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121.
Hansen SG Ford JC Lewis MS Ventura AB Hughes CM Coyne-Johnson L Whizin N Oswald K Shoemaker R Swanson T Legasse AW Chiuchiolo MJ Parks CL Axthelm MK Nelson JA Jarvis MA Piatak M Lifson JD Picker LJ 《Nature》2011,473(7348):523-527
The acquired immunodeficiency syndrome (AIDS)-causing lentiviruses human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) effectively evade host immunity and, once established, infections with these viruses are only rarely controlled by immunological mechanisms. However, the initial establishment of infection in the first few days after mucosal exposure, before viral dissemination and massive replication, may be more vulnerable to immune control. Here we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors establish indefinitely persistent, high-frequency, SIV-specific effector memory T-cell (T(EM)) responses at potential sites of SIV replication in rhesus macaques and stringently control highly pathogenic SIV(MAC239) infection early after mucosal challenge. Thirteen of twenty-four rhesus macaques receiving either RhCMV vectors alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors (versus 0 of 9 DNA/Ad5-vaccinated rhesus macaques) manifested early complete control of SIV (undetectable plasma virus), and in twelve of these thirteen animals we observed long-term (≥1 year) protection. This was characterized by: occasional blips of plasma viraemia that ultimately waned; predominantly undetectable cell-associated viral load in blood and lymph node mononuclear cells; no depletion of effector-site CD4(+) memory T cells; no induction or boosting of SIV Env-specific antibodies; and induction and then loss of T-cell responses to an SIV protein (Vif) not included in the RhCMV vectors. Protection correlated with the magnitude of the peak SIV-specific CD8(+) T-cell responses in the vaccine phase, and occurred without anamnestic T-cell responses. Remarkably, long-term RhCMV vector-associated SIV control was insensitive to either CD8(+) or CD4(+) lymphocyte depletion and, at necropsy, cell-associated SIV was only occasionally measurable at the limit of detection with ultrasensitive assays, observations that indicate the possibility of eventual viral clearance. Thus, persistent vectors such as CMV and their associated T(EM) responses might significantly contribute to an efficacious HIV/AIDS vaccine. 相似文献
122.
Thakur JK Arthanari H Yang F Pan SJ Fan X Breger J Frueh DP Gulshan K Li DK Mylonakis E Struhl K Moye-Rowley WS Cormack BP Wagner G Näär AM 《Nature》2008,452(7187):604-609
123.
Fünfschilling U Supplie LM Mahad D Boretius S Saab AS Edgar J Brinkmann BG Kassmann CM Tzvetanova ID Möbius W Diaz F Meijer D Suter U Hamprecht B Sereda MW Moraes CT Frahm J Goebbels S Nave KA 《Nature》2012,485(7399):517-521
Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function. 相似文献
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Clathrin self-assembly is mediated by a tandemly repeated superhelix. 总被引:12,自引:0,他引:12
J A Ybe F M Brodsky K Hofmann K Lin S H Liu L Chen T N Earnest R J Fletterick P K Hwang 《Nature》1999,399(6734):371-375
Clathrin is a triskelion-shaped cytoplasmic protein that polymerizes into a polyhedral lattice on intracellular membranes to form protein-coated membrane vesicles. Lattice formation induces the sorting of membrane proteins during endocytosis and organelle biogenesis by interacting with membrane-associated adaptor molecules. The clathrin triskelion is a trimer of heavy-chain subunits (1,675 residues), each binding a single light-chain subunit, in the hub domain (residues 1,074-1,675). Light chains negatively modulate polymerization so that intracellular clathrin assembly is adaptor-dependent. Here we report the atomic structure, to 2.6 A resolution, of hub residues 1,210-1,516 involved in mediating spontaneous clathrin heavy-chain polymerization and light-chain association. The hub fragment folds into an elongated coil of alpha-helices, and alignment analyses reveal a 145-residue motif that is repeated seven times along the filamentous leg and appears in other proteins involved in vacuolar protein sorting. The resulting model provides a three-dimensional framework for understanding clathrin heavy-chain self-assembly, light-chain binding and trimerization. 相似文献
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The majority of earthquakes are aftershocks, yet aftershock physics is not well understood. Many studies suggest that static stress changes trigger aftershocks, but recent work suggests that shaking (dynamic stresses) may also play a role. Here we measure the decay of aftershocks as a function of distance from magnitude 2-6 mainshocks in order to clarify the aftershock triggering process. We find that for short times after the mainshock, when low background seismicity rates allow for good aftershock detection, the decay is well fitted by a single inverse power law over distances of 0.2-50 km. The consistency of the trend indicates that the same triggering mechanism is working over the entire range. As static stress changes at the more distant aftershocks are negligible, this suggests that dynamic stresses may be triggering all of these aftershocks. We infer that the observed aftershock density is consistent with the probability of triggering aftershocks being nearly proportional to seismic wave amplitude. The data are not fitted well by models that combine static stress change with the evolution of frictionally locked faults. 相似文献