全文获取类型
收费全文 | 453篇 |
免费 | 58篇 |
出版年
2022年 | 4篇 |
2018年 | 5篇 |
2017年 | 6篇 |
2016年 | 5篇 |
2015年 | 16篇 |
2014年 | 10篇 |
2013年 | 17篇 |
2012年 | 12篇 |
2011年 | 16篇 |
2010年 | 17篇 |
2009年 | 7篇 |
2008年 | 26篇 |
2007年 | 17篇 |
2006年 | 20篇 |
2005年 | 13篇 |
2004年 | 11篇 |
2003年 | 11篇 |
2002年 | 7篇 |
2001年 | 13篇 |
2000年 | 16篇 |
1999年 | 9篇 |
1998年 | 13篇 |
1997年 | 6篇 |
1996年 | 3篇 |
1994年 | 7篇 |
1992年 | 9篇 |
1991年 | 5篇 |
1990年 | 10篇 |
1989年 | 14篇 |
1988年 | 14篇 |
1987年 | 5篇 |
1986年 | 12篇 |
1985年 | 5篇 |
1984年 | 13篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1980年 | 5篇 |
1979年 | 7篇 |
1978年 | 16篇 |
1977年 | 4篇 |
1976年 | 10篇 |
1975年 | 8篇 |
1974年 | 6篇 |
1973年 | 8篇 |
1972年 | 5篇 |
1971年 | 4篇 |
1970年 | 7篇 |
1969年 | 4篇 |
1968年 | 5篇 |
1967年 | 6篇 |
排序方式: 共有511条查询结果,搜索用时 19 毫秒
41.
Legionella pneumophila is an adaptive pathogen that replicates in the intracellular environment of fundamentally divergent hosts (freshwater protozoa and mammalian cells) and is capable of surviving long periods of starvation in water when between hosts. Physiological adaptation to these quite diverse environments seems to be accompanied by morphological changes (Gardu?o et al., p. 82-85, in Marre et al., ed., Legionella, 2001) and conceivably involves developmental differentiation. In following the fine-structural pathway of L. pneumophila through both in vitro and in vivo growth cycles, we have now discovered that this bacterium displays an unprecedented number of morphological forms, as revealed in ultrathin sections and freeze-fracture replicas for transmission electron microscopy. Many of the forms were identified by the obvious ultrastructural properties of their cell envelope, which included changes in the relative opaqueness of membrane leaflets, vesiculation, and/or profuse invagination of the inner membrane. These changes were best documented with image analysis software to obtain intensity tracings of the envelope in cross sections. Also prominent were changes in the distribution of intramembranous particles (clearly revealed in replicas of freeze-fractured specimens) and the formation of cytoplasmic inclusions. Our results confirm that L. pneumophila is a highly pleomorphic bacterium and clarify some early observations suggesting sporogenic differentiation in L. pneumophila. Since morphological changes occurred in a conserved sequence within the growth cycle, our results also provide strong evidence for the existence of a developmental cycle in L. pneumophila that is likely accompanied by profound physiological alterations and stage-specific patterns of gene expression. 相似文献
42.
Ridley CP Reddy MV Rocha G Bushman FD Faulkner DJ 《Bioorganic & medicinal chemistry》2002,10(10):3285-3290
In order to explore the influence of sulfate groups on the bioactivity profiles of marine alkaloids of the lamellarin class, three such alkaloids, lamellarin alpha, lamellarin alpha 13,20-disulfate and lamellarin H, were synthesized and their activities against HIV-1 integrase and cancer cell lines were compared with those of lamellarin alpha 20-sulfate, which is a selective inhibitor of HIV-1 integrase. Lamellarin alpha does not inhibit HIV-1 integrase but shows moderate cytotoxicity with good cell line selectivity. Lamellarin alpha 13,20-disulfate is a moderate inhibitor of both HIV-1 integrase and cancer cell lines. Lamellarin H is a more potent inhibitor of HIV-1 integrase but lacked the specificity required to be medicinally useful. 相似文献
43.
