The testis and epididymis are productively infected by SIV and SHIV in juvenile macaques during the post-acute stage of infection

BACKGROUND: Little is known about the progression and pathogenesis of HIV-1 infection within the male genital tract (MGT), particularly during the early stages of infection. RESULTS: To study HIV pathogenesis in the testis and epididymis, 12 juvenile monkeys (Macacca nemestrina, 4–4.5 years old) were infected with Simian Immunodeficiency Virus mac 251 (SIV(mac251)) (n = 6) or Simian/Human Immunodeficiency Virus (SHIV(mn229)) (n = 6). Testes and epididymides were collected and examined by light microscopy and electron microscopy, at weeks 11–13 (SHIV) and 23 (SIV) following infection. Differences were found in the maturation status of the MGT of the monkeys, ranging from prepubertal (lacking post-meiotic germ cells) to post-pubertal (having mature sperm in the epididymal duct). Variable levels of viral RNA were identified in the lymph node, epididymis and testis following infection with both SHIV(mn229 )and SIV(mac251). Viral protein was detected via immunofluorescence histochemistry using specific antibodies to SIV (anti-gp41) and HIV-1 (capsid/p24) protein. SIV and SHIV infected macrophages, potentially dendritic cells and T cells in the testicular interstitial tissue were identified by co-localisation studies using antibodies to CD68, DC-SIGN, αβTCR. Infection of spermatogonia, but not more mature spermatogenic cells, was also observed. Leukocytic infiltrates were observed within the epididymal stroma of the infected animals. CONCLUSION: These data show that the testis and epididymis of juvenile macaques are a target for SIV and SHIV during the post-acute stage of infection and represent a potential model for studying HIV-1 pathogenesis and its effect on spermatogenesis and the MGT in general

Infrared Spectroscopy of Symbiotic Stars. IV. V2116 Ophiuchi/GX 1+4, The Neutron Star Symbiotic

We have computed, based on 17 infrared radial velocities, the first set of orbital elements for the M giant in the symbiotic binary V2116 Ophiuchi. The giant's companion is a neutron star, the bright X-ray source GX 1+4. We find an orbital period of 1161 days by far the longest of any known X-ray binary. The orbit has a modest eccentricity of 0.10 with an orbital circularization time of less than 10^6 years. The large mass function of the orbit significantly restricts the mass of the M giant. Adopting a neutron-star mass of 1.35M(Sun), the maximum mass of the M giant is 1.22M(Sun), making it the less massive star. Derived abundances indicate a slightly subsolar metallicity. Carbon and nitrogen are in the expected ratio resulting from the red-giant first dredge-up phase. The lack of O-17 suggests that the M-giant has a mass less than 1.3M(Sun), consistent with our maximum mass. The red giant radius is 103R(Sun), much smaller than the estimated Roche lobe radius. Thus, the mass loss of the red giant is via a stellar wind. Although the M giant companion to the neutron star has a mass similar to the late-type star in low-mass X-ray binaries, its near-solar abundances and apparent runaway velocity are not fully consistent with the properties of this class of stars.Comment: In press to The Astrophysical Journal (10 April 2006 issue). 23 page

Search for Pairs of Isolated Radio Pulsars - Components in Disrupted Binary Systems

We have developed a method for analyzing the kinematic association of isolated relativistic objects - possible remnants of disrupted close binary systems. We investigate pairs of fairly young radio pulsars with known proper motions and estimated distances (dispersion measures) that are spaced no more than 2-3 kpc apart. Using a specified radial velocity distribution for these objects, we have constructed 100-300 thousand trajectories of their possible motion in the Galactic gravitational field on a time scale of several million years. The probabilities of their close encounters at epochs consistent with the age of the younger pulsar in the pair are analyzed. When these probabilities exceed considerably their reference values obtained by assuming a purely random encounter between the pulsars under consideration, we conclude that the objects may have been gravitationally bound in the past. As a result, we have detected six pulsar pairs (J0543+2329/J0528+2200, J1453-6413/J1430-6623, J2354+6155/J2321+6024, J1915+1009/J1909+1102, J1832-0827/J1836-1008, and J1917+1353/J1926+1648) that are companions in disrupted binary systems with a high probability. Estimates of their kinematic ages and velocities at binary disruption and at the present epoch are provided

Period and period change measurements for 143 SuperWASP eclipsing binary candidates near the short-period limit and discovery of a doubly eclipsing quadruple system

