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151.
Several phosphoramidate analogues of CMP-N-acetylneuraminic acid were prepared for evaluation as inhibitors of alpha-2,3- and alpha-2,6-sialyltransferase. Central to the synthesis was the oxidative coupling of an amino acid ester with an H-phosphonate to construct the phosphoramidate linkage. All compounds synthesized were weak inhibitors of both of the sialyltransferases as determined by an HPLC-based inhibition assay. 相似文献
152.
Krajewska M You Z Rong J Kress C Huang X Yang J Kyoda T Leyva R Banares S Hu Y Sze CH Whalen MJ Salmena L Hakem R Head BP Reed JC Krajewski S 《PloS one》2011,6(9):e24341
Background
Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8 −/−), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system.Methodology/Principal Findings
Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8 −/− mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging.Conclusions
Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma. 相似文献153.
Agrawal N Leaman DP Rowcliffe E Kinkead H Nohria R Akagi J Bauer K Du SX Whalen RG Burton DR Zwick MB 《PloS one》2011,6(6):e21339
The HIV-1 envelope glycoprotein (Env) spike is challenging to study at the molecular level, due in part to its genetic variability, structural heterogeneity and lability. However, the extent of lability in Env function, particularly for primary isolates across clades, has not been explored. Here, we probe stability of function for variant Envs of a range of isolates from chronic and acute infection, and from clades A, B and C, all on a constant virus backbone. Stability is elucidated in terms of the sensitivity of isolate infectivity to destabilizing conditions. A heat-gradient assay was used to determine T90 values, the temperature at which HIV-1 infectivity is decreased by 90% in 1 h, which ranged between ∼40 to 49°C (n = 34). For select Envs (n = 10), the half-lives of infectivity decay at 37°C were also determined and these correlated significantly with the T90 (p = 0.029), though two ‘outliers’ were identified. Specificity in functional Env stability was also evident. For example, Env variant HIV-1ADA was found to be labile to heat, 37°C decay, and guanidinium hydrochloride but not to urea or extremes of pH, when compared to its thermostable counterpart, HIV-1JR-CSF. Blue native PAGE analyses revealed that Env-dependent viral inactivation preceded complete dissociation of Env trimers. The viral membrane and membrane-proximal external region (MPER) of gp41 were also shown to be important for maintaining trimer stability at physiological temperature. Overall, our results indicate that primary HIV-1 Envs can have diverse sensitivities to functional inactivation in vitro, including at physiological temperature, and suggest that parameters of functional Env stability may be helpful in the study and optimization of native Env mimetics and vaccines. 相似文献
154.
We introduce a theory of sequential causal inference in which learners in a chain estimate a structural model from their upstream "teacher" and then pass samples from the model to their downstream "student". It extends the population dynamics of genetic drift, recasting Kimura's selectively neutral theory as a special case of a generalized drift process using structured populations with memory. We examine the diffusion and fixation properties of several drift processes and propose applications to learning, inference, and evolution. We also demonstrate how the organization of drift process space controls fidelity, facilitates innovations, and leads to information loss in sequential learning with and without memory. 相似文献
155.
A microelectrode for measuring intracellular PO2 总被引:5,自引:0,他引:5
156.
Thyroid hormone induces a nerve-independent precocious expression of fast myosin heavy chain mRNA in rat hindlimb skeletal muscle 总被引:2,自引:0,他引:2
S D Russell N Cambon B Nadal-Ginard R G Whalen 《The Journal of biological chemistry》1988,263(13):6370-6374
The appearance of the mRNA for the adult fast IIB myosin heavy chain (MHC) was examined during postnatal development of rats using an S1 nuclease assay. In normal rats, a large increase in the adult MHC mRNA began at 6-7 days after birth, whereas daily injections of newborn rats with 3 micrograms of triiodothyronine (T3) resulted in a precocious increase of the mRNA as early as 3 days after birth. Injection of a range of doses of T3 demonstrated that a large effect was obtained between 30 and 300 ng of T3/day/rat. Fast myosin protein was also precociously induced over the same range of T3 doses. This effect was also seen in denervated muscles, and muscles responded similarly to the different doses of T3 whether they were denervated or not. These results suggest that either thyroid hormone or some circulating factors induced by thyroid hormone are limiting factors in controlling the neonatal-to-adult fast MHC transition and that these factors may act directly on muscle tissue. 相似文献
157.