E?DimitriadisEmail author L?Robb Y-X?Liu AC?Enders H?Martin C?Stoikos E?Wallace LA?Salamonsen 《Reproductive biology and endocrinology : RB&E》2003,1(1):34
Embryo implantation, endometrial stromal cell decidualization and formation of a functional placenta are critical processes in the establishment and maintenance of pregnancy. Interleukin (IL)-11 signalling is essential for adequate decidualization in the mouse uterus and IL-11 promotes decidualization in the human. IL-11 action is mediated via binding to the specific IL-11 receptor α (IL-11Rα). The present study examined immunoreactive IL-11 and IL-11Rα in cycling rhesus monkey endometrium, at implantation sites in cynomolgus and rhesus monkeys and in human first trimester decidua and defined distinct spatial and temporal patterns. In cycling rhesus monkey endometrium, IL-11 and IL-11Rα increased in both basalis and functionalis regions during the secretory compared with the proliferative phase, with changing cellular locations in luminal and glandular epithelium and stroma. The patterns were similar overall to those previously described in human endometrium. Differences were seen in immunostaining during implantation in cynomologus and rhesus monkey. In the cynomolgus, very little staining for IL-11 or IL-11Rα was seen in syncytio- and cyto-trophoblast cells in the villi between days 12 and 150 of pregnancy although there was moderate staining in cytotrophoblast in the shell between days 12 and 17 and in subpopulations of cytotrophoblast cells invading the arteries at day 17. By contrast in the rhesus monkey between days 24 and 35 of pregnancy and in human first trimester placenta, cyto- and syncytio-trophoblast in the villi but not cytotrophoblast in the shell were positively stained. The most intense staining for both IL-11 and IL-11Rα was present within the decidua in the maternal component of implantation sites in all three primates but moderate staining was also present in maternal vascular smooth muscle and glands perivascular cells and epithelial plaques. These results are consistent with a role for IL-11 both during decidualization and placentation in primates. 相似文献
44.
Dennis RG Kosnik PE Gilbert ME Faulkner JA 《American journal of physiology. Cell physiology》2001,280(2):C288-C295
The purpose of this study was to compare the excitability and contractility of three-dimensional skeletal muscle constructs, termed myooids, engineered from C2C12 myoblast and 10T1/2 fibroblast cell lines, primary muscle cultures from adult C3H mice, and neonatal and adult Sprague-Dawley rats. Myooids were 12 mm long, with diameters of 0.1-1 mm, were excitable by transverse electrical stimulation, and contracted to produce force. After approximately 30 days in culture, myooid cross-sectional area, rheobase, chronaxie, resting baseline force, twitch force, time to peak tension, one-half relaxation time, and peak isometric force were measured. Specific force was calculated by dividing peak isometric force by cross-sectional area. The specific force generated by the myooids was 2-8% of that generated by skeletal muscles of control adult rodents. Myooids engineered from C2C12-10T1/2 cells exhibited greater rheobase, time to peak tension, and one-half relaxation time than myooids engineered from adult rodent cultures, and myooids from C2C12-10T1/2 and neonatal rat cells had greater resting baseline forces than myooids from adult rodent cultures. 相似文献
45.
Faulkner NE Dujardin DL Tai CY Vaughan KT O'Connell CB Wang Y Vallee RB 《Nature cell biology》2000,2(11):784-791
Mutations in the LIS1 gene cause gross histological disorganization of the developing human brain, resulting in a brain surface that is almost smooth. Here we show that LIS1 protein co-immunoprecipitates with cytoplasmic dynein and dynactin, and localizes to the cell cortex and to mitotic kinetochores, which are known sites for binding of cytoplasmic dynein. Overexpression of LIS1 in cultured mammalian cells interferes with mitotic progression and leads to spindle misorientation. Injection of anti-LIS1 antibody interferes with attachment of chromosomes to the metaphase plate, and leads to chromosome loss. We conclude that LIS1 participates in a subset of dynein functions, and may regulate the division of neuronal progenitor cells in the developing brain. 相似文献
46.
