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31.
32.
Young adult rats, either control or essential fatty acid deficient, were administered either [3-H] oleic acid or [3-H] arachidonic acid by stomach tube. In addition, a group of control rats was given [3-H] palmitic acid. The rats were killed at various times therafter, and the radioactivity of the lipids of brain and plasma was examined. In confirmation of previous work, the blood lipid label was found to rise rapidly and then fall, wheras the activity of brain lipids increased slowly and did not show a decline through the 24-h period studied. Analysis of the brain uptake data according to first-order kinetics confirmed the impressions gained from visual inspection of the data. The initial rate of uptake of arachidonic acid was about 4.5 times that of oleic acid in control animals and in deficient animals. Essential fatty acid deficiency, however, did not induce an altered rate of uptake for either oleic acid or arachidonic acid. The rate of uptake of palmitic acid by control rats was not significantly different from that of oleic acid. Even though the initial rates of incorporation of oleic and arachidonic acids were not changed during essential fatty acid deficiency, the final levels of radioactivity obtained in brain lipids were higher in deficient rats with both fatty acids. The plateau value obtained with oleic acid was 1.5 times higher in deficient animals, while the plateau value for arachidonic acid was 1.7 times higher. An experiment in which deficient animals were allowed access to a control diet for 12 or 24 h prior to the labeling experiment suggested that the higher levels of radioactivity found in brain lipids of deficient animals was not due to an isotope dilution effect. Such animals still displayed the labeling pattern of deficient animals with arachidonic acid, while the results with oleic acid varied somewhat. Our results suggest that essential fatty acid deficiency does not alter the ability of the brain to take up the fatty acids studied. However, the fatty acids, especially arachidonic, are retained in the brain to a greater extent in the deficient animals. 相似文献
33.
The envelope glycoprotein (G protein) of vesicular stomatitis virus is a transmembrane protein that exists as a trimer of identical subunits in the virus envelope. We have examined the effect of modifying the environment surrounding the membrane-spanning sequence on the association of G protein subunits using resonance energy transfer. G protein subunits were labeled with either fluorescein isothiocyanate or rhodamine isothiocyanate. When the labeled G proteins were mixed in the presence of the detergent octyl glucoside, mixed trimers containing both fluorescent labels were formed as a result of subunit exchange, as shown by resonance energy transfer between the two labels. In contrast when fluorescein- and rhodamine-labeled G proteins were mixed in the presence of Triton X-100, no resonance energy transfer was observed, indicating that subunit exchange did not occur in Triton X-100 micelles. However, if labeled G proteins were first mixed in the presence of octyl glucoside, energy transfer persisted after dilution with buffer containing Triton X-100. This result indicates that the G protein subunits remained associated in Triton X-100 micelles and that the failure to undergo subunit exchange was due to lack of dissociation of G protein subunits. Chemical cross-linking experiments confirmed that G protein was trimeric in the presence of Triton X-100. The efficiency of resonance energy transfer between labeled G protein was higher when G proteins were incorporated into dimyristoylphosphatidylcholine liposomes compared to detergent micelles. This result indicates that the labels exist in a more favorable environment for energy transfer in membranes than in detergent micelles.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
34.
The M protein of vesicular stomatitis virus (VSV) was localized in the nuclei and cytoplasm of VSV-infected cells by subcellular fractionation and immunofluorescence microscopy. Nuclei isolated from VSV-infected Friend erythroleukemia cells were fractionated into a nuclear membrane and a nucleoplasm fraction by DNase digestion and differential centrifugation. G protein was present in the membrane fraction, and M protein was present in the nucleoplasm fraction. Immunofluorescence detection of M protein in the nucleus required that fixed cells be permeabilized with higher concentrations of detergent than were required for detection of M protein in the cytoplasm of VSV-infected BHK cells. 相似文献
35.
36.
Vesicular Stomatitis Virus Matrix Protein Mutations That Affect
Association with Host Membranes and Viral
Nucleocapsids 总被引:1,自引:0,他引:1
Brooke Dancho Margie O. McKenzie John H. Connor Douglas S. Lyles 《The Journal of biological chemistry》2009,284(7):4500-4509
Viral matrix (M) proteins bind the nucleoprotein core (nucleocapsid) to
host membranes during the process of virus assembly by budding. Previous
studies using truncated M proteins had implicated the N-terminal 50 amino
acids of the vesicular stomatitis virus M protein in binding both membranes
and nucleocapsids and a sequence from amino acids 75-106 as an additional
membrane binding region. Structure-based mutations were introduced into these
two regions, and their effects on membrane association and incorporation into
nucleocapsid-M protein complexes were determined using quantitative assays.
The results confirmed that the N terminus of M protein is involved in
association with plasma membranes as well as nucleocapsids, although these two
activities were differentially affected by individual mutations. Mutations in
the 75-106 region affected incorporation into nucleocapsid-M complexes but had
only minor effects on association with membranes. The ability of site-specific
mutant M proteins to complement growth of temperature-sensitive M mutant virus
did not correlate well with the ability to associate with membranes or
nucleocapsids, suggesting that complementation involves an additional activity
of M protein. Mutants with similar abilities to associate with membranes and
nucleocapsids but differing in complementation activity were incorporated into
infectious cDNA clones. Infectious virus was repeatedly recovered containing
mutant M proteins capable of complementation but was never recovered with
mutant M proteins that lacked complementation activity, providing further
evidence for a separate activity of M protein that is essential for virus
replication.Most viruses that have a membrane or envelope as part of their structure
acquire their envelopes by budding from the plasma membrane of the host cell.
