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61.
62.
Autophagy has been shown to contribute to defense against intracellular
bacteria and parasites. In comparison, the ability of such pathogens to
manipulate host cell autophagy to their advantage has not been examined. Here
we present evidence that infection by Toxoplasma gondii, an
intracellular protozoan parasite, induces host cell autophagy in both HeLa
cells and primary fibroblasts, via a mechanism dependent on host Atg5 but
independent of host mammalian target of rapamycin suppression. Infection led
to the conversion of LC3 to the autophagosome-associated form LC3-II, to the
accumulation of LC3-containing vesicles near the parasitophorous vacuole, and
to the relocalization toward the vacuole of structures labeled by the
phosphatidylinositol 3-phosphate indicator YFP-2×FYVE. The autophagy
regulator beclin 1 was concentrated in the vicinity of the parasitophorous
vacuole in infected cells. Inhibitor studies indicated that parasite-induced
autophagy is dependent on calcium signaling and on abscisic acid. At
physiologically relevant amino acid levels, parasite growth became defective
in Atg5-deficient cells, indicating a role for host cell autophagy in parasite
recovery of host cell nutrients. A flow cytometric analysis of cell size as a
function of parasite content revealed that autophagy-dependent parasite growth
correlates with autophagy-dependent consumption of host cell mass that is
dependent on parasite progression. These findings indicate a new role for
autophagy as a pathway by which parasites may effectively compete with the
host cell for limiting anabolic resources.Macroautophagy (hereafter referred to as autophagy) is a major catabolic
process in which cytosolic constituents are sequestered within
double-membraned vesicles (autophagosomes) and subsequently delivered to
lysosomes for degradation. Current evidence indicates at least two distinct
functions for this process. On the one hand, autophagy can be up-regulated
under nutrient-limiting conditions to increase nutrient supply via recycling
of the products of autophagic degradation, which may be exported from the
lysosome (1). The up-regulation
of autophagy upon starvation is thought to be mediated by the suppression of
signaling through the mTOR pathway
(2). On the other hand,
autophagy can serve to maintain cellular homeostasis by facilitating the
removal of damaged or deleterious elements, such as misfolded protein
aggregates (3). An important
example of the latter function is the role of autophagy in restricting the
growth of intracellular pathogens, including both free bacteria that have
escaped into host cytosol, such as group A Streptococcus, and
pathogens, such as Mycobacterium tuberculosis, that reside in
parasitophorous vacuoles in macrophages
(4,
5). In macrophages infected
with Toxoplasma gondii, fusion of the parasitophorous vacuole with
lysosomes can be induced in an autophagy-dependent manner when host cell
anti-parasitic function is activated via CD40
(6). Autophagy as a component
of host defense may be up-regulated by inflammatory agents such as
lipopolysaccharide (7) and
interferon-γ (8).Although the clearance function of autophagy may enhance pathogen killing
in host cells that have been activated to generate antimicrobial or
antiparasitic function, in permissive host cells, in which the pathogen is
less susceptible to sequestration by the autophagosome, autophagy may
conceivably play a quite different role. Modulation of the balance between
anabolic and catabolic processes may affect the outcome of competition between
pathogen and host cell for limiting nutrients. In particular, the nutritive
function of autophagy could favor pathogen expansion by providing greater
access to host cell biomass. The intracellular apicomplexan parasite, T.
gondii, is a suitable agent for the investigation of this hypothesis,
because it has been shown to be highly dependent on its host cell for the
supply of several nutrients, including amino acids
(9), lipids
(10), and purines
(11). T. gondii
replicates within a parasitophorous vacuole that, in permissive host cells, is
protected from lysosomal fusion. Recent evidence indicates that in such
permissive cells, in which the parasite can differentiate into bradyzoites
associated with chronic infection, the pathogen is able to actively sequester
host cell lysosome-derived vesicles, thereby potentially gaining access to
their contents (12).The ability of intracellular parasites to regulate host cell autophagy has
been little examined, and there is also little information with respect to the
impact of these pathogens on host cell signals that potentially affect the
autophagic pathway. In addition to mTOR, these include calcium ions, which
have been implicated in autophagy induced by endoplasmic reticulum stress
(13). In this study, we
provide evidence that T. gondii induces host cell autophagy by a
mechanism dependent on calcium but independent of mTOR and that it exploits
the nutritive function of host autophagy to enhance its proliferation. 相似文献
63.
Tomsheck AR Strobel GA Booth E Geary B Spakowicz D Knighton B Floerchinger C Sears J Liarzi O Ezra D 《Microbial ecology》2010,60(4):903-914
An endophytic fungus of Persea indica was identified, on the basis of its anamorphic stage, as Nodulosporium sp. by SEM. Partial sequence analysis of ITS rDNA revealed the identity of the teleomorphic stage of the fungus as Hypoxylon sp. It produces an impressive spectrum of volatile organic compounds (VOCs), most notably 1,8-cineole, 1-methyl-1,4-cyclohexadiene, and tentatively identified (+)-.alpha.-methylene-.alpha.-fenchocamphorone, among many others, most of which are unidentified. Six-day-old cultures of Hypoxylon sp. displayed maximal VOC-antimicrobial activity against Botrytis cinerea, Phytophthora cinnamomi, Cercospora beticola, and Sclerotinia sclerotiorum suggesting that the VOCs may play some role in the biology of the fungus and its survival in its host plant. Media containing starch- or sugar-related substrates best supported VOC production by the fungus. Direct on-line quantification of VOCs was measured by proton transfer mass spectrometry covering a continuous range with optimum VOC production occurred at 6 days at 145 ppmv with a rate of production of 7.65 ppmv/h. This report unequivocally demonstrates that 1,8-cineole (a monoterpene) is produced by a microorganism, which represents a novel and important source of this compound. This monoterpene is an octane derivative and has potential use as a fuel additive as do the other VOCs of this organism. Thus, fungal sourcing of this compound and other VOCs as produced by Hypoxylon sp. greatly expands their potential applications in medicine, industry, and energy production. 相似文献
64.
65.
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68.
When phage lambda lysogenizes a cell that lacks the primary bacterial attachment site, integrase catalyzes insertion of the phage chromosome into one of many secondary sites. Here, we characterize the secondary sites that are preferred by wild-type lambda and by lambda int mutants with altered insertion specificity. The sequences of these secondary sites resembled that of the primary site: they contained two imperfect inverted repeats flanking a short spacer. The imperfect inverted repeats of the primary site bind integrase, while the 7 bp spacer, or overlap region, swaps strands with a complementary sequence in the phage attachment site during recombination. We found substantial sequence conservation in the imperfect inverted repeats of secondary sites, and nearly perfect conservation in the leftmost three bases of the overlap region. By contrast, the rightmost bases of the overlap region were much more variable. A phage with an altered overlap region preferred to insert into secondary sites with the corresponding bases. We suggest that this difference between the left and right segments is a result of the defined order of strand exchanges during integrase-promoted recombination. This suggestion accounts for the unexpected segregation pattern of the overlap region observed after insertion into several secondary sites. Some of the altered specificity int mutants differed from wild-type in secondary site preference, but we were unable to identify simple sequence motifs that account for these differences. We propose that insertion into secondary sites is a step in the evolutionary change of phage insertion specificity and present a model of how this might occur. 相似文献
69.
70.