Tracking TCRß sequence clonotype expansions during antiviral therapy using high-throughput sequencing of the hypervariable region

To maintain a persistent infection viruses such as hepatitis C virus (HCV) employ a range of mechanisms that subvert protective T cell responses. The suppression of antigen-specific T cell responses by HCV hinders efforts to profile T cell responses during chronic infection and antiviral therapy. Conventional methods of detecting antigen-specific T cells utilize either antigen stimulation (e.g., ELISpot, proliferation assays, cytokine production) or antigen-loaded tetramer staining. This limits the ability to profile T cell responses during chronic infection due to suppressed effector function and the requirement for prior knowledge of antigenic viral peptide sequences. Recently, high-throughput sequencing (HTS) technologies have been developed for the analysis of T cell repertoires. In the present study, we have assessed the feasibility of HTS of the TCRβ complementarity determining region (CDR)3 to track T cell expansions in an antigen-independent manner. Using sequential blood samples from HCV-infected individuals undergoing antiviral therapy, we were able to measure the population frequencies of >35,000 TCRβ sequence clonotypes in each individual over the course of 12 weeks. TRBV/TRBJ gene segment usage varied markedly between individuals but remained relatively constant within individuals across the course of therapy. Despite this stable TRBV/TRBJ gene segment usage, a number of TCRβ sequence clonotypes showed dramatic changes in read frequency. These changes could not be linked to therapy outcomes in the present study; however, the TCRβ CDR3 sequences with the largest fold changes did include sequences with identical TRBV/TRBJ gene segment usage and high junction region homology to previously published CDR3 sequences from HCV-specific T cells targeting the HLA-B*0801-restricted 1395HSKKKCDEL1403 and HLA-A*0101-restricted 1435ATDALMTGY1443 epitopes. The pipeline developed in this proof of concept study provides a platform for the design of future experiments to accurately address the question of whether T cell responses contribute to SVR upon antiviral therapy. This pipeline represents a novel technique to analyze T cell dynamics in situations where conventional antigen-dependent methods are limited due to suppression of T cell functions and highly diverse antigenic sequences

The Relationship Between Molecular Gas Tracers and Kennicutt-Schmidt Laws

We provide a model for how Kennicutt-Schmidt (KS) laws, which describe the correlation between star formation rate and gas surface or volume density, depend on the molecular line chosen to trace the gas. We show that, for lines that can be excited at low temperatures, the KS law depends on how the line critical density compares to the median density in a galaxy's star-forming molecular clouds. High critical density lines trace regions with similar physical properties across galaxy types, and this produces a linear correlation between line luminosity and star formation rate. Low critical density lines probe regions whose properties vary across galaxies, leading to a star formation rate that varies superlinearly with line luminosity. We show that a simple model in which molecular clouds are treated as isothermal and homogenous can quantitatively reproduce the observed correlations between galactic luminosities in far infrared and in the CO(1->0) and HCN(1->0) lines, and naturally explains why these correlations have different slopes. We predict that IR-line luminosity correlations should change slope for galaxies in which the median density is close to the line critical density. This prediction may be tested by observations of lines such as HCO^+(1->0) with intermediate critical densities, or by HCN(1->0) observations of intensely star-forming high redshift galaxies with very high densities. Recent observations by Gao et al. hint at just such a change in slope. We argue that deviations from linearity in the HCN(1->0)-IR correlation at high luminosity are consistent with the assumption of a constant star formation efficiency.Comment: Accepted to ApJ. 11 pages, 4 figures, emulateapj format. This version has some additional models exploring the effects of varying metallicity and temperature. The conclusions are unchange

Non cell autonomous upregulation of CDKN2 transcription linked to progression of chronic hepatitis C disease

Chronic hepatitis C virus infection (C-HC) is associated with higher mortality arising from hepatic and extrahepatic disease. This may be due to accelerated biological aging; however, studies in C-HC have thus far been based solely on telomere length as a biomarker of aging (BoA). In this study, we have evaluated CDKN2 locus transcripts as alternative BoAs in C-HC. Our results suggest that C-HC induces non-cell-autonomous senescence and accelerates biological aging. The CDKN2 locus may provide a link between C-HC and increased susceptibility to age-associated diseases and provides novel biomarkers for assessing its impact on aging processes in man

