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排序方式: 共有152条查询结果,搜索用时 46 毫秒
11.
Birong Zhang James R. Kiefer Robert A. Blake Jae H. Chang Steven Hartman Ellen Rei Ingalla Tracy Kleinheinz Vidhi Mody Michelle Nannini Daniel F. Ortwine Yingqing Ran Amy Sambrone Deepak Sampath Maia Vinogradova Yu Zhong Jerome C. Nwachukwu Kendall W. Nettles Tommy Lai Jun Liang 《Bioorganic & medicinal chemistry letters》2019,29(7):905-911
Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays. 相似文献
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From July 1998 through October 2002, radiometric culture (ileocecal lymph node, mesenteric lymph node, and feces) and serologic testing by enzyme-linked immunosorbent assay (ELISA) were used to survey white-tailed deer (Odocoilens virgianus) from the soutlheastern United States for infection by Mycobacterium avium subsp. paratuberculosis (Mptb), the causative agent of paratuberculosis (Johne's disease). Mycobacterium avium subsp. paratuberculosis was isolated from the ileocecal lymph node of one of 313 deer (0.3%) originating from 63 populations in Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina, South Carolina, Tennessee, and West Virginia (USA). Six deer (2%), all from different populations, had ELISA results above a 0.25 sample-to-positive cutoff value, but none of the ELISA reactors originated from the population from which the single Mptb isolation was made. These six deer were seronegative when tested by agar gel immunodiffusion (AGID). Collectively, these data indicate that white-tailed deer currently do not constitute a broad regional reservoir for Mptb; however, further study is warranted to clarify the significance, if any, of infected deer to the epizootiology of paratuberculosis on a local scale. Adaptation and validation of an ELISA or another serologic assay for use with deer and other wildlife would markedly enhance Mptb surveillanece among wild populations and would be a powerful tool for gaining information on the role of wild species in epidemiology of paratuberculosis. 相似文献
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Nettles VF Quist CF Lopez RR Wilmers TJ Frank P Roberts W Chitwood S Davidson WR 《Journal of wildlife diseases》2002,38(4):685-692
The population health of endangered Key deer (Odocoileus virginianus clavium) was monitored from 10 February 1986 to 28 September 2000 by necropsy of animals that were killed by vehicles, euthanized because of terminal injuries or disease conditions, or found dead. The predominant mortality factor during the period was collision with motor vehicles; however, several infectious diseases were diagnosed, including infections with Arcanobacterium pyogenes, Haemonchus contortus, Salmonella spp., and Mycobacterium avium subsp. paratuberculosis. During the period monitored, the only infectious disease that was thought to have affected population dynamics was haemonchosis. Nevertheless, several of the observed diseases have potential to impact viability of the Key deer population under appropriate environmental conditions. 相似文献
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Aflatoxins, toxic metabolites of Aspergillus flavus or Aspergillus parasiticus, cause poor feed utilization, decreased weight gains, depressed immune function, liver dysfunction, coagulation abnormalities, and death in a wide variety of species including humans. Conservationists have become concerned that increasingly popular wildlife feeding or baiting practices could expose wildlife to toxic amounts of aflatoxin-contaminated grains. In particular, the effects of aflatoxins on the wild turkey (Meleagris gallopova silvestris) are of concern because the conspecific domestic turkey is highly susceptible to aflatoxins. To evaluate the effect of dietary aflatoxin on wild turkeys, four groups of 4-mo-old wild turkeys were fed diets containing either 0, 100, 200, or 400 micrograms aflatoxin/kg feed for 2 wk in September and October 1996. Aflatoxin-fed poults had decreased feed consumption and weight gains as compared with control poults. Decreased liver-to-body weight ratios, liver enzyme alterations, slightly altered blood coagulation patterns, and mild histologic changes indicated low-level liver damage. Compromise of cell-mediated immunity was indicated by decreased lymphoblast transformation. The effects were apparent in all treatment groups to variable levels, but significant differences most often were found at 400 micrograms aflatoxin/kg feed. This study shows that short-term aflatoxin ingestion by wild turkeys can induce undesirable physiologic changes; therefore, exposure of wild turkeys to feeds containing aflatoxin levels of 100 micrograms aflatoxin/kg feed or more should be avoided. 相似文献
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Improved tests for heterogeneity across a region of DNA sequence in the ratio of polymorphism to divergence 总被引:15,自引:9,他引:6
The neutral theory of molecular evolution predicts that the ratio of
polymorphisms to fixed differences should be fairly uniform across a region
of DNA sequence. Significant heterogeneity in this ratio can indicate the
effects of balancing selection, selective sweeps, mildly deleterious
mutations, or background selection. Comparing an observed heterogeneity
statistic with simulations of the heterogeneity resulting from random
phylogenetic and sampling variation provides a test of the statistical
significance of the observed pattern. When simulated data sets containing
heterogeneity in the polymorphism-to-divergence ratio are examined,
different statistics are most powerful for detecting different patterns of
heterogeneity. The number of runs is most powerful for detecting patterns
containing several peaks of polymorphism; the Kolmogorov-Smirnov statistic
is most powerful for detecting patterns in which one end of the gene has
high polymorphism and the other end has low polymorphism; and a newly
developed statistic, the mean sliding G statistic, is most powerful for
detecting patterns containing one or two peaks of polymorphism with reduced
polymorphism on either side. Nine out of 27 genes from the Drosophila
melanogaster subgroup exhibit heterogeneity that is significant under at
least one of these three tests, with five of the nine remaining significant
after a correction for multiple comparisons, suggesting that detectable
evidence for the effects of some kind of selection is fairly common.
相似文献
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David?E?Comings Thomas?JH?Chen Kenneth?BlumEmail author Julie?F?Mengucci Seth?H?Blum Brian?Meshkin 《Theoretical biology & medical modelling》2005,2(1):50