Pro-Apoptotic Apoptosis Protease–Activating Factor 1 (Apaf-1) Has a Cytoplasmic Localization Distinct from Bcl-2 or Bcl-XL

How Bcl-2 and its pro-survival relatives prevent activation of the caspases that mediate apoptosis is unknown, but they appear to act through the caspase activator apoptosis protease–activating factor 1 (Apaf-1). According to the apoptosome model, the Bcl-2–like proteins preclude Apaf-1 activity by sequestering the protein. To explore Apaf-1 function and to test this model, we generated monoclonal antibodies to Apaf-1 and used them to determine its localization within diverse cells by subcellular fractionation and confocal laser scanning microscopy. Whereas Bcl-2 and Bcl-xL were prominent on organelle membranes, endogenous Apaf-1 was cytosolic and did not colocalize with them, even when these pro-survival proteins were overexpressed or after apoptosis was induced. Immunogold electron microscopy confirmed that Apaf-1 was dispersed in the cytoplasm and not on mitochondria or other organelles. After the death stimuli, Bcl-2 and Bcl-xL precluded the release of the Apaf-1 cofactor cytochrome c from mitochondria and the formation of larger Apaf-1 complexes, which are steps that presage apoptosis. However, neither Bcl-2 nor Bcl-xL could prevent the in vitro activation of Apaf-1 induced by the addition of exogenous cytochrome c. Hence, rather than sequestering Apaf-1 as proposed by the apoptosome model, Bcl-2–like proteins probably regulate Apaf-1 indirectly by controlling upstream events critical for its activation

Galaxy Populations and Evolution in Clusters IV: Deep HI Observations of Dwarf Ellipticals in the Virgo Cluster

We present in this paper the deepest Arecibo HI observations of Virgo cluster dwarf ellipticals (dEs) taken to date. Based on this data we argue that a significant fraction of Virgo cluster dEs recently underwent evolution. Our new observations consist of HI 21-cm line observations for 22 classified dE galaxies with optical radial velocities consistent with membership in the Virgo cluster. Cluster members VCC 390 and VCC 1713 are detected with HI masses M(HI) = 6*10^7 M_solar and 8*10^7 M_solar, respectively, while M(HI) in the remaining 20 dE galaxies have upper limits as low as 5*10^5 M_solar. We combine our results with those for 27 other Virgo cluster dEs with HI observations in the literature, 7 of which have HI detection claims. New optical images from the WIYN telescope of 5 of these HI-detected dEs, along with archival data, suggest that seven of the claimed detections are real, yielding a ~ 15% detection rate. These HI-detected classified dEs are preferentially located near the periphery of the Virgo cluster. Three Virgo dEs have observed HI velocity widths > 200 km/s, possibly indicating the presence of a large dark matter content, or transient extended HI. We discuss the possible origins of these objects and argue that they originate from field galaxies accreted onto high angular momentum orbits by Virgo in the last few Gyr. As a result these galaxies are slowly transformed within the cluster by gradual gas stripping processes, associated truncation of star formation, and passive fading of stellar populations. Low-mass early-type cluster galaxies are therefore currently being produced as the product of cluster environmental effects. We utilize our results to estimate the recent (past 1-3 Gyr) average mass accretion rate into the Virgo cluster, finding dM/dt ~ 50 M_solar/year.Comment: Accepted to ApJ, 21 page

Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antibodies directed against self antigens. Immune complex glomerulonephritis (GN) is one of the most serious complications of this disorder and can lead to potentially fatal renal failure. The aetiology of SLE is complex and multifactorial, characterized by interacting environmental and genetic factors. Here we examine the nature of the renal pathology in mycobacteria-treated non-obese diabetic (NOD) mice, in order to assess its suitability as a model for studying the aetiopathogenesis of, and possible treatment options for, lupus nephritis (LN) in humans. Both global and segmental proliferative lesions, characterized by increased mesangial matrix and cellularity, were demonstrated on light microscopy, and lesions varied in severity from very mild mesangiopathic GN through to obliteration of capillary lumina and glomerular sclerosis. Mixed isotype immune complexes (IC) consisting of immunoglobulin G (IgG), IgM, IgA and complement C3c were detected using direct immunofluorescence. They were deposited in multiple sites within the glomeruli, as confirmed by electron microscopy. The GN seen in mycobacteria-treated NOD mice therefore strongly resembles the pathology seen in human LN, including mesangiopathic, mesangiocapillary and membranous subclasses of LN. The development of spontaneous mixed isotype IC in the glomeruli of some senescent NOD mice suggests that mycobacterial exposure is accelerating, rather than inducing, the development of GN in this model