OPTIC: Orbiting Plutonian Topographic Image Craft Proposal for an Unmanned Mission to Pluto

The proposal for an unmanned probe to Pluto is presented and described. The Orbiting Plutonian Topographic Image Craft's (OPTIC's) trip will take twenty years and after its arrival, will begin its data collection which includes image and radar mapping, surface spectral analysis, and magnetospheric studies. This probe's design was developed based on the request for proposal of an unmanned probe to Pluto requirements. The distinct problems which an orbiter causes for each subsystem of the craft are discussed. The final design revolved around two important factors: (1) the ability to collect and return the maximum quantity of information on the Plutonian system; and (2) the weight limitations which the choice of an orbiting craft implied. The velocity requirements of this type of mission severely limited the weight available for mission execution-owing to the large portion of overall weight required as fuel to fly the craft with present technology. The topics covered include: (1) scientific instrumentation; (2) mission management; (3) power and propulsion; (4) attitude and articulation control; (5) structural subsystems; and (6) command, control, and communication

Identifying Very Metal-Rich Stars with Low-Resolution Spectra: Finding Planet-Search Targets

We present empirical calibrations that estimate stellar metallicity, effective temperature and surface gravity as a function of Lick/IDS indices. These calibrations have been derived from a training set of 261 stars for which (1) high-precision measurements of [Fe/H], T_eff and log g have been made using spectral-synthesis analysis of HIRES spectra, and (2) Lick indices have also been measured. Our [Fe/H] calibration, which has precision 0.07 dex, has identified a number of bright (V < 9) metal-rich stars which are now being screened for hot Jupiter-type planets. Using the Yonsei-Yale stellar models, we show that the calibrations provide distance estimates accurate to 20% for nearby stars. This paper outlines the second tier of the screening of planet-search targets by the N2K Consortium, a project designed to identify the stars most likely to harbor extrasolar planets. Discoveries by the N2K Consortium include the transiting hot Saturn HD 149026 b (Sato et al. 2005, astro-ph/0507009) and HD 88133 b (Fischer et al. 2005). See Ammons et al. (2005, In Press) for a description of the first tier of N2K metallicity screening, calibrations using broadband photometry.Comment: Accepted for publication in the Astrophysical Journa

Effects of In-Season Velocity- Versus Percentage-Based Training in Academy Rugby League Players

Purpose: To compare the effects of velocity-based training (VBT) versus percentage-based training (PBT) on strength, speed and jump performance in academy rugby league players during a 7-week in-season mesocycle. Methods: Twenty-seven rugby league players competing in the Super League U19s Championship were randomised to VBT (n = 12) or PBT (n = 15). Both groups completed a 7-week resistance training intervention (2x/week) that involved the back squat. The PBT group used a fixed load based on a percentage of one repetition maximum (1RM), whereas the VBT group used a modifiable load based on individualised velocity thresholds. Biomechanical and perceptual data were collected during each training session. Back squat 1RM, countermovement jump (CMJ), reactive strength index (RSI), sprint times, and back squat velocity at 40-90% 1RM were assessed pre- and post-training. Results: The PBT group showed likely to most likely improvements in 1RM strength and RSI, whereas the VBT group showed likely to very likely improvements in 1RM strength, CMJ height, and back squat velocity at 40 and 60% 1RM. Sessional velocity and power were most likely greater during VBT compared with PBT (standardised mean differences [SMDs] = 1.8 to 2.4), whilst time under tension and perceptual training stress were likely lower (SMDs = 0.49 to 0.66). The improvement in back squat velocity at 60% 1RM was likely greater following VBT compared with PBT (SMD = 0.50). Conclusion: VBT can be implemented during the competitive season, instead of traditional PBT, to improve training stimuli, decrease training stress, and promote velocity-specific adaptations

