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John Culver Taylor Xinsheng Gao Juan Xu Michael Holder Joseph Petrosino Ritesh Kumar Wen Liu Magnus Hk Chris Mackenzie Andrew Hillhouse Wesley Brashear Maria Patricia Nunez Yi Xu 《PLoS pathogens》2021,17(1)
Streptococcus gallolyticus subspecies gallolyticus (Sgg) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. However, the molecular determinants involved in Sgg pathogenicity in the gut are unknown. Bacterial type VII secretion systems (T7SS) mediate pathogen interactions with their host and are important for virulence in pathogenic mycobacteria and Staphylococcus aureus. Through genome analysis, we identified a locus in Sgg strain TX20005 that encodes a putative type VII secretion system (designated as SggT7SST05). We showed that core genes within the SggT7SST05 locus are expressed in vitro and in the colon of mice. Western blot analysis showed that SggEsxA, a protein predicted to be a T7SS secretion substrate, is detected in the bacterial culture supernatant, indicating that this SggT7SST05 is functional. Deletion of SggT7SST05 (TX20005Δesx) resulted in impaired bacterial adherence to HT29 cells and abolished the ability of Sgg to stimulate HT29 cell proliferation. Analysis of bacterial culture supernatants suggest that SggT7SST05-secreted factors are responsible for the pro-proliferative activity of Sgg, whereas Sgg adherence to host cells requires both SggT7SST05-secreted and bacterial surface-associated factors. In a murine gut colonization model, TX20005Δesx showed significantly reduced colonization compared to the parent strain. Furthermore, in a mouse model of CRC, mice exposed to TX20005 had a significantly higher tumor burden compared to saline-treated mice, whereas those exposed to TX20005Δesx did not. Examination of the Sgg load in the colon in the CRC model suggests that SggT7SST05-mediated activities are directly involved in the promotion of colon tumors. Taken together, these results reveal SggT7SST05 as a previously unrecognized pathogenicity determinant for Sgg colonization of the colon and promotion of colon tumors. 相似文献
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Horizontal and parasagittal knife cuts in the hypothalamus of female hamsters (Mesocricetus auratus) were employed to investigate the neural pathways that mediate gonadal responses to photoperiod. Bilateral horizontal knife cuts placed dorsal to the paraventricular nucleus (PVN) did not prevent short-day-induced acyclicity and uterine regression. On the other hand, regardless of photoperiod, animals with bilateral parasagittal knife cuts placed lateral to the PVN continued to exhibit regular 4-day estrous cycles and stimulated uteri. Thus, parasagittal cuts prevented the effects of short days on reproductive physiology. This finding suggests that the lateral efferent projections from the PVN represent an important component of the neural pathway mediating reproductive photoperiodism in female hamsters. 相似文献
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Abstract– Various aspects of amino acid metabolism were studied in striatum of rats with unilateral, kainic acid-induced lesions. Tissue slices were prepared from the lesioned and the contralateral, unlesioned, striatum. The preparations were incubated with a mixture of d -[2-14C]glucose and [3H]acetate in a Krebs-Ringer bicarbonate medium to evaluate oxidative metabolism. Glutamate and aspartate levels were decreased in the slices prepared from the lesioned striata by 35-40% and that of GABA by 75% compared to the levels found in the slices from the contralateral striata; glutamine levels were not different in the two preparations. Glucose utilization was decreased 60% in the slices from the lesioned striatum; this was caused not only by decreased levels of glutamate, aspartate and GABA but also by a decreased rate of labelling of glutamate and aspartate. On the other hand, the metabolism of [3H]acetate was greatly increased. The specific activities of glutamate and aspartate were 4-5-fold higher in the slices from kainic acid-lesioned striata; those of glutamine and GABA were unchanged. Thus, there was a 6-7-fold increase in the ratio of 3H to 14C in the specific activities of glutamate, aspartate and GABA with no change in this ratio in glutamine. The labelling of glutamine relative to that of glutamate, especially from [3H]acetate, suggested that the compartmentation of the glutamate-glutamine system was greatly altered in the kainate-lesioned striatum which now more closely resembled a single compartment system. The activities of lactate dehydrogenase, glutamate dehydrogenase, GABA transaminase and ‘cytoplasmic’ aspartate aminotransferase were decreased in homogenates of lesioned striatum. Succinate dehydrogenase, glutaminase (phosphate-activated) and ‘mitochondrial’ aspartate aminotransferase activities were unchanged whilst that of glutamine synthetase was increased. The results are consistent with hypotheses concerning the assignment of labelled acetate metabolism to glial cells as well as the distribution of the above enzymes between glia, neurones and nerve endings. 相似文献
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The inhibitory effect of calmodulin on the assembly of mature and immature rat brain microtubules was compared with that of the two major structural domains of this protein, the COOH-terminal fragment (amino acids 78-148) and the NH2-terminal fragment (amino acids 1-77), to determine the calmodulin structural domain responsible for the inhibitory effect on microtubule assembly. Microtubules prepared during the early stages of brain development, i.e., during intensive neurite outgrowth, are more sensitive to inhibition by the Ca2(+)-calmodulin complex than those obtained from adult brain. Significant inhibition of immature microtubule assembly was observed with both fragments in the absence of Ca2+, but the effects were more important when Ca2+ was present. With adult brain microtubules, the two fragments remained without effect on assembly in the absence of Ca2+, whereas some inhibition was seen in its presence but only with the COOH-terminal polypeptide. Under all these conditions, the COOH-terminal fragment was always more active than the NH2-terminal fragment on microtubule polymerization, albeit to a lesser extent than native calmodulin. 相似文献
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