Exonerations in the United States 1989 through 2003

On August 14, 1989, the Cook County Circuit Court in Chicago, Illinois, vacated Gary Dotson\u27s 1979 rape conviction and dismissed the charges.1 Mr. Dotson-who had spent ten years in and out of prison and on parole for this conviction-was not the first innocent prisoner to be exonerated and released in America. But his case was a breakthrough nonetheless: he was the first who was cleared by DNA identification technology. It was the beginning of a revolution in the American criminal justice system. Until then, exonerations of falsely convicted defendants were seen as aberrational. Since 1989, these once-rare events have become disturbingly commonplace

Exonerations in the United States 1989 Through 2003

On August 14, 1989, the Cook County Circuit Court in Chicago, Illinois, vacated Gary Dotson\u27s 1979 rape conviction and dismissed the charges.1 Mr. Dotson-who had spent ten years in and out of prison and on parole for this conviction-was not the first innocent prisoner to be exonerated and released in America. But his case was a breakthrough nonetheless: he was the first who was cleared by DNA identification technology. It was the beginning of a revolution in the American criminal justice system. Until then, exonerations of falsely convicted defendants were seen as aberrational. Since 1989, these once-rare events have become disturbingly commonplace

GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells.

Forward genetic screens in Drosophila melanogaster for modifiers of position-effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A nonlethal forward genetic screen in near-haploid KBM7 cells identified the HUSH (human silencing hub) complex, comprising three poorly characterized proteins, TASOR, MPP8, and periphilin; this complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased H3K9me3 both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Our results suggest that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 is required for further H3K9me3 deposition to maintain transcriptional silencing.This work was supported by a Wellcome Trust Principal Research Fellowship to P.J.L. (084957/Z/08/Z) and studentship to I.A.T., an MRC Centenary Award to R.T.T., and the Cambridge Biomedical Research Centre (UK). The CIMR is in receipt of a Wellcome Trust Strategic Award.This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaa722

Promiscuous Targeting of Cellular Proteins by Vpr Drives Systems-Level Proteomic Remodeling in HIV-1 Infection.

HIV-1 encodes four "accessory proteins" (Vif, Vpr, Vpu, and Nef), dispensable for viral replication in vitro but essential for viral pathogenesis in vivo. Well characterized cellular targets have been associated with Vif, Vpu, and Nef, which counteract host restriction and promote viral replication. Conversely, although several substrates of Vpr have been described, their biological significance remains unclear. Here, we use complementary unbiased mass spectrometry-based approaches to demonstrate that Vpr is both necessary and sufficient for the DCAF1/DDB1/CUL4 E3 ubiquitin ligase-mediated degradation of at least 38 cellular proteins, causing systems-level changes to the cellular proteome. We therefore propose that promiscuous targeting of multiple host factors underpins complex Vpr-dependent cellular phenotypes and validate this in the case of G2/M cell cycle arrest. Our model explains how Vpr modulates so many cell biological processes and why the functional consequences of previously described Vpr targets, identified and studied in isolation, have proved elusive.This work was supported by the Wellcome Trust (PRF 210688/Z/18/Z to PJL), the MRC (CSF MR/P008801/1 to NJM), NHSBT (WPA15-02 to NJM), the NIHR Cambridge BRC, and a Wellcome Trust Strategic Award to the CIMR

Functional proteomic atlas of HIV infection in primary human CD4+ T cells.

Viruses manipulate host cells to enhance their replication, and the identification of cellular factors targeted by viruses has led to key insights into both viral pathogenesis and cell biology. In this study, we develop an HIV reporter virus (HIV-AFMACS) displaying a streptavidin-binding affinity tag at the surface of infected cells, allowing facile one-step selection with streptavidin-conjugated magnetic beads. We use this system to obtain pure populations of HIV-infected primary human CD4+ T cells for detailed proteomic analysis, and quantitate approximately 9000 proteins across multiple donors on a dynamic background of T cell activation. Amongst 650 HIV-dependent changes (q < 0.05), we describe novel Vif-dependent targets FMR1 and DPH7, and 192 proteins not identified and/or regulated in T cell lines, such as ARID5A and PTPN22. We therefore provide a high-coverage functional proteomic atlas of HIV infection, and a mechanistic account of host factors subverted by the virus in its natural target cell

Imaging and Demography of the Host Galaxies of High-Redshift Type Ia Supernovae

We present the results of a study of the host galaxies of high redshift Type Ia supernovae (SNe Ia). We provide a catalog of 18 hosts of SNe Ia observed with the Hubble Space Telescope (HST) by the High-z Supernova Search Team (HZT), including images, scale-lengths, measurements of integrated (Hubble equivalent) BVRIZ photometry in bands where the galaxies are brighter than m ~ 25 mag, and galactocentric distances of the supernovae. We compare the residuals of SN Ia distance measurements from cosmological fits to measurable properties of the supernova host galaxies that might be expected to correlate with variable properties of the progenitor population, such as host galaxy color and position of the supernova. We find mostly null results; the current data are generally consistent with no correlations of the distance residuals with host galaxy properties in the redshift range 0.42 < z < 1.06. Although a subsample of SN hosts shows a formally significant (3-sigma) correlation between apparent V-R host color and distance residuals, the correlation is not consistent with the null results from other host colors probed by our largest samples. There is also evidence for the same correlations between SN Ia properties and host type at low redshift and high redshift. These similarities support the current practice of extrapolating properties of the nearby population to high redshifts pending more robust detections of any correlations between distance residuals from cosmological fits and host properties.Comment: 35 pages, 12 figures, 4 tables, accepted for publication in A

