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JC virus is a member of the Polyomavirus family, infects humans worldwide, and 90% of the population carry antibodies to the virus by adult life. The initial infection is asymptomatic, but it may become persistent. JC virus DNA is frequently present in the upper and lower gastrointestinal tracts of healthy adults. Chronic idiopathic intestinal pseudo-obstruction, one of the most severe gastrointestinal motility disorders, is a condition characterized by a clinical picture mimicking small bowel occlusion with related symptoms and signs in the absence of demonstrable mechanical obstruction. Because of the known neuropathic capability of this virus, and its frequent presence in the gut, it has been proposed that JCV might be detectable in tissues of patients with chronic idiopathic intestinal pseudo-obstruction, and possibly be involved in the pathogenesis of this disease, because the virus may actively infect the enteroglial cells of the myenteric plexuses of the patients with chronic idiopathic intestinal pseudo-obstruction. We report two cases of upper idiopathic intestinal pseudo-obstruction associated with JCV infection. [ABSTRACT FROM AUTHOR]

In this article, we will briefly review the current empirical understanding of the relation between accretion state and outflows in accreting stellar mass black holes. The focus will be on the empirical connections between X-ray states and relativistic ('radio') jets, although we are now also able to draw accretion disc winds into the picture in a systematic way. We will furthermore consider the latest attempts to measure/order jet power, and to compare it to other (potentially) measurable quantities, most importantly black hole spin. [ABSTRACT FROM AUTHOR]

In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-? signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-? signaling, including either subunit of the TGF-? receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-?2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-? signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2+/? mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-? signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1C1039G/+) and Tgfb2 haploinsufficiency show increased TGF-? signaling and phenotypic worsening in association with normalization of TGF-?2 expression and high expression of TGF-?1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-?-mediated vasculopathies. [ABSTRACT FROM AUTHOR]

The influence of signals transmitted by the phosphatase calcineurin and the transcription factor NFAT on the development and function of natural killer T (NKT) cells is unclear. In this report, we demonstrate that the transcription factor early growth response 2 (Egr2), a target gene of NFAT, was specifically required for the ontogeny of NKT cells but not that of conventional CD4+ or CD8+ T cells. NKT cells developed normally in the absence of Egr1 or Egr3, which suggests that Egr2 is a specific regulator of NKT cell differentiation. We found that Egr2 was important in the selection, survival and maturation of NKT cells. Our findings emphasize the importance of the calcineurin-NFAT-Egr2 pathway in the development of the NKT lymphocyte lineage. [ABSTRACT FROM AUTHOR]

At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the αβ T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide–MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf–MEK–ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to ‘weak’ positive selecting signals but not in response to ‘strong’ negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates. [ABSTRACT FROM AUTHOR]

With their relatively fast variability time-scales, Galactic X-ray binaries provide an excellent laboratory to explore the physics of accretion and related phenomena, most notably outflows, over different regimes. After comparing the phenomenology of jets in black hole systems to that of neutron stars, here I discuss the role of the jet at very low Eddington ratios, and present preliminary results obtained by fitting the broadband spectral energy distribution of a quiescent black hole binary with a ‘maximally jet-dominated’ model. [ABSTRACT FROM AUTHOR]

Ca2+ signals control a variety of lymphocyte responses, ranging from short-term cytoskeletal modifications to long-term changes in gene expression. The identification of molecules and channels that modulate Ca2+ entry into T and B lymphocytes has both provided details of the molecular events leading to immune responses and raised controversy. Here we review studies of the pathways that allow Ca2+ entry, the function of Ca2+ in the regulation of cell polarity and motility and the principles by which Ca2+-dependent transcription regulates lymphocyte function. [ABSTRACT FROM AUTHOR]

We have recently put forward a ‘unified’ semi-empirical model for the coupling between accretion and jet production in galactic black hole X-ray binaries. In this paper, we summarise this model and briefly discuss relevant considerations that have arisen since its publication. [ABSTRACT FROM AUTHOR]

Black holes undergoing accretion are thought to emit the bulk of their power in the X-ray band by releasing the gravitational potential energy of the infalling matter. At the same time, they are capable of producing highly collimated jets of energy and particles flowing out of the system with relativistic velocities. Here we show that the 10-solar-mass (10M\cirċ) black hole in the X-ray binary Cygnus X-1 (refs 3–5) is surrounded by a large-scale (∼5 pc in diameter) ring-like structure that appears to be inflated by the inner radio jet. We estimate that in order to sustain the observed emission of the ring, the jet of Cygnus X-1 has to carry a kinetic power that can be as high as the bolometric X-ray luminosity of the binary system. This result may imply that low-luminosity stellar-mass black holes as a whole dissipate the bulk of the liberated accretion power in the form of ‘dark’, radiatively inefficient relativistic outflows, rather than locally in the X-ray-emitting inflow. [ABSTRACT FROM AUTHOR]