For budding to occur, the nucleoprotein core of the virus (nucleocapsid) must
interact with the cytoplasmic surface of the host membrane. For many viruses
this interaction is mediated by a matrix
(M)2 protein that
binds to both the nucleocapsid and the host membrane
(1,
2). Despite the similarity in
the functions of viral M proteins, there is little structural or sequence
similarity among the M proteins of different virus families
(3). Thus, understanding the
relationship of structure to function must be undertaken for individual M
proteins before the general principles involved in virus budding can be
understood. The goal of the experiments described here was to determine
sequences in the M protein of vesicular stomatitis virus (VSV) involved in
binding to membranes and nucleocapsids.VSV is the prototype member of the Rhabdoviridae family and has
been widely studied to determine mechanisms involved in virus budding
(2). The core of the virus
contains an ∼11-kilobase negative-stranded RNA genome covered by 1300
copies of a single nucleocapsid protein
(4). The nucleocapsid also
contains lesser amounts of two proteins, P and L, which constitute the viral
RNA-dependent RNA polymerase. The envelope contains a single species of
transmembrane glycoprotein (G protein) that mediates virus attachment and
entry into host cells. The virion contains ∼2000 copies of the M protein
(4), which binds the
nucleocapsid to the envelope and condenses the nucleocapsid into a tightly
coiled helical nucleocapsid-M protein (NCM) complex that gives the virion its
bullet-like shape
(5-8).
In cells infected with VSV and in transfected cells that express M protein in
the absence of other VSV components, M protein is present both in a soluble
form and bound to the cytoplasmic surface of the host plasma membrane
(9-18).
Mutagenesis studies, affinity labeling, and membrane reconstitution
experiments have suggested that a combination of hydrophobic and ionic
interactions mediate M protein binding to membranes by binding acidic
phospholipids on the inner surface of the host plasma membrane (for review,
see Ref. 19). Binding of M
protein to nucleocapsids is less well understood than its binding to
membranes. Most of the M protein in isolated NCM complexes is bound in a
rapidly reversible equilibrium
(20). However, M protein does
not bind to nucleocapsids from which all of the M protein has been dissociated
or to intracellular nucleocapsids that have never been assembled with M
protein (11,
20). This suggests that
binding of M protein to nucleocapsids in infected cells must be initiated in a
separate step, after which most of the M protein is recruited into the NCM
complex through the reversible binding step.M protein does not have separately folded domains that mediate binding to
membranes versus nucleocapsids. The 229-amino acid (aa) M protein
contains a positively charged N terminus (aa 1-50) that is highly exposed to
proteolysis. The remainder of M protein (aa 51-229) is compactly folded to
form a protease-resistant core
(16,
21-23).
The ability to obtain crystals of M protein required proteolytic removal of
both the N-terminal sequence (aa 1-47) and a hydrophobic sequence (aa 121-124)
to prevent M protein self-association
(21,
22); however, the resulting
structure showed a single-domain fold for the crystallized portion of M. In
the present study we focused on two regions of the M protein structure that
had been suggested to be involved in binding to either membranes or
nucleocapsids; 1) previous data had implicated the N-terminal sequence in
binding to both nucleocapsids and membranes
(9,
10,
16,
22-25)
and 2) deletion mutagenesis studies had implicated an additional region from
aa 75-106 in membrane binding
(16).In the experiments described here, M protein sequence substitutions were
made using a scanning approach in the N-terminal sequence, and substitutions
were based on the crystal structure in the 75-106-aa region. These mutants
were used to determine the specific amino acids involved in these
interactions. The results confirm that the N terminus of M protein is involved
in association with plasma membranes as well as nucleocapsids, although these
two activities are differentially affected by individual mutations. Mutations
in the 75-106-aa region affected incorporation into NCM complexes but had only
minor effects on association with membranes. Furthermore, the ability of
mutant M proteins to function in the context of virus infection suggested that
a new activity of M protein that is separate from its ability to associate
with membranes or NCM complexes is critical for virus assembly. 相似文献
37.
38.
Bortezomib is a chemotherapeutic agent used to treat several cancers; however, it exhibits severe side effects in testicular tissue. We investigated the use of agomelatine to prevent testicular tissue damage caused by bortezomib. We used 36 male Sprague-Dawley rats divided randomly into six equal groups: group 1, no treatment control; group 2, agomelatine treatment only; group 3, bortezomib treatment only for 48 h; group 4, bortezomib + agomelatine treatment for 48 h; group 5, bortezomib treatment only for 72 h; and group 6, bortezomib + agomelatine treatment for 72 h. After treatments, the rats were sacrificed and testicular tissue was harvested. Lipid oxidation (LPO) and superoxide dismutase (SOD) levels in the tissues were determined using biochemical methods. Tissue samples also were examined using histopathological and immunohistochemical techniques. The LPO level was increased, while the SOD level was decreased in the bortezomib treated groups. We found that agomelatine treatment normalized LPO and SOD activities in the bortezomib treated groups. In the spermatogonia and Sertoli cells, the staining density of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and caspase 3 were decreased in the bortezomib + agomelatine groups at both 48 and 72 h compared to bortezomib only treated groups. We observed maturation arrest, basal membrane thickening, increase in inflammatory cells and connective tissue, and edema between germ cells in the bortezomib only treated groups. By contrast, normal basal membrane, less edema and more normal maturation were observed in the bortezomib + agomelatine groups at 48 and 72 h. We found that agomelatine reduced the damaging effects of bortezomib. The use of agomelatine to prevent bortezomib induced testicular tissue damage in human patients should be investigated further. 相似文献
39.
40.