Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms

The adapter protein tumor necrosis factor receptor (TNFR)1–associated death domain (TRADD) plays an essential role in recruiting signaling molecules to the TNFRI receptor complex at the cell membrane. Here we show that TRADD contains a nuclear export and import sequence that allow shuttling between the nucleus and the cytoplasm. In the absence of export, TRADD is found within nuclear structures that are associated with promyelocytic leukemia protein (PML) nuclear bodies. In these structures, the TRADD death domain (TRADD-DD) can activate an apoptosis pathway that is mechanistically distinct from its action at the membrane-bound TNFR1 complex. Apoptosis by nuclear TRADD-DD is promyelocytic leukemia protein dependent, involves p53, and is inhibited by Bcl-xL but not by caspase inhibitors or dominant negative FADD (FADD-DN). Conversely, apoptosis induced by TRADD in the cytoplasm is resistant to Bcl-xL, but sensitive to caspase inhibitors and FADD-DN. These data indicate that nucleocytoplasmic shuttling of TRADD leads to the activation of distinct apoptosis mechanisms that connect the death receptor apparatus to nuclear events

Variable Effects of Nicotine, Anabasine, and their Interactions on Parasitized Bumble Bees

Secondary metabolites in floral nectar have been shown to reduce parasite load in two common bumble bee species. Previous studies on the effects of nectar secondary metabolites on parasitizedbees have focused on single compounds in isolation; however, in nature, bees are simultaneously exposed to multiple compounds. We tested for interactions between the effects of two alkaloids found in the nectar of Nicotiana spp. plants, nicotine and anabasine, on parasite load and mortality in bumble bees (Bombus impatiens) infected with the intestinal parasite Crithidia bombi. Adult worker bees inoculated with C. bombi were fed nicotine and anabasine diet treatments in a factorial design, resulting in four nectar treatment combinations: 2 ppm nicotine, 5 ppm anabasine, 2ppm nicotine and 5 ppm anabasine together, or a control alkaloid-free solution. We conducted the experiment twice: first, with bees incubated under variable environmental conditions (‘Variable’; temperatures varied from 10-35°C with ambient lighting); and second, under carefully controlled environmental conditions (‘Stable’; 27°C incubator, constant darkness). In ‘Variable’, each alkaloid alone significantly decreased parasite loads, but this effect was not realized with the alkaloids in combination, suggesting an antagonistic interaction. Nicotine but not anabasine significantly increased mortality, and the two compounds had no interactive effects on mortality. In ‘Stable’, nicotine significantly increased parasite loads, the opposite of its effect in ‘Variable’. While not significant, the relationship between anabasine and parasite loads was also positive. Interactive effects between the two alkaloids on parasite load were non-significant, but the pattern of antagonistic interaction was similar to that in the variable experiment. Neither alkaloid, nor their interaction, significantly affected mortality under controlled conditions. Our results do not indicate synergy between Nicotiana nectar alkaloids; however, they do suggest a complex interaction between secondary metabolites, parasites, and environmental variables, in which secondary metabolites can be either toxic or medicinal depending on context

Open challenges in the management of autoimmune hepatitis

Autoimmune Hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its aetiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimisation of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outline the clinical characteristics, aetiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provide evidence underlying the evolution of diagnostic and clinical management protocols

Inhibition of autophagy impairs tumor cell invasion in an organotypic model

Autophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. It contributes to energy and organelle homeostasis and the preservation of proteome and genome integrity. Although a role in cancer is unquestionable, there are conflicting reports that autophagy can be both oncogenic and tumor suppressive, perhaps indicating that autophagy has different roles at different stages of tumor development. In this report, we address the role of autophagy in a critical stage of cancer progression—tumor cell invasion. Using a glioma cell line containing an inducible shRNA that targets the essential autophagy gene Atg12, we show that autophagy inhibition does not affect cell viability, proliferation or migration but significantly reduces cellular invasion in a 3D organotypic model. These data indicate that autophagy may play a critical role in the benign to malignant transition that is also central to the initiation of metastasis

