TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion

Demographic and Clinical Variation in Veterans Health Administration Provision of Assistive Technology Devices to Veterans Poststroke

Objectives: To examine variation in provision of assistive technology (AT) devices and the extent to which such variation may be explained by patient characteristics or Veterans Health Administration (VHA) administrative region. Design: Retrospective population-based study. Setting: VHA. Participants: Veterans poststroke in fiscal years 2001 and 2002 (N=12,046). Interventions: Not applicable. Main Outcome Measure: Provision of 8 categories of AT devices. Results: There was considerable regional variation in provision of AT. For example, differences across administrative regions in the VHA ranged from 5.1 to 28.1 standard manual wheelchairs per 100 veterans poststroke. Using logistic regression, with only demographic variables as predictors of standard manual wheelchair provision, the c statistic was .62, and the pseudo R2 was 2.5%. Adding disease severity increased the c statistic to .67 and the pseudo R2 to 6.2%, and adding Veteran Integrated Network System further increased the c statistic to .72 and pseudo R2 to 9.8%. Conclusions: Our research showed significant variation in the provision of AT devices to veterans poststroke, and it showed that patient characteristics accounted for only 6.2% of the variation. VHA administrative region and disability severity accounted for equivalent amounts of the variation

The Chiral Potts Models Revisited

In honor of Onsager's ninetieth birthday, we like to review some exact results obtained so far in the chiral Potts models and to translate these results into language more transparent to physicists, so that experts in Monte Carlo calculations, high and low temperature expansions, and various other methods, can use them. We shall pay special attention to the interfacial tension $\epsilon_r$ between the $k$ state and the $k-r$ state. By examining the ground states, it is seen that the integrable line ends at a superwetting point, on which the relation $\epsilon_r=r\epsilon_1$ is satisfied, so that it is energetically neutral to have one interface or more. We present also some partial results on the meaning of the integrable line for low temperatures where it lives in the non-wet regime. We make Baxter's exact results more explicit for the symmetric case. By performing a Bethe Ansatz calculation with open boundary conditions we confirm a dilogarithm identity for the low-temperature expansion which may be new. We propose a new model for numerical studies. This model has only two variables and exhibits commensurate and incommensurate phase transitions and wetting transitions near zero temperature. It appears to be not integrable, except at one point, and at each temperature there is a point, where it is almost identical with the integrable chiral Potts model.Comment: J. Stat. Phys., LaTeX using psbox.tex and AMS fonts, 69 pages, 30 figure

DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo.

Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic

RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions

Photometric Observations of Three High Mass X-Ray Binaries and a Search for Variations Induced by Orbital Motion

We searched for long period variation in V-band, Ic-band and RXTE X-ray light curves of the High Mass X-ray Binaries (HMXBs) LS 1698 / RX J1037.5-5647, HD 110432 / 1H 1249-637 and HD 161103 / RX J1744.7-2713 in an attempt to discover orbitally induced variation. Data were obtained primarily from the ASAS database and were supplemented by shorter term observations made with the 24- and 40-inch ANU telescopes and one of the robotic PROMPT telescopes. Fourier periodograms suggested the existence of long period variation in the V-band light curves of all three HMXBs, however folding the data at those periods did not reveal convincing periodic variation. At this point we cannot rule out the existence of long term V-band variation for these three sources and hints of longer term variation may be seen in the higher precision PROMPT data. Long term V-band observations, on the order of several years, taken at a frequency of at least once per week and with a precision of 0.01 mag, therefore still have a chance of revealing long term variation in these three HMXBs.Comment: Accepted, RAA, May, 201

Mycobacterium tuberculosis Complex Lipid Virulence Factors Preserved in the 17,000-Year-Old Skeleton of an Extinct Bison, Bison antiquus

Tracing the evolution of ancient diseases depends on the availability and accessibility of suitable biomarkers in archaeological specimens. DNA is potentially information-rich but it depends on a favourable environment for preservation. In the case of the major mycobacterial pathogens, Mycobacterium tuberculosis and Mycobacterium leprae, robust lipid biomarkers are established as alternatives or complements to DNA analyses. A DNA report, a decade ago, suggested that a 17,000-year-old skeleton of extinct Bison antiquus, from Natural Trap Cave, Wyoming, was the oldest known case of tuberculosis. In the current study, key mycobacterial lipid virulence factor biomarkers were detected in the same two samples from this bison. Fluorescence high-performance liquid chromatography (HPLC) indicated the presence of mycolic acids of the mycobacterial type, but they were degraded and could not be precisely correlated with tuberculosis. However, pristine profiles of C29, C30 and C32 mycocerosates and C27 mycolipenates, typical of the Mycobacterium tuberculosis complex, were recorded by negative ion chemical ionization gas chromatography mass spectrometry of pentafluorobenzyl ester derivatives. These findings were supported by the detection of C34 and C36 phthiocerols, which are usually esterified to the mycocerosates. The existence of Pleistocene tuberculosis in the Americas is confirmed and there are many even older animal bones with well-characterised tuberculous lesions similar to those on the analysed sample. In the absence of any evidence of tuberculosis in human skeletons older than 9,000 years BP, the hypothesis that this disease evolved as a zoonosis, before transfer to humans, is given detailed consideration and discussion.The study was supported by Leverhulme Trust Project Grant F/00 094/BL (GSB, DEM, OY-CL) and Wellcome Trust Grant 080988/Z/06/Z (GSB, OY-CL). A grant from the UK Natural and Environmental Research Council (DEM, GSB) provided access to the Mass Spectrometry Unit at the University of Bristol, UK

Periodicities in the high-mass X-ray binary system RXJ0146.9+6121/LSI+61 235

The high-mass X-ray binary RX J0146.9+6121, with optical counterpart LS I+61°235 (V831 Cas), is an intriguing system on the outskirts of the open cluster NGC 663. It contains the slowest Be type X-ray pulsar known with a pulse period of around 1400 s and, primarily from the study of variation in the emission line profile of Hα, it is known to have a Be decretion disc with a one-armed density wave period of approximately 1240 d. Here we present the results of an extensive photometric campaign, supplemented with optical spectroscopy, aimed at measuring short time-scale periodicities. We find three significant periodicities in the photometric data at, in order of statistical significance, 0.34, 0.67 and 0.10 d. We give arguments to support the interpretation that the 0.34 and 0.10 d periods could be due to stellar oscillations of the B-type primary star and that the 0.67 d period is the spin period of the Be star with a spin axis inclination of 23+10−8 degrees. We measured a systemic velocity of −37.0 ± 4.3 km s−1 confirming that LS I+61°235 has a high probability of membership in the young cluster NGC 663 from which the system's age can be estimated as 20–25 Myr. From archival RXTE All Sky Monitor (ASM) data we further find ‘super’ X-ray outbursts roughly every 450 d. If these super outbursts are caused by the alignment of the compact star with the one-armed decretion disc enhancement, then the orbital period is approximately 330 d