Addition of abiraterone to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Model to estimate long-term survival, quality-adjusted survival, and cost-effectiveness

Background: Results from randomised trials show adding abiraterone acetate plus prednisolone (AAP) to standard of care (SOC) improves disease-free and overall survival in men with prostate cancer (PC) starting long-term hormone therapy for first time. Formal assessment is required of whether funding AAP here shows appropriate use of resources. This cost-effectiveness decision model tests if giving AAP to these patients is cost-effective using costs from English National Health Service, the largest nation where STAMPEDE recruited. / Methods: Health outcomes and costs were modelled using patient data from AAP comparison of STAMPEDE (recruitment 2011-14). This included 1917 men with high-risk, locally advanced metastatic or recurrent PC starting 1st-line hormone therapy. SOC was hormone therapy for ≥2 years with radiotherapy in pre-selected patients. If allocated to research group, AAP (AA 1000mg/day, P 5mg/day) was added to SOC. The model makes lifetime predictions of survival, costs and quality-adjusted lifeyears (QALYs), with costs and QALYs discounted at 3.5% annually. Sensitivity analyses were performed. / Results: The model predicted AAP would extend survival (discounted quality-adjusted survival) by 2.68y (1.46 QALYs) for metastatic patients and 0.30y (0.29 QALYs) for non-metastatic. The cost of AAP means it is not currently cost-effective in this setting, including with Patient Access Scheme costs for AAP and enzalutamide and similar reductions for cabazitaxel and Ra. If AAP’s price reduces after patent expiry as expected (90% reduction on BNF cost), it would be cost-effective in both patient groups, with incremental cost-effectiveness ratios below £10,000 (US$12,665) per QALY. AAP could also dominate in non-metastatic patients (i.e. lower costs and higher QALYs than SOC alone). / Conclusions: AAP could be cost-effective for patients with non-metastatic and metastatic disease with expected future pricing and may be cost-saving in the former. Policymakers should encourage license submissions and generic price reductions to facilitate use of AAP given cost-saving potential in addition to improving survival. / Clinical trial information: NCT00268476

Berkeley Supernova Ia Program I: Observations, Data Reduction, and Spectroscopic Sample of 582 Low-Redshift Type Ia Supernovae

In this first paper in a series we present 1298 low-redshift (z\leq0.2) optical spectra of 582 Type Ia supernovae (SNe Ia) observed from 1989 through 2008 as part of the Berkeley SN Ia Program (BSNIP). 584 spectra of 199 SNe Ia have well-calibrated light curves with measured distance moduli, and many of the spectra have been corrected for host-galaxy contamination. Most of the data were obtained using the Kast double spectrograph mounted on the Shane 3 m telescope at Lick Observatory and have a typical wavelength range of 3300-10,400 Ang., roughly twice as wide as spectra from most previously published datasets. We present our observing and reduction procedures, and we describe the resulting SN Database (SNDB), which will be an online, public, searchable database containing all of our fully reduced spectra and companion photometry. In addition, we discuss our spectral classification scheme (using the SuperNova IDentification code, SNID; Blondin & Tonry 2007), utilising our newly constructed set of SNID spectral templates. These templates allow us to accurately classify our entire dataset, and by doing so we are able to reclassify a handful of objects as bona fide SNe Ia and a few other objects as members of some of the peculiar SN Ia subtypes. In fact, our dataset includes spectra of nearly 90 spectroscopically peculiar SNe Ia. We also present spectroscopic host-galaxy redshifts of some SNe Ia where these values were previously unknown. [Abridged]Comment: 34 pages, 11 figures, 11 tables, revised version, re-submitted to MNRAS. Spectra will be released in January 2013. The SN Database homepage (http://hercules.berkeley.edu/database/index_public.html) contains the full tables, plots of all spectra, and our new SNID template

23 High Redshift Supernovae from the IfA Deep Survey: Doubling the SN Sample at z>0.7

We present photometric and spectroscopic observations of 23 high redshift supernovae spanning a range of z=0.34-1.03, 9 of which are unambiguously classified as Type Ia. These supernovae were discovered during the IfA Deep Survey, which began in September 2001 and observed a total of 2.5 square degrees to a depth of approximately m=25-26 in RIZ over 9-17 visits, typically every 1-3 weeks for nearly 5 months, with additional observations continuing until April 2002. We give a brief description of the survey motivations, observational strategy, and reduction process. This sample of 23 high-redshift supernovae includes 15 at z>0.7, doubling the published number of objects at these redshifts, and indicates that the evidence for acceleration of the universe is not due to a systematic effect proportional to redshift. In combination with the recent compilation of Tonry et al. (2003), we calculate cosmological parameter density contours which are consistent with the flat universe indicated by the CMB (Spergel et al. 2003). Adopting the constraint that Omega_total = 1.0, we obtain best-fit values of (Omega_m, Omega_Lambda)=(0.33, 0.67) using 22 SNe from this survey augmented by the literature compilation. We show that using the empty-beam model for gravitational lensing does not eliminate the need for Omega_Lambda > 0. Experience from this survey indicates great potential for similar large-scale surveys while also revealing the limitations of performing surveys for z>1 SNe from the ground.Comment: 67 pages, 12 figures, 12 tables, accepted for publication in the Astrophysical Journa