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141.
A battery of in vitro methods has been developed for the prediction of acute oral toxicity, to reduce the number of animals used for this purpose. However, the results of these tests correlate more closely with lethal serum concentrations than with lethal doses. To address this issue, we have further evaluated the HPCT-1E3 model, which may be better able to emulate toxicokinetic factors that occur in vivo, due to the presence in these hepatocytoma cells of endogenous transmembrane carriers and a basal activity of xenobiotic metabolism. IC50 values produced by using the MTT test after a 48-hour incubation with 20 randomly-selected MEIC substances, correlated better with human oral LD50 values than with LC50 data, supporting this hypothesis. As with other models, the toxicity of receptor-specific rather than cytotoxic substances, for example digoxin, was underpredicted. When digoxin was removed from the correlation analysis, the coefficient of determination (r(2)) improved to 0.81, and none of remaining chemicals were wrongly predicted by more than one order of magnitude. IC50 values obtained with HepG2 cells under similar conditions (MEIC Test No. 3, 24 hours, MTT) correlated with human LD50 data with a r(2) value of 0.55. A direct comparison of HPCT-1E3 and HepG2 cells further suggested that the differences between them may be due to transport processes. In conclusion, the HPCT-1E3 model may be valuable in improving the prediction of lethal doses, rather than lethal serum concentrations.  相似文献   
142.
Considerable progress has been made in the treatment of hearing loss with auditory implants. However, there are still many implanted patients that experience hearing deficiencies, such as limited speech understanding or vanishing perception with continuous stimulation (i.e., abnormal loudness adaptation). The present study aims to identify specific patterns of cerebral cortex activity involved with such deficiencies. We performed O-15-water positron emission tomography (PET) in patients implanted with electrodes within the cochlea, brainstem, or midbrain to investigate the pattern of cortical activation in response to speech or continuous multi-tone stimuli directly inputted into the implant processor that then delivered electrical patterns through those electrodes. Statistical parametric mapping was performed on a single subject basis. Better speech understanding was correlated with a larger extent of bilateral auditory cortex activation. In contrast to speech, the continuous multi-tone stimulus elicited mainly unilateral auditory cortical activity in which greater loudness adaptation corresponded to weaker activation and even deactivation. Interestingly, greater loudness adaptation was correlated with stronger activity within the ventral prefrontal cortex, which could be up-regulated to suppress the irrelevant or aberrant signals into the auditory cortex. The ability to detect these specific cortical patterns and differences across patients and stimuli demonstrates the potential for using PET to diagnose auditory function or dysfunction in implant patients, which in turn could guide the development of appropriate stimulation strategies for improving hearing rehabilitation. Beyond hearing restoration, our study also reveals a potential role of the frontal cortex in suppressing irrelevant or aberrant activity within the auditory cortex, and thus may be relevant for understanding and treating tinnitus.  相似文献   
143.
Cooperative collection planning is critical to the future of zoological parks and aquariums, yet few published models currently exist for collection plan development and implementation. In particular, there has been little discussion about the relationship between regional and institutional collection planning or about what defines a quality regional collection plan (RCP). This article documents the regional collection planning process adopted by the AZA Marsupial and Monotreme Taxon Advisory Group (TAG). More specifically, it outlines the philosophical foundation of the North American RCP for Marsupials and Monotremes, the organizational structure developed by the TAG to facilitate communication, evaluation and institutional participation, and other important details of the planning process. It also documents how the RCP was used by one institution (Los Angeles Zoo) to formulate its Institutional Collection Plan (ICP). Zoo Biol 17:433–451, 1998. © 1998 Wiley-Liss, Inc.  相似文献   
144.
