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71.
Kathryn A. Jewett Ruth E. Thomas Chi Q. Phan Bernice Lin Gillian Milstein Selina Yu Lisa F. Bettcher Fausto Carnevale Neto Danijel Djukovic Daniel Raftery Leo J. Pallanck Marie Y. Davis 《PLoS genetics》2021,17(2)
Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson’s disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in glucosidase, beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression. To explore how GBA mutations influence pathogenesis, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. Accordingly, we hypothesized that GBA may influence pathogenic protein aggregate spread via EVs. We found that accumulation of ubiquitinated proteins and Ref(2)P, Drosophila homologue of mammalian p62, were reduced in muscle and brain tissue of Gba1b flies by ectopic expression of wildtype GCase in muscle. Neuronal GCase expression also rescued protein aggregation both cell-autonomously in brain and non-cell-autonomously in muscle. Muscle-specific GBA expression reduced the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Perturbing EV biogenesis through neutral sphingomyelinase (nSMase), an enzyme important for EV release and ceramide metabolism, enhanced protein aggregation when knocked down in muscle, but did not modify Gba1b mutant protein aggregation when knocked down in neurons. Lipidomic analysis of nSMase knockdown on ceramide and glucosylceramide levels suggested that Gba1b mutant protein aggregation may depend on relative depletion of specific ceramide species often enriched in EVs. Finally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency promotes accelerated protein aggregate spread between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread. 相似文献
72.
Two types of membrane particles, both binding α-[125I]bungarotoxin, were obtained from electric tissue of Electrophorus electricus. They were both separated from acetyleholinesterase-containing particle by centrifugation in sucrose density gradients. The differing properties of the bungarotoxin-binding particles suggest that they may represent synaptic and extrasynaptic membrane structures containing acetylcholine receptors. 相似文献
73.
Current information on the structure and function of motile tubular vacuoles in Pisolithus tinctorius and other fungi is reviewed. The use of fluorochromes to label the vacuole lumen is evaluated and observations on the structure and motility of vacuoles in P. tinctorius are differentiated from possible artifacts. The styryl dyes FM4-64 and MDY-64, used in yeast to demonstrate endocytosis, show little or no labeling of internal membranes in undamaged P. tinctorius cells. This agrees with our data showing that other probes for endocytosis such as Lucifer yellow CH are not taken up by hyphal tip cells. Overall, the observations do not support endocytosis in hyphal tips. It has been suggested that tubular vacuole systems carry out longitudinal transport, and evidence in favor of this hypothesis is evaluated. New data are presented to show that many of the large vacuoles in subapical cells are attached to the plasma membrane and are relatively immobile, while video sequences show movement of fluorochrome in pulses along a series of several large vacuoles, all interconnected via tubules. Tubular vacuoles from thick sections of hyphae processed under anhydrous conditions are shown by X-ray microanalysis to contain relatively high levels of P and K, as seen previously in the larger vacuoles. These results provide further evidence for a role of the tubular vacuoles in longitudinal transport of P. Copyright 1998 Academic Press. 相似文献
74.
Membrane preparations containing essentially only the four polypeptides considered to constitute the acetylcholine receptor are purified from electroplax. Treatment of these membranes with 2% ( aqueous sodium cholate followed by removal of all insoluble matter results in a solubilized purified receptor preparation that can be reassociated with phospholipids during dialysis to remove the detergent. Such reconstituted receptor is shown to retain the capability of translocating 22Na+ across the membrane in response to carbamylcholine binding in a highly reproducible manner. The dose response for this effect is similar to that observed for the original electroplax membrane preparation and the carbamylcholine induced signal is completely blocked by α-bungarotoxin. 相似文献
75.
