is not viable.Comment: 4 pages, 1 figure, Published in Phys. Rev. D. Rapid Communication

Regulation Of Cyclic-amp-dependent Protein Kinases During Skeletal Myogenesis

L6 myoblasts are a permanent rat skeletal myoblast cell line which differentiates in culture to form multinucleate myotubes. The regulation of the levels of cAMP-dependent protein kinases during myogenesis in L6 was studied, as these enzymes have been proposed to be involved in the control of this process. Measurement of the mRNA levels for the type I regulatory subunit (R{dollar}\sb{lcub}\rm I{rcub}{dollar}) of cAMP-dependent protein kinase, and studies on the rates of transcription from the gene coding for this protein, showed that the increase in R{dollar}\sb{lcub}\rm I{rcub}{dollar} which occurs during myogenesis is is not regulated transcriptionally. Measurement of R{dollar}\sb{lcub}\rm I{rcub}{dollar} half-lives showed that a decrease in the rate of R{dollar}\sb{lcub}\rm I{rcub}{dollar} degradation during myogenesis probably causes its increase. Studies on the regulation of the catalytic subunit (C) of cAMP-dependent protein kinase showed that the increase in this subunit, which also occurs during myogenesis, is probably regulated at the level of transcription, and not by a change in its rate of degradation. On the basis of these results it is proposed that the increase in R{dollar}\sb{lcub}\rm I{rcub}{dollar} during myogenesis is due to a decrease in its proteolysis caused by an increase in the amount of C available to bind with it. This type of mechanism may have relevance to the regulation of increases in other multisubunit complexes during differentiation.;The regulation of R{dollar}\sb{lcub}\rm I{rcub}{dollar} was also studied in a spontaneously-transformed L6 cell line which is unable to differentiate. Measurement of R{dollar}\sb{lcub}\rm I{rcub}{dollar} degradation rates in this cell line showed that R{dollar}\sb{lcub}\rm I{rcub}{dollar} proteolysis is altered in the presence of certain types of cAMP analogues. As R{dollar}\sb{lcub}\rm I{rcub}{dollar} from this cell line and normal L6 appeared to be structurally the same, it is proposed that a change in some protease accounts for the altered R{dollar}\sb{lcub}\rm I{rcub}{dollar} degradation. This change in proteolysis was not a common feature of myoblast transformation, as it was not observed in L6 myoblasts transformed by transfection of the Ha-ras oncogene

Activation of extracellular-regulated kinases by normal and mutant EGF receptors

AbstractGlioblastoma cells express a mutant EGF receptor (EGFRvIII) that has constitutive tyrosine kinase activity and enhances their tumorigenicity. Here we show that EGFRvIII promotes constitutive phosphorylation of extracellular regulated kinases (ERKs) in glioblastoma cells in the absence of EGF. EGFRvIII also promoted constitutive activation of phosphoinositide 3-kinase in these cells, as assessed by phosphorylation of protein kinase B/akt. As expected, phosphorylation of protein kinase B/akt was blocked by the phosphoinositide 3-kinase inhibitors wortmannin and LY294002. Less expectedly, we found that this treatment also blocked EGFRvIII-induced phosphorylation of ERKs. In contrast, ERK phosphorylation induced by EGF-activated normal EGF receptor in the same cells was largely unaffected by treatment with phosphoinositide 3-kinase inhibitors. This difference in behavior between the normal receptor and EGFRvIII was not due to differences in the levels of activated EGFRvIII and wild-type EGF receptor, as the two types of receptor were tyrosine phosphorylated to a similar extent under the experimental conditions used. EGFRvIII activation of ERKs was also sensitive to the phospholipase C inhibitor U73122, whereas ERK activation by normal EGF receptor was not. These results show that EGFRvIII and wild-type EGF receptor preferentially use different signaling pathways to induce ERK phosphorylation. The different mechanisms of ERK activation used by normal and mutant EGF receptors may be important in understanding the potent tumorigenic activity of EGFRvIII

Interaction of Hsp90 with the Nascent Form of the Mutant Epidermal Growth Factor Receptor EGFRvIII

