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181.
Ting-Yu Yeh Nicholas J. Quintyne Brett R. Scipioni D. Mark Eckley Trina A. Schroer 《Molecular biology of the cell》2012,23(19):3827-3837
Dynactin is an essential part of the cytoplasmic dynein motor that enhances motor processivity and serves as an adaptor that allows dynein to bind cargoes. Much is known about dynactin''s interaction with dynein and microtubules, but how it associates with its diverse complement of subcellular binding partners remains mysterious. It has been suggested that cargo specification involves a group of subunits referred to as the “pointed-end complex.” We used chemical cross-linking, RNA interference, and protein overexpression to characterize interactions within the pointed-end complex and explore how it contributes to dynactin''s interactions with endomembranes. The Arp11 subunit, which caps one end of dynactin''s Arp1 filament, and p62, which binds Arp11 and Arp1, are necessary for dynactin stability. These subunits also allow dynactin to bind the nuclear envelope prior to mitosis. p27 and p25, by contrast, are peripheral components that can be removed without any obvious impact on dynactin integrity. Dynactin lacking these subunits shows reduced membrane binding. Depletion of p27 and p25 results in impaired early and recycling endosome movement, but late endosome movement is unaffected, and mitotic spindles appear normal. We conclude that the pointed-end complex is a bipartite structural domain that stabilizes dynactin and supports its binding to different subcellular structures. 相似文献
182.
Amanda D. Buskirk Brett J. Green Angela R. Lemons Ajay P. Nayak W. Travis Goldsmith Michael L. Kashon Stacey E. Anderson Justin M. Hettick Steven P. Templeton Dori R. Germolec Donald H. Beezhold 《PloS one》2014,9(10)
Most murine models of fungal exposure are based on the delivery of uncharacterized extracts or liquid conidia suspensions using aspiration or intranasal approaches. Studies that model exposure to dry fungal aerosols using whole body inhalation have only recently been described. In this study, we aimed to characterize pulmonary immune responses following repeated inhalation of conidia utilizing an acoustical generator to deliver dry fungal aerosols to mice housed in a nose only exposure chamber. Immunocompetent female BALB/cJ mice were exposed to conidia derived from Aspergillus fumigatus wild-type (WT) or a melanin-deficient (Δalb1) strain. Conidia were aerosolized and delivered to mice at an estimated deposition dose of 1×105 twice a week for 4 weeks (8 total). Histopathological and immunological endpoints were assessed 4, 24, 48, and 72 hours after the final exposure. Histopathological analysis showed that conidia derived from both strains induced lung inflammation, especially at 24 and 48 hour time points. Immunological endpoints evaluated in bronchoalveolar lavage fluid (BALF) and the mediastinal lymph nodes showed that exposure to WT conidia led to elevated numbers of macrophages, granulocytes, and lymphocytes. Importantly, CD8+ IL17+ (Tc17) cells were significantly higher in BALF and positively correlated with germination of A. fumigatus WT spores. Germination was associated with specific IgG to intracellular proteins while Δalb1 spores elicited antibodies to cell wall hydrophobin. These data suggest that inhalation exposures may provide a more representative analysis of immune responses following exposures to environmentally and occupationally prevalent fungal contaminants. 相似文献
183.
Samantha E. Franks D. Ryan Norris T. Kurt Kyser Guillermo Fernández Birgit Schwarz Roberto Carmona Mark A. Colwell Jorge Correa Sandoval Alexey Dondua H. River Gates Ben Haase David J. Hodkinson Ariam Jiménez Richard B. Lanctot Brent Ortego Brett K. Sandercock Felicia Sanders John Y. Takekawa Nils Warnock Ron C. Ydenberg David B. Lank 《Journal of avian biology》2012,43(2):155-167
Understanding the population dynamics of migratory animals and predicting the consequences of environmental change requires knowing how populations are spatially connected between different periods of the annual cycle. We used stable isotopes to examine patterns of migratory connectivity across the range of the western sandpiper Calidris mauri. First, we developed a winter isotope basemap from stable‐hydrogen (δD), ‐carbon (δ13C), and ‐nitrogen (δ15N) isotopes of feathers grown in wintering areas. δD and δ15N values from wintering individuals varied with the latitude and longitude of capture location, while δ13C varied with longitude only. We then tested the ability of the basemap to assign known‐origin individuals. Sixty percent of wintering individuals were correctly assigned to their region of origin out of seven possible regions. Finally, we estimated the winter origins of breeding and migrant individuals and compared the resulting empirical distribution against the distribution that would be expected based on patterns of winter relative abundance. For breeding birds, the distribution of winter origins differed from expected only among males in the Yukon‐Kuskokwim (Y‐K) Delta and Nome, Alaska. Males in the Y‐K Delta originated overwhelmingly from western Mexico, while in Nome, there were fewer males from western North America and more from the Baja Peninsula than expected. An unexpectedly high proportion of migrants captured at a stopover site in the interior United States originated from eastern and southern wintering areas, while none originated from western North America. In general, we document substantial mixing between the breeding and wintering populations of both sexes, which will buffer the global population of western sandpipers from the effects of local habitat loss on both breeding and wintering grounds. 相似文献
184.