Dockendorff TC Robertson SE Faulkner DL Jongens TA 《Molecular & general genetics : MGG》2000,263(1):137-143
We have performed an F2 genetic screen to identify lethal mutations that map to the 44D-45B region of the Drosophila melanogaster genome. By screening 8500 mutagenized chromosomes for lethality over Df(2R)Np3, a deficiency which encompasses nearly 1% of the D. melanogaster euchromatic genome, we recovered 125 lines with lethal mutations that represent 38 complementation groups. The lethal mutations
have been mapped to deficiencies that span the 44D-45B region, producing an approximate map position for each complementation
group. Lethal mutations were analyzed to determine the phase of development at which lethality occurred. In addition, we have
linked some of the complementation groups to P element-induced lethals that map to 44D-45B, thus possibly providing new alleles of a previously tagged gene. Some of the
complementation groups represent potentially novel alleles of previously identified genes that map to the region. Several
genes have been mapped by molecular means to the 44D-45B region, but do not have any reported mutant alleles. This screen
may have uncovered mutant alleles of these genes. The results of complementation tests with previously identified genes in
44D-45B suggests that over half of the complementation groups identified in this screen may be novel.
Received: 13 July 1999 / Accepted: 4 November 1999 相似文献
47.
Melek Güler-Yüksel Naomi B Klarenbeek Yvonne PM Goekoop-Ruiterman Jeska K de Vries-Bouwstra Sjoerd M van der Kooij Andreas H Gerards H Karel Ronday Tom WJ Huizinga Ben AC Dijkmans Cornelia F Allaart Willem F Lems 《Arthritis research & therapy》2010,12(3):R96
Introduction
To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years.Methods
In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years.Results
68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage.Conclusions
In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year. 相似文献48.
Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain 总被引:10,自引:0,他引:10
Duan X Chang JH Ge S Faulkner RL Kim JY Kitabatake Y Liu XB Yang CH Jordan JD Ma DK Liu CY Ganesan S Cheng HJ Ming GL Lu B Song H 《Cell》2007,130(6):1146-1158
Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis. 相似文献
49.
Several species of Lolium and other cool-season grasses (Poaceae subfamily Pooideae) tend to harbor symbiotic, seed-transmitted, fungi that enhance their fitness by various means. These fungal endophytes--species of Neotyphodium or Epichlo? (Clavicipitaceae)--are known for production of antiherbivore metabolites such as the bioprotective loline alkaloids. Lolines are saturated pyrrolizidines with an exo-1-amine and an ether bridge between C-2 and C-7. The ether bridge is an unusual feature for a biogenic compound in that it links two bridgehead carbon atoms. Much of the loline-biosynthetic pathway has been elucidated by administering isotopically labeled precursors to fungal cultures and by comparisons of loline biosynthesis genes to known gene families. The first step appears to be an unusual gamma-substitution reaction involving an enzyme related to O-acetylhomoserine (thiol) lyase, but which uses the secondary amine of L-proline rather than a sulfhydryl group as the nucleophile. The strained ether bridge is added after formation of the pyrrolizidine rings. Lolines with dimethylated or acylated 1-amines have insect antifeedant and insecticidal activities comparable to nicotine, but little or no toxicity to mammals. Considering the surprising abundance of lolines in some grass-endophyte symbiota, possible additional effects on plant stress tolerance and physiology are worth future consideration. In this review, we discuss the history of loline discovery, methods of analysis, biological activities and distribution in nature, as well as progress on the genetics and biochemistry of their biosynthesis, and on the chemical synthesis of these alkaloids. 相似文献
50.