Hypoxic chemosensitivity of peripheral arterial chemoreceptors and the ventilatory response to O2 deprivation increases with postnatal development. Multiple putative neurotransmitters, which are synthesized in the carotid body (CB), are thought to mediate signals generated by hypoxia. Acetylcholine (ACh) is believed to be a major excitatory neurotransmitter participating in hypoxic chemosensitivity. However, it is not known whether ACh originates from type I cells in the CB. In these studies, we tested the hypothesis that choline acetyltransferase (ChAT) and vesicular ACh transporter (VAChT) mRNAs are expressed in the CB and that mRNA levels would increase with postnatal maturation or exposure to hypoxia. Semiquantitative in situ hybridization histochemistry and immunohistochemistry were used to localize cholinergic markers within neurons and cells of the rat CB, the nodose-petrosal-jugular ganglion complex, and the superior cervical ganglion up to postnatal day 28. We show that the pattern of distribution, in tissue sections, is similar for both ACh markers; however, the level of VAChT mRNA is uniformly greater than that of ChAT. VAChT mRNA and immunoreactivity are detected abundantly in the nodose-petrosal-jugular ganglion complex in a number of microganglion cells embedded in nerve fibers innervating the CB for all postnatal groups, whereas ChAT mRNA is detected in only a few of these cells. Contrary to our hypothesis, postnatal maturation caused a reduction in ACh trait expression, whereas hypoxic exposure did not induce the upregulation of VAChT and ChAT mRNA levels in the CB, microganglion, or within the ganglion complex. The present findings indicate that the source of ACh in the CB is likely within autonomic microganglion cells and cholinergic nerve terminals.  相似文献   
145.
146.
Over the past 50 years, mean annual water temperature in northeastern U.S. estuaries has increased by approximately 1.2°C, with most of the warming recorded in the winter and early spring. A recent survey and synthesis of data from four locations in Southern Rhode Island has led us to hypothesize that this warming may be amplified in the shallow (<1 m), nearshore portions of these estuaries. While intertidal areas are not typically selected as locations for long-term monitoring, we compiled data from published literature, theses, and reports that suggest that enhanced warming may be occurring, perhaps at rates three times higher than deeper estuarine waters. Warmer spring waters may be one of the factors influencing biota residing in intertidal regions both in general as well as at our specific sites. We observed greater abundance of fish, and size of Menidia sp., in recent (2010–2012) seine surveys compared to similar collections in 1962. While any linkages are speculative and data are preliminary, taken together they suggest that shallow intertidal portions of estuaries may be important places to look for the effects of climate change.  相似文献   
147.
148.
Human peripheral blood monocyte-macrophages (M) generate a novel eicosanoid during in vitro culture. The metabolite is generated during incubation of the cells with 14C — arachidonic acid (AA). Lack of prior recognition of this metabolite probably results from the facts that: 1) on thin-layer chromatography (TLC) in two standard solvent systems, the novel metabolite co-chromatographed with either prostaglandin D2 or thromboxane B2, and 2) its generation, under the conditions studied, does not occur until between 90 and 180 minutes after culture initiaton which is a time period beyond that used for most leukocyte studies. The generation of the metabolite is inhibited by nordihydroguaiaretic acid (NDGA) but not by indomethacin. Base hydrolysis did not alter its migration on TLC. On both reversed phase and straight phase high pressure liquid chromatography (HPLC), the novel peak isolated by TLC elutes as a single major peak of radioactivity with a retention time different from the known leukotrienes, hydroxy acids, or their metabolites. Furthermore, the peak isolated on HPLC has a single ultraviolet absorption maximum at 270 nm. M cultured for 1 week prior to a 24 hour incubation with 14C-AA generated proportionally less of the novel eicosanoid (roughly 68% of total radiolabeled product) than did M cultured for 3 weeks prior to a similar incubation with 14C-AA (roughly 86% of total radiolabeled product). Under the conditions studied, the novel eicosanoid is the major AA metabolite generated from exogenous AA by cultured M and it appears to be generated in increasing quantity as the M differentiate.  相似文献   
149.
Parkinson''s disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1–2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments similar to PD patients and may provide useful endpoints for assessing novel therapeutic interventions for PD.  相似文献   
150.
Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.  相似文献   
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