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991.
For more than half a century, researchers have studied the basic biology of Adenovirus (Ad), unraveling the subtle, yet profound, interactions between the virus and the host. These studies have uncovered previously unknown proteins and pathways crucial for normal cell function that the virus manipulates to achieve optimal virus replication and gene expression. In the infecting virion, the viral DNA is tightly condensed in a virally encoded protamine-like protein which must be remodeled within the first few hours of infection to allow for efficient expression of virus-encoded genes and subsequent viral DNA replication. This review discusses our current knowledge of Ad DNA-protein complex within the infected cell nucleus, the cellular proteins the virus utilizes to achieve chromatinization, and how this event contributes to efficient gene expression and progression of the virus life cycle. 相似文献
992.
A Gdalyahu E Tring PO Polack R Gruver P Golshani MS Fanselow AJ Silva JT Trachtenberg 《Neuron》2012,75(1):121-132
Several models of associative learning predict that stimulus processing changes during association formation. How associative learning reconfigures neural circuits in primary sensory cortex to "learn" associative attributes of a stimulus remains unknown. Using 2-photon in vivo calcium imaging to measure responses of networks of neurons in primary somatosensory cortex, we discovered that associative fear learning, in which whisker stimulation is paired with foot shock, enhances sparse population coding and robustness of the conditional stimulus, yet decreases total network activity. Fewer cortical neurons responded to stimulation of the trained whisker than in controls, yet their response strength was enhanced. These responses were not observed in mice exposed to a nonassociative learning procedure. Our results define how the cortical representation of a sensory stimulus is shaped by associative fear learning. These changes are proposed to enhance efficient sensory processing after associative learning. 相似文献
993.
A mandatory requirement for any reliable prediction of the mechanical response of bones, based on quantitative computer tomography, is an accurate relationship between material properties (usually Young's modulus E) and bone density ρ. Many such E-ρ relationships are available based on different experiments on femur specimens with a large spread due to uncertainties. The first goal of this study is to pool and analyze the relevant available experimental data and develop a stochasticE-ρ relationship. This analysis highlights that there is no experimental data available to cover the entire density range of the human femur and that some "popular" E-ρ relationships are based on data that contains extreme scatter, while others are based on a very limited amount of information. The second goal is to use the newly developed stochastic E-ρ relationship in high-order finite element analyses (FEAs) for the computation of strains and displacements in two human proximal femurs, mimicking in vitro experiments. When compared with the experimental observations, the FEA predictions using the median of the stochastic E-ρ relationship follow the underlying distribution of the stochastic E-ρ relationship. Thus, most deviations of the FEA predictions from experimental observations can possibly be explained by uncertain elastic properties of the femur. 相似文献
994.
Haberman A Williamson WR Epstein D Wang D Rina S Meinertzhagen IA Hiesinger PR 《The Journal of cell biology》2012,196(2):261-276
Soluble NSF attachment protein receptors (SNAREs) are the core proteins in membrane fusion. The neuron-specific synaptic v-SNARE n-syb (neuronal Synaptobrevin) plays a key role during synaptic vesicle exocytosis. In this paper, we report that loss of n-syb caused slow neurodegeneration independent of its role in neurotransmitter release in adult Drosophila melanogaster photoreceptor neurons. In addition to synaptic vesicles, n-Syb localized to endosomal vesicles. Loss of n-syb lead to endosomal accumulations, transmembrane protein degradation defects, and a secondary increase in autophagy. Our evidence suggests a primary defect of impaired delivery of vesicles that contain degradation proteins, including the acidification-activated Cathepsin proteases and the neuron-specific proton pump and V0 adenosine triphosphatase component V100. Overexpressing V100 partially rescued n-syb-dependent degeneration through an acidification-independent endosomal sorting mechanism. Collectively, these findings reveal a role for n-Syb in a neuron-specific sort-and-degrade mechanism that protects neurons from degeneration. Our findings further shed light on which intraneuronal compartments exhibit increased or decreased neurotoxicity. 相似文献
995.
