Functional Tolerance is Maintained Despite Proliferation of CD4 T Cells after Encounter with Tissue-derived Antigen

Since negative selection in the thymus is incomplete, some self-reactive T cells are able to mature and seed the periphery. To study how these T cells interact following encounter with the self-protein they recognize in the periphery, we have developed an adoptive transfer system in which HEL-specific TCR transgenic CD4 T cells are transferred to mice expressing HEL protein in the pancreas under the control of the rat insulin promoter. Here we show that after adoptive transfer of HEL-specific T cells functional tolerance is maintained despite evidence that the T cells encounter and respond to pancreas-expressed antigen. Even the provision of an additional activation stimulus by peripheral immunization with HEL protein is insufficient to induce the T cells to cause autoimmune tissue injury. However, in the presence of blocking anti-CTLA-4-mAb, immunized adoptive transfer recipients rapidly developed diabetes. These data suggest that the CTLA-4 pathway regulates the pathogenicity of antigen-specific T cells following a peripheral activation stimulus

The UV/optical spectra of the Type Ia supernova SN 2010jn: a bright supernova with outer layers rich in iron-group elements

Radiative transfer studies of Type Ia supernovae (SNe Ia) hold the promise of constraining both the time-dependent density profile of the SN ejecta and its stratification by element abundance which, in turn, may discriminate between different explosion mechanisms and progenitor classes. Here we present a detailed analysis of Hubble Space Telescope ultraviolet (UV) and ground-based optical spectra and light curves of the SN Ia SN 2010jn (PTF10ygu). SN 2010jn was discovered by the Palomar Transient Factory (PTF) 15 days before maximum light, allowing us to secure a time-series of four UV spectra at epochs from -11 to +5 days relative to B-band maximum. The photospheric UV spectra are excellent diagnostics of the iron-group abundances in the outer layers of the ejecta, particularly those at very early times. Using the method of 'Abundance Tomography' we have derived iron-group abundances in SN 2010jn with a precision better than in any previously studied SN Ia. Optimum fits to the data can be obtained if burned material is present even at high velocities, including significant mass fractions of iron-group elements. This is consistent with the slow decline rate (or high 'stretch') of the light curve of SN 2010jn, and consistent with the results of delayed-detonation models. Early-phase UV spectra and detailed time-dependent series of further SNe Ia offer a promising probe of the nature of the SN Ia mechanism.Comment: 17 pages, 9 figures (v3: several small updates to content including models; v2: metadata fixed), MNRAS, in pres

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

The effects of dust on the optical and infrared evolution of SN 2004et

We present an analysis of multi-epoch observations of the Type II-P supernova SN 2004et. New and archival optical spectra of SN 2004et are used to study the evolution of the Halpha and [O I] 6300A line profiles between days 259 and 646. Mid-infrared imaging was carried out between 2004 to 2010. We include Spitzer `warm' mission photometry at 3.6 and 4.5um obtained on days 1779, 1931 and 2151, along with ground-based and HST optical and near-infrared observations obtained between days 79 and 1803. Multi-wavelength light curves are presented, as well as optical-infrared spectral energy distributions (SEDs) for multiple epochs. Starting from about day 300, the optical light curves provide evidence for an increasing amount of circumstellar extinction attributable to newly formed dust, with the additional extinction reaching 0.8-1.5 magnitudes in the V-band by day 690. The overall SEDs were fitted with multiple blackbody components, in order to investigate the luminosity evolution of the supernova, and then with Monte Carlo radiative transfer models using smooth or clumpy dust distributions, in order to estimate how much new dust condensed in the ejecta. The luminosity evolution was consistent with the decay of 56Co in the ejecta up until about day 690, after which an additional emission source is required, in agreement with the findings of Kotak et al. (2009). Clumped dust density distributions consisting of 20% amorphous carbons and 80% silicates by mass were able to match the observed optical and infrared SEDs, with dust masses that increased from 8x10^{-5} Msun on day 300 to 1.5x10^{-3} Msun on day 690, still significantly lower than the values needed for core collapse supernovae to make a significant contribution to the dust enrichment of galaxies.Comment: 24 pages, 12 figures, 9 tables, published in MNRA

