Synthesis of 4-Thiazolidinone Small Molecules as Potential Inhibitors of the Arp2/3 Complex

Life-essential cellular processes such as endocytosis, motility, and division rely on a cell’s ability to precisely regulate construction of actin filaments in response to external factors and signals. Intrinsically involved in this process is the Actin Related Protein 2/3 (Arp2/3) Complex, a seven-subunit ATPase that functions by nucleating a daughter branch of actin from the side of a pre-existing microfilament. Active Arp2/3 complex is necessary for the proliferation of certain metastatic cancers, and inhibition of Arp2/3 complex is emerging as a potentially useful treatment strategy for such cancers. We describe synthesis and in vitro assays of 4-thiazolidinones predicted by computational methods to inhibit of Arp2/3 Complex strongly, and therefore serve as potential lead compounds for drug development. Known Arp2/3 inhibitor CK-869 serves as the starting point for derivative synthesis. We discuss the efforts towards the synthesis of new compounds and the biochemical data collected about their potency

Ovine reference materials and assays for prion genetic testing

<p>Abstract</p> <p>Background</p> <p>Genetic predisposition to scrapie in sheep is associated with several variations in the peptide sequence of the prion protein gene (<it>PRNP</it>). DNA-based tests for scoring <it>PRNP </it>codons are essential tools for eradicating scrapie and for evaluating rare alleles for increased resistance to disease. In addition to those associated with scrapie, there are dozens more <it>PRNP </it>polymorphisms that may occur in various flocks. If not accounted for, these sites may cause base-pair mismatching with oligonucleotides used in DNA testing. Thus, the fidelity of scrapie genetic testing is enhanced by knowing the position and frequency of <it>PRNP </it>polymorphisms in targeted flocks.</p> <p>Results</p> <p>An adaptive DNA sequencing strategy was developed to determine the 771 bp <it>PRNP </it>coding sequence for any sheep and thereby produce a consensus sequence for targeted flocks. The strategy initially accounted for 43 known polymorphisms and facilitates the detection of unknown polymorphisms through an overlapping amplicon design. The strategy was applied to 953 sheep DNAs from multiple breeds in U.S. populations. The samples included two sets of reference sheep: one set for standardizing <it>PRNP </it>genetic testing and another set for discovering polymorphisms, estimating allele frequencies, and determining haplotype phase. DNA sequencing revealed 16 previously unreported polymorphisms, including a L237P variant on the F₁₄₁haplotype. Two mass spectrometry multiplex assays were developed to score five codons of interest in U.S. sheep: 112, 136, 141, 154, and 171. Reference tissues, DNA, trace files, and genotypes from this project are publicly available for use without restriction.</p> <p>Conclusion</p> <p>Identifying ovine <it>PRNP </it>polymorphisms in targeted flocks is critical for designing efficient scrapie genetic testing systems. Together with reference DNA panels, this information facilitates training, certification, and development of new tests and knowledge that may expedite the eradication of sheep scrapie.</p

Measuring nickel masses in Type Ia supernovae using cobalt emission in nebular phase spectra

The light curves of Type Ia supernovae (SNe Ia) are powered by the radioactive decay of $^{56}$Ni to $^{56}$Co at early times, and the decay of $^{56}$Co to $^{56}$Fe from ~60 days after explosion. We examine the evolution of the [Co III] 5892 A emission complex during the nebular phase for SNe Ia with multiple nebular spectra and show that the line flux follows the square of the mass of $^{56}$Co as a function of time. This result indicates both efficient local energy deposition from positrons produced in $^{56}$Co decay, and long-term stability of the ionization state of the nebula. We compile 77 nebular spectra of 25 SN Ia from the literature and present 17 new nebular spectra of 7 SNe Ia, including SN2014J. From these we measure the flux in the [Co III] 5892 A line and remove its well-behaved time dependence to infer the initial mass of $^{56}$Ni ($M_{Ni}$) produced in the explosion. We then examine $^{56}$Ni yields for different SN Ia ejected masses ($M_{ej}$ - calculated using the relation between light curve width and ejected mass) and find the $^{56}$Ni masses of SNe Ia fall into two regimes: for narrow light curves (low stretch s~0.7-0.9), $M_{Ni}$ is clustered near $M_{Ni}$ ~ 0.4$M_\odot$ and shows a shallow increase as $M_{ej}$ increases from ~1-1.4$M_\odot$; at high stretch, $M_{ej}$ clusters at the Chandrasekhar mass (1.4$M_\odot$) while $M_{Ni}$ spans a broad range from 0.6-1.2$M_\odot$. This could constitute evidence for two distinct SN Ia explosion mechanisms.Comment: 16 pages, 12 figures (main text), plus data tables in appendix. Spectra released on WISeREP. Submitted to MNRAS, comments welcom

Obliged to calculate: My School, markets, and equipping parents for calculativeness

This paper argues neoliberal programs of government in education are equipping parents for calculativeness. Regimes of testing and the publication of these results and other organizational data are contributing to a public economy of numbers that increasingly oblige citizens to calculate. Using the notions of calculative and market devices, this paper examines the Australian Government’s My School website, which publishes academic and organizational information about schools, including national test results. While it is often assumed that such performance technologies contribute to neoliberal reform of education through school choice, the paper argues the website is technically limited in its capacity to facilitate the economic calculations and calculated action of parents resulting in school choice. The paper instead opens My School to analysis as a technique of governmental self-formation. Using the theoretical resources of actor-network theory and Foucauldian scholarship, this paper complicates assumptions in the literature about the extent to which My School actually operates as a ‘market mechanism’. It argues My School attempts to cultivate a calculated form of parental educational agency, irreducible to economic market agency

Early Infrared Spectral Development of V1187 Scorpii (Nova Scorpii 2004 No. 2)

We report on an unprecedented infrared time series of spectra of V1187 Sco, a very fast ONeMg nova. The observations covered a 56 day period (2004 August 6-September 30) starting 2 days after the nova's peak brightness. Time evolution of the spectra revealed changing line strengths and profiles on timescales of less than a day to weeks as the nova evolved from early postmaximum to early coronal phases. When our ground-based optical and Spitzer Space Telescope data were combined, the wavelength coverage of 0.38-36 μm allowed an accurate spectral energy distribution to be derived when it was about 6 weeks after outburst. Developing double structure in the He I lines showed them changing from narrow to broad in only a few days. Using the O I lines in combination with the optical spectra, we derived a reddening of E(B - V) = 1.56 ± 0.08 and a distance of 4.9 ± 0.5 kpc. Modeling of the ejected material strongly suggested that it was geometrically thick with ΔR/R = 0.8-0.9 (more of a wind than a shell) and a low filling factor of order a few percent. The line shapes were consistent with a cylindrical jet, bipolar, or spherical Hubble flow expansion with a maximum speed of about -3000 km s-1. The central peak appeared to be more associated with the spherical component, while the two peaks (especially in Hβ) suggested a ring with either a lower velocity component or with its axis inclined to the line of sight