Harrison CA Raftery MJ Walsh J Alewood P Iismaa SE Thliveris S Geczy CL 《The Journal of biological chemistry》1999,274(13):8561-8569
The myeloid cell-derived calcium-binding murine protein, S100A8, is secreted to act as a chemotactic factor at picomolar concentrations, stimulating recruitment of myeloid cells to inflammatory sites. S100A8 may be exposed to oxygen metabolites, particularly hypochlorite, the major oxidant generated by activated neutrophils at inflammatory sites. Here we show that hypochlorite oxidizes the single Cys residue (Cys41) of S100A8. Electrospray mass spectrometry and SDS-polyacrylamide gel electrophoresis analysis indicated that low concentrations of hypochlorite (40 microM) converted 70-80% of S100A8 to the disulfide-linked homodimer. The mass was 20,707 Da, 92 Da more than expected, indicating additional oxidation of susceptible amino acids (possibly methionine). Phorbol 12-myristate 13-acetate activation of differentiated HL-60 granulocytic cells generated an oxidative burst that was sufficient to efficiently oxidize exogenous S100A8 within 10 min, and results implicate involvement of the myeloperoxidase system. Moreover, disulfide-linked dimer was identified in lung lavage fluid of mice with endotoxin-induced pulmonary injury. S100A8 dimer was inactive in chemotaxis and failed to recruit leukocytes in vivo. Positive chemotactic activity of recombinant Ala41S100A8 indicated that Cys41 was not essential for function and suggested that covalent dimerization may structurally modify accessibility of the chemotactic hinge domain. Disulfide-dependent dimerization may be a physiologically significant regulatory mechanism controlling S100A8-provoked leukocyte recruitment. 相似文献
76.
Bone morphogenetic proteins (BMP) direct dorsal–ventral patterning in both invertebrate and vertebrate embryos, with strong evolutionary conservation of molecular components of the pathway. Dorsal–ventral patterning of the early Drosophila embryo is a powerful experimental system to probe mechanisms of BMP gradient formation and interpretation. Recent studies have found that spatial patterns of activated BMP signal transducers in Drosophila go through an unexpected transition: a shallow gradient of weak responses at mid-cellularization changes to a step gradient of stronger responses in cellularized embryos. The transition between two gradients of different shape yields new insights into the progression of Drosophila dorsal–ventral patterning and raises new issues about the mechanisms of gradient formation. 相似文献
77.
Differential antiviral response of endothelial cells after infection with pathogenic and nonpathogenic hantaviruses 总被引:9,自引:0,他引:9
Kraus AA Raftery MJ Giese T Ulrich R Zawatzky R Hippenstiel S Suttorp N Krüger DH Schönrich G 《Journal of virology》2004,78(12):6143-6150
Hantaviruses represent important human pathogens and can induce hemorrhagic fever with renal syndrome (HFRS), which is characterized by endothelial dysfunction. Both pathogenic and nonpathogenic hantaviruses replicate without causing any apparent cytopathic effect, suggesting that immunopathological mechanisms play an important role in pathogenesis. We compared the antiviral responses triggered by Hantaan virus (HTNV), a pathogenic hantavirus associated with HFRS, and Tula virus (TULV), a rather nonpathogenic hantavirus, in human umbilical vein endothelial cells (HUVECs). Both HTNV- and TULV-infected cells showed increased levels of molecules involved in antigen presentation. However, TULV-infected HUVECs upregulated HLA class I molecules more rapidly. Interestingly, HTNV clearly induced the production of beta interferon (IFN-beta), whereas expression of this cytokine was barely detectable in the supernatant or in extracts from TULV-infected HUVECs. Nevertheless, the upregulation of HLA class I on both TULV- and HTNV-infected cells could be blocked by neutralizing anti-IFN-beta antibodies. Most strikingly, the antiviral MxA protein, which interferes with hantavirus replication, was already induced 16 h after infection with TULV. In contrast, HTNV-infected HUVECs showed no expression of MxA until 48 h postinfection. In accordance with the kinetics of MxA expression, TULV replicated only inefficiently in HUVECs, whereas HTNV-infected cells produced high titers of virus particles that decreased after 48 h postinfection. Both hantavirus species, however, could replicate equally well in Vero E6 cells, which lack an IFN-induced MxA response. Thus, delayed induction of antiviral MxA in endothelial cells after infection with HTNV could allow viral dissemination and contribute to the pathogenesis leading to HFRS. 相似文献
78.
