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

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

An approach to complex texts in multiple documents

This entry gives a link to the full publication, free to read from this link. You may NOT repost the link on social media, etc.SSHRC, CFIPeer ReviewedThis article describes an approach to the treatment of texts in complex large textual traditions. Editors are interested in the text as it appears line-by-line in each document, and in how the versions of the text differ from document to document. It is useful to define a text as the record of an act of communication, inscribed in a document: thus, the instance of the act of communication we identify as Geoffrey Chaucer’s Canterbury Tales, as it appears in the Hengwrt manuscript. In this view, every text has a dual aspect: it is both the words as they are inscribed in a particular document, and as they constitute an act of communication and its parts. This presents challenges for scholars who wish to record both aspects. In encoding implementations, these two aspects are commonly treated as ‘overlapping hierarchies’. However, the ‘overlapping hierarchy’ model does not deal with cases where text segments are not contiguous in either aspect and cannot overlap cleanly. To meet these cases, the Textual Communities project developed an architecture in which the two aspects are represented as distinct and independent hierarchies (trees), with text segments referenced to nodes on each tree. The linking of text segments to the two trees is managed by a JSON database, accessed through transcription and collation tools presented in a Web interface. Textual Communities does not implement the whole of this architecture in terms of validation, ingestion, and processing. Full exploration and implementation of the architecture here described are challenges for future scholars

High Grade Acadian Regional Metamorphism in South-Central Massachusetts

Guidebook for field trips in Connecticut and south central Massachusetts: New England Intercollegiate Geological Conference 74th annual meeting, University of Connecticut, Storrs Connecticut , October 2 and 3, 1982: Trip P-

L'Escola d'Estiu de Mallorca davant la formació del professorat

Abstract not availabl

HST Imaging Polarimetry of the Gravitational Lens FSC10214+4724

We present imaging polarimetry of the extremely luminous, redshift 2.3 IRAS source FSC10214+4724. The observations were obtained with HST's Faint Object Camera in the F437M filter, which is free of strong emission lines. The 0.7 arcsec long arc is unresolved to 0.04 arcsec FWHM in the transverse direction, and has an integrated polarization of 28 +/- 3 percent, in good agreement with ground-based observations. The polarization position angle varies along the arc by up to 35 deg. The overall position angle is 62 +/- 3 deg east of north. No counterimage is detected to B = 27.5 mag ($3\sigma$), giving an observed arc to counterimage flux ratio greater than 250, considerably greater than the flux ratio of 100 measured previously in the I-band. This implies that the configuration of the object in the source plane at the B-band is different from that at I-band, and/or that the lensing galaxy is dusty.Comment: 17 pages, 3 figures. Accepted for publication in Astronomical Journal, February 199

Two Jovian-Mass Planets in Earthlike Orbits

We report the discovery of two new planets: a 1.94 M_Jup planet in a 1.8-year orbit of HD 5319, and a 2.51 M_Jup planet in a 1.1-year orbit of HD 75898. The measured eccentricities are 0.12 for HD 5319 b and 0.10 for HD 75898 b, and Markov Chain Monte Carlo simulations based on derived orbital parameters indicate that the radial velocities of both stars are consistent with circular planet orbits. With low eccentricity and 1 < a < 2 AU, our new planets have orbits similar to terrestrial planets in the solar system. The radial velocity residuals of both stars have significant trends, likely arising from substellar or low-mass stellar companions.Comment: 32 pages, including 11 figures and 5 tables. Accepted by Ap

Isomerization dynamics of a buckled nanobeam

We analyze the dynamics of a model of a nanobeam under compression. The model is a two mode truncation of the Euler-Bernoulli beam equation subject to compressive stress. We consider parameter regimes where the first mode is unstable and the second mode can be either stable or unstable, and the remaining modes (neglected) are always stable. Material parameters used correspond to silicon. The two mode model Hamiltonian is the sum of a (diagonal) kinetic energy term and a potential energy term. The form of the potential energy function suggests an analogy with isomerisation reactions in chemistry. We therefore study the dynamics of the buckled beam using the conceptual framework established for the theory of isomerisation reactions. When the second mode is stable the potential energy surface has an index one saddle and when the second mode is unstable the potential energy surface has an index two saddle and two index one saddles. Symmetry of the system allows us to construct a phase space dividing surface between the two "isomers" (buckled states). The energy range is sufficiently wide that we can treat the effects of the index one and index two saddles in a unified fashion. We have computed reactive fluxes, mean gap times and reactant phase space volumes for three stress values at several different energies. In all cases the phase space volume swept out by isomerizing trajectories is considerably less than the reactant density of states, proving that the dynamics is highly nonergodic. The associated gap time distributions consist of one or more `pulses' of trajectories. Computation of the reactive flux correlation function shows no sign of a plateau region; rather, the flux exhibits oscillatory decay, indicating that, for the 2-mode model in the physical regime considered, a rate constant for isomerization does not exist.Comment: 42 pages, 6 figure