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211.
cAMP analogs and activation of adenylyl cyclase by forskolin strongly potentiate synaptic transmission at the Drosophila neuromuscular junction. These effects are generally attributed to activation of cAMP‐dependent protein kinase. Recent reports on crustacean and mammalian synapses have implicated other cAMP‐dependent effectors in synaptic potentiation. Drosophila neuromuscular junctions were tested for effects of two known cAMP‐dependent effectors: hyperpolarization‐activated, cyclic nucleotide‐regulated channels (HCNCs) and guanine nucleotide exchange protein activated by cAMP (Epac). Forskolin‐induced enhancement of synaptic transmission was drastically reduced by a blocker of HCNCs, but not completely eliminated. A specific agonist for Epac modestly enhanced synaptic potentials. This agonist also stabilized their amplitudes in the presence of a blocker of HCNCs. The observations implicate HCNCs and Epac in cAMP‐dependent potentiation that does not require cAMP‐dependent protein kinase, indicating that additional previously unexplored factors contribute to synaptic plasticity in Drosophila. Genetic and molecular techniques available for Drosophila can be used to define the underlying molecular basis for cAMP‐dependent synaptic potentiation. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 相似文献
212.
JC virus (JCV) and BK virus (BKV) are human polyomaviruses that infect approximately 85% of the population worldwide [1,2].
JCV is the underlying cause of the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML), a condition
resulting from JCV induced lytic destruction of myelin producing oligodendrocytes in the brain [3]. BKV infection of kidneys
in renal transplant recipients results in a gradual loss of graft function known as polyomavirus associated nephropathy (PVN)
[4]. Following the identification of these viruses as the etiological agents of disease, there has been greater interest in
understanding the basic biology of these human pathogens [5,6]. Recent advances in the field have shown that viral entry of
both JCV and BKV is dependent on the ability to interact with sialic acid. This review focuses on what is known about the
human polyomaviruses and the role that sialic acid plays in determining viral tropism. 相似文献
213.
Wilson AC Clemente L Liu T Bowen RL Meethal SV Atwood CS 《Biochimica et biophysica acta》2008,1782(6):401-407
Reproductive hormones have been demonstrated to modulate both gap and tight junction protein expression in the ovary and other reproductive tissues, however the effects of changes in reproductive hormones on the selective permeability of the blood-brain barrier (BBB) remain unclear. Age-related declines in BBB integrity correlate with the loss of serum sex steroids and increase in gonadotropins with menopause/andropause. To examine the effect of reproductive senescence on BBB permeability and gap and tight junction protein expression/localization, female mice at 3 months of age were either sham operated (normal serum E2 and gonadotropins), ovariectomized (low serum E2 and high serum gonadotropins) or ovariectomized and treated with the GnRH agonist leuprolide acetate (low serum E2 and gonadotropins). Ovariectomy induced a 2.2-fold increase in Evan's blue dye extravasation into the brain. The expression and localization of the cytoplasmic membrane-associated tight junction protein zona occludens 1 (ZO-1) in microvessels was not altered among groups indicating that the increased paracellular permeability was not due to changes in this tight junction protein. However, ovariectomy induced a redistribution of the gap junction protein connexin-43 (Cx43) such that immunoreactivity relocalized from along the extracellular microvascular endothelium to become associated with endothelial cells. An increase in Cx43 expression in the mouse brain following ovariectomy was suppressed in ovariectomized animals treated with leuprolide acetate, indicating that serum gonadotropins rather than sex steroids were modulating Cx43 expression. These results suggest that elevated serum gonadotropins following reproductive senescence may be one possible cause of the loss of selective permeability of the BBB at this time. Furthermore, these findings implicate Cx43 in mediating changes in BBB permeability, and serum gonadotropins in the cerebropathophysiology of age-related neurodegenerative diseases such as stroke and Alzheimer's disease. 相似文献
214.
A. Todd Richmond Justin Atwood John Bream Corey H. Mjaatvedt Stanley Hoffman Anthony A. Capehart 《Cytotechnology》2004,46(2-3):173-182
Lateral plate mesoderm is native to the developing limb while other cells such as neurons extend migratory axonal processes
from the neural tube. Questions regarding how axons migrate to their proper location in the developing limb remain unanswered.