Pig to human xenotransplantation is considered a possible solution to the
prevailing chronic lack of human donor organs for allotransplantation. The
Galalpha1,3Gal determinant is the major porcine xenogeneic epitope causing
hyperacute rejection following human antibody binding and complement
activation. In order to characterize the tissue distribution of
Galalpha1,3Gal-containing and blood group- type glycosphingolipids in pig,
acid and nonacid glycosphingolipids were isolated from the kidney, small
intestine, spleen, salivary gland, liver, and heart of a single pig
obtained from a semi-inbred strain homozygous at the SLA locus. Glycolipids
were analyzed by thin-layer immunostaining using monoclonal antibodies, and
following ceramide glycanase cleavage as permethylated oligosaccharides by
gas chromatography, gas chromatography-mass spectrometry, and matrix-
assisted laser desorption/ionization mass spectrometry. The kidney
contained large amounts of Galalpha1,3Gal-containing penta- and
hexasaccharides having carbohydrate sequences consistent with the
Galalpha1,3nLc4and Galalpha1,3Lexstructures, respectively. The former
structure was tentatively identified in all organs by GC/MS. The presence
of extended Galalpha1,3Gal-terminated structures in the kidney and heart
was suggested by antibody binding, and GC/MS indicated the presence of a
Galalpha1,3nLc6structure in the heart. The kidney, spleen, and heart
contained blood group H pentaglycosylceramides based on type 1 (H-5-1) and
type 2 (H-5-2) chains, and H hexaglycosylceramides based on the type 4
chain (H-6-4). In the intestine H-5-1 and H-6-4 were expressed, in the
salivary gland H-5-1 and H-5-2, whereas only the H-5-1 structure was
identified in the liver. Blood group A structures were identified in the
salivary gland and the heart by antibody binding and GC/MS, indicating an
organ- specific expression of blood group AH antigens in the pig.
相似文献
79.
J Raftery 《BMJ (Clinical research ed.)》1993,307(6912):1121-1124
OBJECTIVE--To assess the effect of each of the components of the national capitation funding formula--population projections and age and mortality weighting--at regional and district level. DESIGN--Application of age-cost and mortality weights to the projected 1997 populations of regions and districts, based on the Department of Health public health common dataset. SETTING--Regional and district health authorities in England. RESULTS--The application of the age-cost and mortality weights to projected populations resulted in greater changes in the shares of weighted populations relative to the estimated 1991 population at district level (mean 0, range -17% to 28%) than at regional level (mean 0, range -9% to 6%). At district level mortality weights had less scope for influence (mean 0, range -9% to 14%) than population projections (mean 0, range -16% to 31%) or age weights (mean 0, range -20% to 30%). CONCLUSIONS--The adjustments to the 1991 population shares due to the application of the national capitation funding formula depend on the interaction of three elements: the projected population by age group, the age-cost weight, and the mortality weight. Since each is open to uncertainty, either in terms of measurement (projected population, particularly for births and the over 85s) or method (derivation of the age-cost and mortality weights), the formula should be implemented cautiously at district level. Ways should be considered of incorporating elements of uncertainty into the model. Further research is required on the elements and degree of uncertainty in each of these components, as well as on the relative health needs of different populations. 相似文献
80.
D S Middlemas M A Raftery 《Biochemical and biophysical research communications》1983,115(3):1075-1082
All four subunits of the acetylcholine receptor in membrane fragments isolated from T. californica have been labeled with a photolabile hydrophobic probe, [3H]adamantanediazirine, which selectively labels regions of integral membrane proteins in contact with the hydrocarbon core of the lipid bilayer. As all of the homologous subunits are exposed to the lipid bilayer, it is probable that they each interact with the surrounding membrane in a similar fashion. 相似文献