Hubble Space Telescope studies of low-redshift Type Ia supernovae: Evolution with redshift and ultraviolet spectral trends

We present an analysis of the maximum light, near ultraviolet (NUV; 2900-5500 A) spectra of 32 low redshift (0.001<z<0.08) Type Ia supernovae (SNe Ia), obtained with the Hubble Space Telescope (HST). We combine this spectroscopic sample with high-quality gri light curves obtained with robotic telescopes to measure photometric parameters, such as stretch, optical colour, and brightness. By comparing our data to a comparable sample of SNe Ia at intermediate-z (0.4<z<0.9), we detect modest spectral evolution (3-sigma), in the sense that our mean low-z NUV spectrum has a depressed flux compared to its intermediate-z counterpart. We also see a strongly increased dispersion about the mean with decreasing wavelength, confirming the results of earlier surveys. These trends are consistent with changes in metallicity as predicted by contemporary SN Ia spectral models. We also examine the properties of various NUV spectral diagnostics in the individual spectra. We find a general correlation between stretch and the velocity (or position) of many NUV spectral features. In particular, we observe that higher stretch SNe have larger Ca II H&K velocities, that also correlate with host galaxy stellar mass. This latter trend is probably driven by the well-established correlation between stretch and stellar mass. We find no trends between UV spectral features and optical colour. Mean spectra constructed according to whether the SN has a positive or negative Hubble residual show very little difference at NUV wavelengths, indicating that the NUV evolution and variation we identify do not directly correlate with Hubble residuals. Our work confirms and strengthens earlier conclusions regarding the complex behaviour of SNe Ia in the NUV spectral region, but suggests the correlations we find are more useful in constraining progenitor models than improving the use of SNe Ia as cosmological probes.Comment: 22 pages, 14 figures, accepted in MNRAS with minor changes - Spectra are available on WISeREP, http://www.weizmann.ac.il/astrophysics/wiserep

Social Class Differences in Secular Trends in Established Coronary Risk Factors over 20 Years: A Cohort Study of British Men from 1978–80 to 1998–2000

Background: Coronary heart disease (CHD) mortality in the UK since the late 1970s has declined more markedly among higher socioeconomic groups. However, little is known about changes in coronary risk factors in different socioeconomic groups. This study examined whether changes in established coronary risk factors in Britain over 20 years between 1978-80 and 1998-2000 differed between socioeconomic groups.Methods and Findings: A socioeconomically representative cohort of 7735 British men aged 40-59 years was followed-up from 1978-80 to 1998-2000; data on blood pressure (BP), cholesterol, body mass index (BMI) and cigarette smoking were collected at both points in 4252 survivors. Social class was based on longest-held occupation in middle-age. Compared with men in non-manual occupations, men in manual occupations experienced a greater increase in BMI (mean difference=0.33 kg/m(2); 95%CI 0.14-0.53; p for interaction=0.001), a smaller decline in non-HDL cholesterol (difference in mean change=0.18 mmol/l; 95%CI 0.11-0.25, p for interaction <= 0.0001) and a smaller increase in HDL cholesterol (difference in mean change=0.04 mmol/l; 95%CI 0.02-0.06, p for interaction <= 0.0001). However, mean systolic BP declined more in manual than non-manual groups (difference in mean change=3.6; 95%CI 2.1-5.1, p for interaction <= 0.0001). The odds of being a current smoker in 1978-80 and 1998-2000 did not differ between non-manual and manual social classes (p for interaction = 0.51).Conclusion: Several key risk factors for CHD and type 2 diabetes showed less favourable changes in men in manual occupations. Continuing priority is needed to improve adverse cardiovascular risk profiles in socially disadvantaged groups in the UK