Extracellular matrix molecules expressed in developing limb cartilages, such as the versican proteoglycan, may function as
inhibitory cues to nerve migration, thus facilitating its proper patterning. In the present study, a method is described for
co-culture of neural tissue with high density micromass preparations of mouse limb mesenchyme in order to investigate neurite
patterning during limb chondrogenesis in vitro. Comparison of hdf (heart defect) mouse limb mesenchyme, which bears an insertional mutation in the versican proteoglycan core protein, with
wild type demonstrated that the described technique provides a useful method for transgenic analysis in studies of chondrogenic
regulation of neurite patterning. Differentiating wild type limb mesenchyme expressed cartilage characteristic Type II collagen
and versican at 1 day and exhibited numerous well defined cartilage foci by 3 days. Wild type neurites extended into central
regions of host cultures between 3 and 6 days and consistently avoided versican positive chondrogenic aggregates. Wild type
neural tubes cultured with hdf limb mesenchyme, which does not undergo cartilage differentiation in a wild type pattern, showed that axons exhibited no
avoidance characteristics within the host culture. Results suggest that differentiating limb cartilages may limit migration
of axons thus aiding in the ultimate patterning of peripheral nerve in the developing limb. 相似文献
215.
Bioethics, the term now usually standing in for Biomedical Ethics, is a field of medical anthropological engagement. While many anthropologists and other social scientists work with bioethicists and physicians, this paper instead takes Bioethics as a topic of cultural research from the perspective of Cultural Bioethics and Interpretive Medical Anthropology. Application of useful findings of vintage anthropological research in cultural anthropology and the anthropology of religion and an interpretive lens reveal a field without a single origin or unified methodology. The paper suggests the appropriateness of a literal meaning of current conceptual commonality of the term Bioethics: that the term does in fact refer to a plurality of distinct enterprises with distinct origins and, hence, justifications. 相似文献
216.
Dugan AS Maginnis MS Jordan JA Gasparovic ML Manley K Page R Williams G Porter E O'Hara BA Atwood WJ 《The Journal of biological chemistry》2008,283(45):31125-31132
BK virus (BKV) is a polyomavirus that establishes a lifelong persistence in most humans and is a major impediment to success of kidney grafts. The function of the innate immune system in BKV infection and pathology has not been investigated. Here we examine the role of antimicrobial defensins in BKV infection of Vero cells. Our data show that alpha-defensin human neutrophil protein 1 (HNP1) and human alpha-defensin 5 (HD5) inhibit BKV infection by targeting an early event in the viral lifecycle. HD5 treatment of BKV reduced viral attachment to cells, whereas cellular treatment with HD5 did not. Colocalization studies indicated that HD5 interacts directly with BKV. Ultrastructural analysis revealed HD5-induced aggregation of virions. HD5 also inhibited infection of cells by other related polyomaviruses. This is the first study to demonstrate polyomavirus sensitivity to defensins. We also show a novel mechanism whereby HD5 binds to BKV leading to aggregation of virion particles preventing normal virus binding to the cell surface and uptake into cells. 相似文献
217.
Friedland RP Tedesco JM Wilson AC Atwood CS Smith MA Perry G Zagorski MG 《The Journal of biological chemistry》2008,283(33):22550-22556
Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid beta (Abeta) protein or passive immunization with anti-Abeta antibodies has beneficial effects on the development of disease. Although a trial of Abeta vaccination in humans was halted because of autoimmune meningoencephalitis, favorable effects on Abeta deposition in the brain and on behavior were seen. Conflicting results have been observed concerning the relationship of circulating anti-Abeta antibodies and AD. Although these autoantibodies are thought to arise from exposure to Abeta, it is also possible that homologous proteins may induce antibody synthesis. We propose that the long-standing presence of anti-Abeta antibodies or antibodies to immunogens homologous to the Abeta protein may produce protective effects. The amino acid sequence of the potato virus Y (PVY) nuclear inclusion b protein is highly homologous to the immunogenic N-terminal region of Abeta. PVY infects potatoes and related crops worldwide. Here, we show through immunocytochemistry, enzyme-linked immunosorbent assay, and NMR studies that mice inoculated with PVY develop antibodies that bind to Abeta in both neuritic plaques and neurofibrillary tangles, whereas antibodies to material from uninfected potato leaf show only modest levels of background immunoreactivity. NMR data show that the anti-PVY antibody binds to Abeta within the Phe4-Ser8 and His13-Leu17 regions. Immune responses generated from dietary exposure to proteins homologous to Abeta may induce antibodies that could influence the normal physiological processing of the protein and the development or progression of AD. 相似文献
218.