Benet M Dulman RY Suzme R de Miera EV Vega ME Nguyen T Zavadil J Pellicer A 《Journal of cellular physiology》2012,227(6):2341-2351
Previously, we have shown that wild type N-ras (wt N-ras) harbors an anti-malignant effect against mutated Ras and in tumors without Ras mutations. To investigate the molecular bases of this anti-malignant activity, we have studied the potency of this anti-malignant effect in a model system against SV40 large T antigen (SV40T). We show that wild-type N-ras (wt N-ras) counteracts the effects of SV40T in NIH3T3 cells as seen by a decrease in proliferation, anchorage independence and changes in migration. We also show that wt N-ras elicits the same anti-malignant effects in some human tumor cell lines (HT1080 and MDA-MB-231). Through mRNA and microRNA (miRNAs) expression profiling we have identified genes (decorin) and miRNAs (mir-29A, let-7b) modulated by wt N-ras potentially responsible for the anti-malignant effect. Wt N-ras appears to mediate its anti-malignant effect by downregulating some of the targets of the TGFβ pathway and decorin, which are able to reverse the inhibition of migration induced by wt N-ras. Our experiments show that the molecules that mediate the anti-malignant effect by wt N-ras appear to be different from those modulated by transforming N-ras. The components of the pathways modulated by wt N-ras mediating its anti-malignant effects are potential targets for therapeutic intervention in cancer. 相似文献
996.
Elastic conformational changes of the protein backbone are essential for catalytic activities of enzymes. To follow relative movements within the protein, F?rster-type resonance energy transfer (FRET) between two specifically attached fluorophores can be applied. FRET provides a precise ruler between 3 and 8nm with subnanometer resolution. Corresponding submillisecond time resolution is sufficient to identify conformational changes in FRET time trajectories. Analyzing single enzymes circumvents the need for synchronization of various conformations. F(O)F(1)-ATP synthase is a rotary double motor which catalyzes the synthesis of adenosine triphosphate (ATP). A proton-driven 10-stepped rotary F(O) motor in the Escherichia coli enzyme is connected to a 3-stepped F(1) motor, where ATP is synthesized. To operate the double motor with a mismatch of step sizes smoothly, elastic deformations within the rotor parts have been proposed by W. Junge and coworkers. Here we extend a single-molecule FRET approach to observe both rotary motors simultaneously in individual F(O)F(1)-ATP synthases at work. We labeled this enzyme with two fluorophores specifically, that is, on the ε- and c-subunits of the two rotors. Alternating laser excitation was used to select the FRET-labeled enzymes. FRET changes indicated associated transient twisting within the rotors of single enzyme molecules during ATP hydrolysis and ATP synthesis. Supported by Monte Carlo simulations of the FRET experiments, these studies reveal that the rotor twisting is greater than 36° and is largely suppressed in the presence of the rotation inhibitor DCCD. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). 相似文献
997.
Fournier B Andargachew R Robin AZ Laur O Voelker DR Lee WY Weber D Parkos CA 《The Journal of biological chemistry》2012,287(23):19386-19398
Signal regulatory protein α (SIRPα), a highly glycosylated type-1 transmembrane protein, is composed of three immunoglobulin-like extracellular loops as well as a cytoplasmic tail containing three classical tyrosine-based inhibitory motifs. Previous reports indicate that SIRPα binds to humoral pattern recognition molecules in the collectin family, namely surfactant proteins D and A (Sp-D and Sp-A, respectively), which are heavily expressed in the lung and constitute one of the first lines of innate immune defense against pathogens. However, little is known about molecular details of the structural interaction of Sp-D with SIRPs. In the present work, we examined the molecular basis of Sp-D binding to SIRPα using domain-deleted mutant proteins. We report that Sp-D binds to the membrane-proximal Ig domain (D3) of SIRPα in a calcium- and carbohydrate-dependent manner. Mutation of predicted N-glycosylation sites on SIRPα indicates that Sp-D binding is dependent on interactions with specific N-glycosylated residues on the membrane-proximal D3 domain of SIRPα. Given the remarkable sequence similarity of SIRPα to SIRPβ and the lack of known ligands for the latter, we examined Sp-D binding to SIRPβ. Here, we report specific binding of Sp-D to the membrane-proximal D3 domain of SIRPβ. Further studies confirmed that Sp-D binds to SIRPα expressed on human neutrophils and differentiated neutrophil-like cells. Because the other known ligand of SIRPα, CD47, binds to the membrane-distal domain D1, these findings indicate that multiple, distinct, functional ligand binding sites are present on SIRPα that may afford differential regulation of receptor function. 相似文献
998.