EGFRvIII is a mutant epidermal growth factor that promotes aggressive growth of glioblastomas. We made a plasmid that directed the expression of an EGFRvIII with three copies of the Flag epitope at its amino terminus. Flag-tagged EGFRvIII was expressed at the same levels as unmodified EGFRvIII, and showed the same subcellular localization. However, the Flag epitope could only be detected on EGFRvIII present in the endoplasmic reticulum; the epitope was covalently modified during trafficking of the receptor through the Golgi so that it was no longer recognized by anti-Flag antibody. This property was exploited to selectively purify nascent EGFRvIII from glioblastoma cells. Nascent EGFRvIII was found to copurify with a set of other proteins, identified by mass spectrometry as the two endoplasmic reticulum chaperones Grp94 and BiP, and the two cytosolic chaperones Hsc70 and Hsp90. The Hsp90-associated chaperone Cdc37 also co-purified with EGFRvIII, suggesting that Hsp90 binds EGFRvIII as a complex with this protein. Geldanamycin and radicicol, two chemically unrelated inhibitors of Hsp90, decreased the expression of EGFRvIII in glioblastoma cells. These studies show that nascent EGFRvIII in the endoplasmic reticulum associates with Hsp90 and Cdc37, and that the Hsp90 association is necessary to maintain expression of EGFRvIII

Detecting binary neutron star systems with spin in advanced gravitational-wave detectors

The detection of gravitational waves from binary neutron stars is a major goal of the gravitational-wave observatories Advanced LIGO and Advanced Virgo. Previous searches for binary neutron stars with LIGO and Virgo neglected the component stars' angular momentum (spin). We demonstrate that neglecting spin in matched-filter searches causes advanced detectors to lose more than 3% of the possible signal-to-noise ratio for 59% (6%) of sources, assuming that neutron star dimensionless spins, $c\mathbf{J}/GM^2$, are uniformly distributed with magnitudes between 0 and 0.4 (0.05) and that the neutron stars have isotropically distributed spin orientations. We present a new method for constructing template banks for gravitational wave searches for systems with spin. We present a new metric in a parameter space in which the template placement metric is globally flat. This new method can create template banks of signals with non-zero spins that are (anti-)aligned with the orbital angular momentum. We show that this search loses more than 3% of the maximium signal-to-noise for only 9% (0.2%) of BNS sources with dimensionless spins between 0 and 0.4 (0.05) and isotropic spin orientations. Use of this template bank will prevent selection bias in gravitational-wave searches and allow a more accurate exploration of the distribution of spins in binary neutron stars.Comment: 11 pages, 10 figure

Nurse clinic versus home delivery of evidence-based community leg ulcer care: A randomized health services trial

BACKGROUND: International studies report that nurse clinics improve healing rates for the leg ulcer population. However, these studies did not necessarily deliver similar standards of care based on evidence in the treatment venues (home and clinic). A rigorous evaluation of home versus clinic care is required to determine healing rates with equivalent care and establish the acceptability of clinic-delivered care. METHODS: Health Services RCT was conducted where mobile individuals were allocated to either home or nurse clinic for leg ulcer management. In both arms, care was delivered by specially trained nurses, following an evidence protocol. Primary outcome: 3-month healing rates. Secondary outcomes: durability of healing (recurrence), time free of ulcers, HRQL, satisfaction, resource use. Data were collected at base-line, every 3 months until healing occurred, with 1 year follow-up. Analysis was by intention to treat. RESULTS: 126 participants, 65 randomized to receive care in their homes, 61 to nurse-run clinics. No differences found between groups at baseline on socio-demographic, HRQL or clinical characteristics. mean age 69 years, 68% females, 84% English-speaking, half with previous episode of ulceration, 60% ulcers at inclusion < 5 cm(2 )for < 6 months. No differences in 3-month healing rates: clinic 58.3% compared to home care at 56.7% (p = 0.5) or in secondary outcomes. CONCLUSION: Our findings indicate that organization of care not the setting where care is delivered influences healing rates. Key factors are a system that supports delivery of evidence-based recommendations with care being provided by a trained nursing team resulting in equivalent healing rates, HRQL whether care is delivered in the home or in a community nurse-led clinic. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: NCT0065638