Building on previous work, a new search of the SuperWASP archive was carried out to identify eclipsing binary systems near the short-period limit. 143 candidate objects were detected with orbital periods between 16 000 and 20 000 s, of which 97 are new discoveries. Period changes significant at 1σ or more were detected in 74 of these objects, and in 38 the changes were significant at 3σ or more. The significant period changes observed followed an approximately normal distribution with a half-width at half-maximum of ~0.1 s yr-1. There was no apparent relationship between period length and magnitude or direction of period change. Amongst several interesting individual objects studied, 1SWASP J093010.78+533859.5 is presented as a new doubly eclipsing quadruple system, consisting of a contact binary with a 19 674.575 s period and an Algol-type binary with a 112 799.109 s period, separated by 66.1 AU, being the sixth known system of this type

BAFF Promotes Th17 Cells and Aggravates Experimental Autoimmune Encephalomyelitis

BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE.Th17 cells were increased in BAFF-Tg B6 (B6.BTg) mice and decreased in B6.Baff(-/-) mice. Th17 cells in B6.Baff(-/-) mice bearing a BAFF Tg (B6.Baff(-/-).BTg mice) were identical to those in B6.BTg mice, indicating that membrane BAFF is dispensable for Th17 cell generation as long as soluble BAFF is plentiful. In T + non-T cell criss-cross co-cultures, Th17 cell generation was greatest in cultures containing B6.BTg T cells and lowest in cultures containing B6.Baff(-/-) T cells, regardless of the source of non-T cells. In cultures containing only T cells, Th17 cell generation followed an identical pattern. CD4(+) cell expression of CD126 (IL-6R α chain) was increased in B6.BTg mice and decreased in B6.Baff(-/-) mice, and activation of STAT3 following stimulation with IL-6 + TGF-β was also greatest in B6.BTg cells and lowest in B6.Baff(-/-) cells. EAE was clinically and pathologically most severe in B6.BTg mice and least severe in B6.Baff(-/-) mice and correlated with MOG(35-55) peptide-induced Th17 cell responses.Collectively, these findings document a contribution of BAFF to pathogenic Th17 cell responses and suggest that BAFF antagonism may be efficacious in Th17 cell-driven diseases

Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

Long-Term Programming of Antigen-Specific Immunity from Gene Expression Signatures in the PBMC of Rhesus Macaques Immunized with an SIV DNA Vaccine

While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays

A Concerted HIF-1α/MT1-MMP Signalling Axis Regulates the Expression of the 3BP2 Adaptor Protein in Hypoxic Mesenchymal Stromal Cells

Increased plasticity, migratory and immunosuppressive abilities characterize mesenchymal stromal cells (MSC) which enable them to be active participants in the development of hypoxic solid tumours. Our understanding of the oncogenic adaptation of MSC to hypoxia however lacks the identification and characterization of specific biomarkers. In this study, we assessed the hypoxic regulation of 3BP2/SH3BP2 (Abl SH3-binding protein 2), an immune response adaptor/scaffold protein which regulates leukocyte differentiation and motility. Gene silencing of 3BP2 abrogated MSC migration in response to hypoxic cues and generation of MSC stably expressing the transcription factor hypoxia inducible factor 1alpha (HIF-1α) resulted in increased endogenous 3BP2 expression as well as cell migration. Analysis of the 3BP2 promoter sequence revealed only one potential HIF-1α binding site within the human but none in the murine sequence. An alternate early signalling cascade that regulated 3BP2 expression was found to involve membrane type-1 matrix metalloproteinase (MT1-MMP) transcriptional regulation which gene silencing abrogated 3BP2 expression in response to hypoxia. Collectively, we provide evidence for a concerted HIF-1α/MT1-MMP signalling axis that explains the induction of adaptor protein 3BP2 and which may link protein binding partners together and stimulate oncogenic MSC migration. These mechanistic observations support the potential for malignant transformation of MSC within hypoxic tumour stroma and may contribute to evasion of the immune system by a tumour

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Does narrative drive dynamic attention to a prolonged stimulus?

Attention in the "real world" fluctuates over time, but these fluctuations are hard to examine using a timed trial-based experimental paradigm. Here we use film to study attention. To achieve short-term engagement, filmmakers make use of low-level cinematic techniques such as color, movement and sound design to influence attention. To engage audiences over prolonged periods of time, narrative structure is used. In this experiment, participants performed a secondary auditory choice reaction time (RT) task to measure attention while watching a film. In order to explore the role of narrative on attention, we manipulated the order that film segments were presented. The influence of narrative was then compared to the contribution of low-level features (extracted using a computer-based saliency model) in a multiple regression analysis predicting choice RT. The regression model successfully predicted 28% of the variance in choice RT: 13% was due to low-level saliency, and 8% due to the narrative. This study shows the importance of narrative in determining attention and the value of studying attention with a prolonged stimulus such as film