The number of neurons in the geniculate ganglion that are available to innervate taste buds is regulated by neurotrophin-4 (NT-4) and brain-derived neurotrophic factor (BDNF). Our goal for the current study was to examine the timing and mechanism of NT-4-mediated regulation of geniculate neuron number during development. We discovered that NT-4 mutant mice lose 33% of their geniculate neuronal cells between E10.5 and E11.5. By E11.5, geniculate axons have just reached the tongue and do not yet innervate their gustatory targets; thus, NT-4 does not function as a target-derived growth factor. At E11.5, no difference was observed in proliferating cells or the rate at which cells exit the cell cycle between NT-4 mutant and wild type ganglia. Instead, there was an increase in TUNEL-labeling, indicating an increase in cell death in Ntf4(-/-) mice compared with wild types. However, activated caspase-3, which is up-regulated in the absence of BDNF, was not increased. This finding indicates that cell death initiated by NT-4-removal occurs through a different cell death pathway than BDNF-removal. We observed no additional postnatal loss of taste buds or neurons in Ntf4(-/-) mice. Thus, during early embryonic development, NT-4 produced in the ganglion and along the projection pathway inhibits cell death through an activated caspase-3 independent mechanism. Therefore, compared to BDNF, NT-4 plays distinct roles in gustatory development; differences include timing, source of neurotrophin, and mechanism of action. 相似文献
999.
Michael E. Talkowski Gilles Maussion Liam Crapper Jill A. Rosenfeld Ian Blumenthal Carrie Hanscom Colby Chiang Amelia Lindgren Shahrin Pereira Douglas Ruderfer Alpha B. Diallo Juan Pablo Lopez Gustavo Turecki Elizabeth S. Chen Carolina Gigek David J. Harris Va Lip Yu An Marta Biagioli Marcy E. MacDonald Michael Lin Stephen J. Haggarty Pamela Sklar Shaun Purcell Manolis Kellis Stuart Schwartz Lisa G. Shaffer Marvin R. Natowicz Yiping Shen Cynthia C. Morton James F. Gusella Carl Ernst 《American journal of human genetics》2012
1000.
Nack M Radu I Schultz BJ Resler T Schlesinger R Bondar AN del Val C Abbruzzetti S Viappiani C Bamann C Bamberg E Heberle J 《FEBS letters》2012,586(9):1344-1348
Electrophysiological experiments showed that the light-activated cation channel channelrhodopsin-2 (ChR2) pumps protons in the absence of a membrane potential. We determined here the kinetics of transient pH change using a water-soluble pH-indicator. It is shown that ChR2 released protons prior to uptake with a stoichiometry of 0.3 protons per ChR2. Comparison to the photocycle kinetics revealed that proton release and uptake match rise and decay of the P(3)(520) intermediate. As the P(3)(520) state also represents the conductive state of cation channeling, the concurrence of proton pumping and channel gating implies an intimate mechanistic link of the two functional modes. Studies on the E123T and S245E mutants show that these residues are not critically involved in proton translocation. 相似文献