Nilüfer N. Turan Karni S. Moshal Karim Roder Brett C. Baggett Anatoli Y. Kabakov Saroj Dhakal Ryota Teramoto David Yi-Eng Chiang Mingwang Zhong An Xie Yichun Lu Samuel C. Dudley Jr. Calum A. MacRae Alain Karma Gideon Koren 《The Journal of biological chemistry》2020,295(52):18148
The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation. 相似文献
185.
Leigh‐Ann Woolley Hayley M. Geyle Brett P. Murphy Sarah M. Legge Russell Palmer Christopher R. Dickman John Augusteyn Sarah Comer Tim S. Doherty Charlie Eager Glenn Edwards Dan K.P. Harley Ian Leiper Peter J. McDonald Hugh W. McGregor Katherine E. Moseby Cecilia Myers John L. Read Joanna Riley Danielle Stokeld Jeff M. Turpin John C.Z. Woinarski 《Mammal Review》2019,49(4):354-368
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186.
Jyotsna L. Pandey Bo Wang Brett G. Diehl Tom L. Richard Gong Chen Charles T. Anderson 《PloS one》2015,10(4)
Lignin plays important structural and functional roles in plants by forming a hydrophobic matrix in secondary cell walls that enhances mechanical strength and resists microbial decay. While the importance of the lignin matrix is well documented and the biosynthetic pathways for monolignols are known, the process by which lignin precursors or monolignols are transported and polymerized to form this matrix remains a subject of considerable debate. In this study, we have synthesized and tested an analog of coniferyl alcohol that has been modified to contain an ethynyl group at the C-3 position. This modification enables fluorescent tagging and imaging of this molecule after its incorporation into plant tissue by click chemistry-assisted covalent labeling with a fluorescent azide dye, and confers a distinct Raman signature that could be used for Raman imaging. We found that this monolignol analog is incorporated into in vitro-polymerized dehydrogenation polymer (DHP) lignin and into root epidermal cell walls of 4-day-old Arabidopsis seedlings. Incorporation of the analog in stem sections of 6-week-old Arabidopsis thaliana plants and labeling with an Alexa-594 azide dye revealed the precise locations of new lignin polymerization. Results from this study indicate that this molecule can provide high-resolution localization of lignification during plant cell wall maturation and lignin matrix assembly. 相似文献
187.
Burkholderia mallei lipopolysaccharide (LPS) has been previously shown to cross-react with polyclonal antibodies raised against B. pseudomallei LPS; however, we observed that B. mallei LPS does not react with a monoclonal antibody (Pp-PS-W) specific for B. pseudomallei O polysaccharide (O-PS). In this study, we identified the O-PS biosynthetic gene cluster from B. mallei ATCC 23344 and subsequently characterized the molecular structure of the O-PS produced by this organism. 相似文献
188.
Garner B Mellor HR Butters TD Dwek RA Platt FM 《Biochemical and biophysical research communications》2002,290(5):1361-1367
Macrophages synthesize and secrete apolipoprotein E (apoE) constitutively. This process is upregulated under conditions of cholesterol loading. The response to cholesterol is antiatherogenic as it is believed to promote cholesterol efflux from the artery wall. The concentration of lactosyl ceramide (LacCer), a glycosphingolipid recently discovered to regulate cellular signaling, proliferation, and expression of adhesion molecules, is also increased in atherosclerotic tissues. Here we have investigated the effect of exogenous LacCer on macrophage apoE levels. We show that increasing macrophage LacCer levels sevenfold led to reductions in cellular and secreted apoE (15 and 30%, respectively, over a 24-h period) as determined by enzyme-linked immunosorbent assay. A similar effect was also induced by glucosyl ceramide (GlcCer) but not by ganglioside species. When macrophages were converted to cholesterol-loaded foam cells by incubation with acetylated LDL, the resulting increase in cellular apoE levels was inhibited by 26% when the cells were subsequently enriched with LacCer. After metabolic labeling of cellular glycosphingolipids with [14C]palmitate, we also discovered that high-density lipoprotein (HDL) stimulates the efflux of glycosphingolipids from foam cells. These data imply that LacCer and GlcCer may be proatherogenic due to the suppression of macrophage apoE production. Furthermore, the efflux of glycosphingolipids from macrophage foam cells to HDL could indicate a potential pathway for their removal from the artery wall and subsequent delivery to the liver. 相似文献
189.
190.
Aspects of metabolic regulation can be fruitfully studied with a combination of generic modelling, control analysis and graphical analysis using rate characteristics. This paper analyses a prototypical supply-demand system consisting of a biosynthetic subsystem subject to allosteric inhibition by its product and a demand process that consumes this product. The effect of changes in affinity of the committing supply enzyme for the pathway substrate on the regulatory properties of the supply subsystem is compared for the Monod-Wyman-Changeux and the reversible Hill allosteric enzyme models. We found that the Hill model has a distinct advantage in that the steady-state concentration at which it maintains the product is set by the half-saturating product concentration and is independent of changes in the degree of saturation for substrate. In contrast, with the Monod-Wyman-Changeux model this set point varies with affinity for substrate. Explicitly incorporating reversibility in all rate equations made it possible to distinguish between kinetic and thermodynamic aspects of regulation. Combining the supply and demand rate characteristics allows us to explore both the control distribution at steady state and the regulatory performance of the system over a wide range of demand activities. 相似文献