Exploring ‘pro-environmental’ actions through discarded materials in the home

The household is a crucial focus of both waste and wider environmental policy, being seen as a central site of socio -economic-environmental change, a space in which people may perform their civic responsibilities and where individual and wider imperatives are brought together. Yet policy makers have shown limited appreciation and understanding of what happens inside the home. So in contemporary waste policy, for example, households remain a ‘closed entity’ in which everyday routines and practices remain hidden. Increasingly, though, it is acknowledged by social scientists that the lived experiences of environmental and waste management in the home are significant issues requiring further study, but how we might go about trying to study them is proving a challenging question. Conventional pro-environmental behaviour research has often tended to study behaviours in ways abstracted from the social contexts in which these take place. This has prompted recent research involving repeat in-depth interviews with householders and more ethnographic approaches, the use of reflexive diaries and narrative methodologies. Curiously, however, there has been little research considering environmental management(s) in the home which has focussed on waste itself. This paper seeks to add to the discussion, by focusing on everyday processes within households, using a qualitative approach of ‘getting in the bin’ of households - that is, an interview approach which takes respondents’ discarded waste as a starting point from which we ask them to discuss the lived experience(s) and activities of everyday life. More broadly by developing insights from what has been termed a ‘realist governmentality’ perspective the paper seeks to offer a more nuanced and finely grained analysis of governing in situ, exploring the extent to which governmental ambitions in relation to waste are accommodated, resisted or [re]worked at the household level. The paper draws illustratively on case studies from a Leverhulme-funded research project based in Kingston-Upon-Thames, an outer London borough in the UK. The approach used a focus on the contents of household waste bins to develop a narrative approach driven by householders centred on stories about pro-environmental practice. The paper will deal with three elements of the research approach: texturing narratives of waste, generating narratives of recycling in practice, and producing narratives of understanding. The outcome is development of a more thoroughgoing understanding of how processes within the home shape waste governance, moving beyond treating the home as a closed entity

Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P&lt;0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fa

Combination of Insecticide Treated Nets and Indoor Residual Spraying in Northern Tanzania Provides Additional Reduction in Vector Population Density and Malaria Transmission Rates Compared to Insecticide Treated Nets Alone: A Randomised Control Trial.

Indoor residual spraying (IRS) combined with insecticide treated nets (ITN) has been implemented together in several sub-Saharan countries with inconclusive evidence that the combined intervention provides added benefit. The impact on malaria transmission was evaluated in a cluster randomised trial comparing two rounds of IRS with bendiocarb plus universal coverage ITNs, with ITNs alone in northern Tanzania. From April 2011 to December 2012, eight houses in 20 clusters per study arm were sampled monthly for one night with CDC light trap collections. Anopheles gambiae s.l. were identified to species using real time PCR Taq Man and tested for the presence of Plasmodium falciparum circumsporozoite protein. ITN and IRS coverage was estimated from household surveys. IRS coverage was more than 85% in two rounds of spraying in January and April 2012. Household coverage with at least one ITN per house was 94.7% after the universal coverage net campaign in the baseline year and the proportion of household with all sleeping places covered by LLIN was 50.1% decreasing to 39.1% by the end of the intervention year. An.gambiae s.s. comprised 80% and An.arabiensis 18.3% of the anopheline collection in the baseline year. Mean An.gambiae s.l. density in the ITN+IRS arm was reduced by 84% (95%CI: 56%-94%, p = 0.001) relative to the ITN arm. In the stratum of clusters categorised as high anopheline density at baseline EIR was lower in the ITN+IRS arm compared to the ITN arm (0.5 versus 5.4 per house per month, Incidence Rate Ratio: 0.10, 95%CI: 0.01-0.66, p-value for interaction <0.001). This trial provides conclusive evidence that combining carbamate IRS and ITNs produces major reduction in Anopheles density and entomological inoculation rate compared to ITN alone in an area of moderate coverage of LLIN and high pyrethroid resistance in An.gambiae s.s