Limits on the Boron Isotopic Ratio in HD 76932

Data in the 2090 A B region of HD 76932 have been obtained at high S/N using the HST GHRS echelle at a resolution of 90,000. This wavelength region has been previously identified as a likely candidate for observing the B11/B10 isotopic splitting. The observations do not match a calculated line profile extremely well at any abundance for any isotopic ratio. If the B abundance previously determined from observations at 2500 A is assumed, the calculated line profile is too weak, indicating a possible blending line. Assuming that the absorption at 2090 A is entirely due to boron, the best-fit total B abundance is higher than but consistent with that obtained at 2500 A, and the best-fit isotopic ratio (B11/B10) is in the range ~10:1 to ~4:1. If the absorption is not entirely due to B and there is an unknown blend, the best-fit isotopic ratio may be closer to 1:1. Future observations of a similar metal-poor star known to have unusually low B should allow us to distinguish between these two possibilities. The constraints that can be placed on the isotopic ratio based on comparisons with similar observations of HD 102870 and HD 61421 (Procyon) are also discussed.Comment: Accepted for Nov 1998 Ap

Identification of climatological sub-regions within the Tully mill area

Identifying optimal nitrogen application rates that reduce nitrogen loss without adversely reducing yields would benefit growers and the environment. In order to identify optimal nitrogen application rates throughout the Tully mill area, it is important to identify sub-regions that share similar topographical, soil, farm management, productivity or climatological attributes. While current SIX EASY STEPS nitrogen guidelines enable a hierarchy of district, soil, block and crop nitrogen requirements for sugarcane, it would be beneficial for management zones to also take spatial climate variability information into account. Unfortunately, spatial climate variability within a region, is generally not considered when developing nitrogen management practices. The objective of this paper was to identify sub-regions within the Tully mill area based on climatological attributes as a first step towards better informing nitrogen management decisions. Rainfall, radiation and temperature data were obtained on a 0.05 by 0.05˚ grid (approximately 5 km by 5 km) for sugarcane-growing areas within the Tully Mill region. A K-means clustering algorithm was then used to cluster these grid cells into distinct sub-regions based on seasonal or annual climate data. Two distinct sub-regions were identified based on total annual rainfall and annual average daily radiation data. These sub-regions were identified as a northern and southern sub-region, divided roughly along the Tully River. The northern sub-region was characterised by lower radiation, lower temperatures and higher rainfall than the southern sub-region. Crop simulation models will now be able to use this knowledge to assess if nitrogen management plans should vary between the two sub-regions in Tully

The Red Rectangle: Its Shaping Mechanism and its Source of Ultraviolet Photons

The proto-planetary Red Rectangle nebula is powered by HD 44179, a spectroscopic binary (P = 318 d), in which a luminous post-AGB component is the primary source of both luminosity and current mass loss. Here, we present the results of a seven-year, eight-orbit spectroscopic monitoring program of HD 44179, designed to uncover new information about the source of the Lyman/far-ultraviolet continuum in the system as well as the driving mechanism for the bipolar outflow producing the current nebula. Our observations of the H-alpha line profile around the orbital phase of superior conjunction reveal the secondary component to be the origin of the fast (max. v~560$km s$^{-1}$) bipolar outflow in the Red Rectangle. The variation of total H-alpha flux from the central H II region with orbital phase also identifies the secondary or its surroundings as the source of the far-ultraviolet ionizing radiation in the system. The estimated mass of the secondary (~0.94 M$\sun$) and the speed of the outflow suggest that this component is a main sequence star and not a white dwarf, as previously suggested. We identify the source of the Lyman/far-ultraviolet continuum in the system as the hot, inner region (T$_{max} \ge 17,000$K) of an accretion disk surrounding the secondary, fed by Roche lobe overflow from the post-AGB primary at a rate of about$2 - 5\times10^{-5}$M$\sun$yr$^{-1}$. The total luminosity of the accretion disk around the secondary is estimated to be at least 300 L$\sun$, about 5% of the luminosity of the entire system. (abridged)Comment: Accepted for publication in Ap

Unusually Weak Diffuse Interstellar Bands toward HD 62542

As part of an extensive survey of diffuse interstellar bands (DIBs), we have obtained optical spectra of the moderately reddened B5V star HD 62542, which is known to have an unusual UV extinction curve of the type usually identified with dark clouds. The typically strongest of the commonly catalogued DIBs covered by the spectra -- those at 5780, 5797, 6270, 6284, and 6614 A -- are essentially absent in this line of sight, in marked contrast with other lines of sight of similar reddening. We compare the HD 62542 line of sight with others exhibiting a range of extinction properties and molecular abundances and interpret the weakness of the DIBs as an extreme case of deficient DIB formation in a dense cloud whose more diffuse outer layers have been stripped away. We comment on the challenges these observations pose for identifying the carriers of the diffuse bands.Comment: 20 pages, 4 figures; aastex; accepted by Ap