Atwood CS Scarpa RC Huang X Moir RD Jones WD Fairlie DP Tanzi RE Bush AI 《Journal of neurochemistry》2000,75(3):1219-1233
Cu and Zn have been shown to accumulate in the brains of Alzheimer's disease patients. We have previously reported that Cu(2+) and Zn(2+) bind amyloid beta (Abeta), explaining their enrichment in plaque pathology. Here we detail the stoichiometries and binding affinities of multiple cooperative Cu(2+)-binding sites on synthetic Abeta1-40 and Abeta1-42. We have developed a ligand displacement technique (competitive metal capture analysis) that uses metal-chelator complexes to evaluate metal ion binding to Abeta, a notoriously self-aggregating peptide. This analysis indicated that there is a very-high-affinity Cu(2+)-binding site on Abeta1-42 (log K(app) = 17.2) that mediates peptide precipitation and that the tendency of this peptide to self-aggregate in aqueous solutions is due to the presence of trace Cu(2+) contamination (customarily approximately 0.1 microM). In contrast, Abeta1-40 has much lower affinity for Cu(2+) at this site (estimated log K(app) = 10.3), explaining why this peptide is less self-aggregating. The greater Cu(2+)-binding affinity of Abeta1-42 compared with Abeta1-40 is associated with significantly diminished negative cooperativity. The role of trace metal contamination in inducing Abeta precipitation was confirmed by the demonstration that Abeta peptide (10 microM) remained soluble for 5 days only in the presence of high-affinity Cu(2+)-selective chelators. 相似文献
219.
A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study 总被引:5,自引:0,他引:5
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Li JL Hayden MR Almqvist EW Brinkman RR Durr A Dodé C Morrison PJ Suchowersky O Ross CA Margolis RL Rosenblatt A Gómez-Tortosa E Cabrero DM Novelletto A Frontali M Nance M Trent RJ McCusker E Jones R Paulsen JS Harrison M Zanko A Abramson RK Russ AL Knowlton B Djoussé L Mysore JS Tariot S Gusella MF Wheeler VC Atwood LD Cupples LA Saint-Hilaire M Cha JH Hersch SM Koroshetz WJ Gusella JF MacDonald ME Myers RH 《American journal of human genetics》2003,73(3):682-687
Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21–23 (LOD=2.29), and 6q24–26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD. 相似文献
220.
Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence 总被引:17,自引:0,他引:17
Dong J Atwood CS Anderson VE Siedlak SL Smith MA Perry G Carey PR 《Biochemistry》2003,42(10):2768-2773
Alzheimer's disease (AD) is characterized by the deposition of amyloid plaques in the parenchyma and vasculature of the brain. Although previous analytical studies have provided much information about the composition and structure of synthetic amyloid-beta fibrils, there is, surprisingly, a dearth of data on intact amyloid plaques from AD brain. Therefore, to elucidate the structure and detailed composition of isolated amyloid plaque cores, we utilized a high-resolution, nondestructive technique, Raman microscopy. The data are of very high quality and contain detailed information about protein composition and conformation, about post-translational modification, and about the chemistry of metal binding sites. Remarkably, spectra obtained for senile plaque (SP) cores isolated from AD brain are essentially identical both within and among brains. The Raman data show for the first time that the SP cores are composed largely of amyloid-beta and confirm inferences from X-ray studies that the structure is beta-sheet with the additional possibility that this may be present as a parallel beta-helix. Raman bands characteristic of methionine sulfoxide show that extensive methionine oxidation has occurred in the intact plaques. The Raman spectra also demonstrate that Zn(II) and Cu(II) are coordinated to histidine residues in the SP cores, at the side chains' N(tau) and N(pi) atoms, respectively. Treatment of the senile plaques with the chelator ethylenediaminetetraacetate reverses Cu binding to SP histidines and leads to a broadening of amide features, indicating a "loosening" of the beta-structure. Our results indicate that Abeta in vivo is a metalloprotein, and the loosening of the structure following chelation treatment suggests a possible means for the solubilization of amyloid deposits. The results also reveal a direct chemical basis for oxidative damage caused by amyloid-beta protein in AD. 相似文献