158.
Julia Kubanek Kristen E. Whalen Sebastian Engel Sarah R. Kelly Timothy P. Henkel William Fenical Joseph R. Pawlik 《Oecologia》2002,131(1):125-136
Despite their high nutritional value and a lack of physical defenses, most marine sponges appear to be minimally affected by predators, competitors, and fouling organisms, possibly due to sponge chemical defenses. In the last 15 years, several triterpene glycosides have been isolated from sponges, but their ecological or physiological roles are largely unknown. We tested triterpene glycosides from Erylus formosus and Ectyoplasia ferox, Caribbean sponges belonging to two different orders, in field and laboratory assays for effects on fish feeding, attachment by potential biofilm-forming bacteria, fouling by invertebrates and algae, and overgrowth by neighboring sponges. Formoside and other triterpene glycosides from Erylus formosus deterred predation, microbial attachment, and fouling by invertebrates and algae. Triterpene glycosides from Ectyoplasia ferox were found to be antipredatory and allelopathic. Thus, triterpene glycosides in these sponges appear to have multiple ecological functions. Tests with different triterpene glycosides at several concentrations indicated that small differences in molecular structure affect ecological activity. In order to establish whether triterpene glycosides could be involved in water-borne versus surface-mediated interactions, the presence of triterpene glycosides in the seawater surrounding live sponges was measured using two in situ sampling methods followed by HPLC and NMR spectral analysis. Water-borne triterpene glycosides were below detection limits for both species. However, top sponge layers and swabs of the surfaces of both sponges contained sufficiently high concentrations of triterpene glycosides to deter bacterial settlement and fouling of Erylus formosus surfaces and overgrowth of Ectyoplasia ferox by neighboring sponges. Enemies of these sponges appear to be deterred by surface contact of triterpene glycosides rather than by water-borne interactions. The dual strategy of employing one group of compounds for multiple purposes and minimizing the loss of compounds into seawater suggests that these organisms utilize chemical defenses with efficiency. 相似文献
159.
Human natural killer (NK) cells are central in immune defense against tumor and virally infected cells. Ziram is used as an
accelerating agent in latex production and as an agricultural fungicide. Previous studies showed that continuous exposure
to ziram inhibits NK lytic function. Additionally, they showed that a brief (1 h) exposure to ziram caused persistent loss
of lytic function. This study examined whether decreases in lytic function were accompanied by decreases in the target-binding
function of NK cells and found that some, but not all, exposures to ziram caused significant decreases in binding function.
Ziram exposures that caused a loss of binding function were examined for effects on expression of key NK cell-surface proteins
needed for binding to targets. Exposure to 2 μM ziram for 1 h followed by 24 or 48 h in ziram-free media decreased CD16 expression,
but no other exposures caused decreases in cell-surface proteins. As decreases in adenosine triphosphate (ATP) could be in
part responsible for loss of lytic function, the effect of ziram exposures on ATP levels of NK cells were examined. Certain
ziram exposures decreased ATP levels in NK cells, but a decrease in ATP was not necessarily associated with a decrease in
lytic function. The results indicate that ziram-induced losses of lytic function cannot be fully explained by alteration in
binding, cell-surface protein expression, or ATP levels 相似文献
160.
Lewinsohn DA Zalwango S Stein CM Mayanja-Kizza H Okwera A Boom WH Mugerwa RD Whalen CC 《PloS one》2008,3(10):e3407