Coordination of glioblastoma cell motility by PKCι

Abstract Background Glioblastoma is one of the deadliest forms of cancer, in part because of its highly invasive nature. The tumor suppressor PTEN is frequently mutated in glioblastoma and is known to contribute to the invasive phenotype. However the downstream events that promote invasion are not fully understood. PTEN loss leads to activation of the atypical protein kinase C, PKCι. We have previously shown that PKCι is required for glioblastoma cell invasion, primarily by enhancing cell motility. Here we have used time-lapse videomicroscopy to more precisely define the role of PKCι in glioblastoma. Results Glioblastoma cells in which PKCι was either depleted by shRNA or inhibited pharmacologically were unable to coordinate the formation of a single leading edge lamellipod. Instead, some cells generated multiple small, short-lived protrusions while others generated a diffuse leading edge that formed around the entire circumference of the cell. Confocal microscopy showed that this behavior was associated with altered behavior of the cytoskeletal protein Lgl, which is known to be inactivated by PKCι phosphorylation. Lgl in control cells localized to the lamellipod leading edge and did not associate with its binding partner non-muscle myosin II, consistent with it being in an inactive state. In PKCι-depleted cells, Lgl was concentrated at multiple sites at the periphery of the cell and remained in association with non-muscle myosin II. Videomicroscopy also identified a novel role for PKCι in the cell cycle. Cells in which PKCι was either depleted by shRNA or inhibited pharmacologically entered mitosis normally, but showed marked delays in completing mitosis. Conclusions PKCι promotes glioblastoma motility by coordinating the formation of a single leading edge lamellipod and has a role in remodeling the cytoskeleton at the lamellipod leading edge, promoting the dissociation of Lgl from non-muscle myosin II. In addition PKCι is required for the transition of glioblastoma cells through mitosis. PKCι therefore has a role in both glioblastoma invasion and proliferation, two key aspects in the malignant nature of this disease

Bridging the Gap Between Science, Economics and Policy to Develop and Implement a Pilot Market Based Instrument for Soil Carbon

Increasing soil organic carbon (SOC) has potential to offset greenhouse gas emissions, but the scope for on-farm carbon sequestration is poorly understood. A pilot scheme was developed in Central West NSW, Australia to trial the use of a market-based instrument to encourage farmers to increase soil organic carbon levels. The pilot considered the relationship between land use, management practices and soil carbon levels; offered alternative contract designs to attract landholders; and developed monitoring and reporting protocols. The pilot was rolled-out in 2011 and 2012 and had 11 successful tenders with an average price of $A37 per t CO2-e. The results of this conservation tender will assist the design of future programs aimed at encouraging mitigation effort from the agricultural sector

Political geographies of the object

This paper examines the role of objects in the constitution and exercise of state power, drawing on a close reading of the acclaimed HBO television series The Wire, an unconventional crime drama set and shot in Baltimore, Maryland. While political geography increasingly recognizes the prosaic and intimate practices of stateness, we argue that objects themselves are central to the production, organization, and performance of state power. Specifically, we analyze how three prominent objects on The Wire—wiretaps, cameras, and standardized tests—arrange and produce the conditions we understand as ‘stateness’. Drawing on object-oriented philosophy, we offer a methodology of power that suggests it is generalized force relations rather than specifically social relations that police a population—without, of course, ever being able to fully capture it. We conclude by suggesting The Wire itself is an object of force, and explore the implications of an object-oriented approach for understanding the nature of power, and for political geography more broadly

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase

Plasmodium falciparum (<i>Pf</i>) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit <i>Pf</i>ProRS enzyme activity versus Homo sapiens (<i>Hs</i>) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of <i>Pf</i>ProRS. We identified two new inhibitors of <i>Pf</i>ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for <i>Pf</i>ProRS compared to <i>Hs</i>ProRS, demonstrating this class of compounds could overcome the toxicity related to <i>Hs</i>ProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with <i>Pf</i>ProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria