全文获取类型
收费全文 | 304篇 |
免费 | 32篇 |
国内免费 | 3篇 |
出版年
2022年 | 1篇 |
2021年 | 5篇 |
2020年 | 2篇 |
2019年 | 3篇 |
2018年 | 7篇 |
2017年 | 5篇 |
2016年 | 8篇 |
2015年 | 12篇 |
2014年 | 15篇 |
2013年 | 17篇 |
2012年 | 27篇 |
2011年 | 22篇 |
2010年 | 19篇 |
2009年 | 19篇 |
2008年 | 12篇 |
2007年 | 15篇 |
2006年 | 14篇 |
2005年 | 14篇 |
2004年 | 12篇 |
2003年 | 11篇 |
2002年 | 7篇 |
2001年 | 9篇 |
2000年 | 8篇 |
1999年 | 4篇 |
1998年 | 6篇 |
1997年 | 7篇 |
1996年 | 3篇 |
1995年 | 2篇 |
1994年 | 7篇 |
1993年 | 6篇 |
1992年 | 5篇 |
1991年 | 5篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1981年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1970年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有339条查询结果,搜索用时 15 毫秒
91.
Improving Keszthelyis simple model the evolutionary appearance of concentration difference of enanthiomeric compounds due to their differential decomposition by -rays is investigated taking into account the racemization as well. It is shown that if the difference in the cross sections is very small then the resulting concentration difference will never exceed the statistical fluctuations, while in the case of a sufficiently large difference in the cross sections the concentration difference can overgrow the statistical fluctuations in an evolutionary reasonable period of time. The relative difference of the concentrations, however, will be generally much smaller than that of the cross sections. Therefore some other, amplifying mechanism must be postulated in order to explain the optical purity of living beings. 相似文献
92.
Daria?Estrada-SmithEmail author Lawrence?W.?Castellani Howard?Wong Ping-Zi?Wen Aileen?Chui Aldons?J.?Lusis Richard?C.?Davis 《Mammalian genome》2004,15(1):14-22
Previous quantitative trait locus mapping (QTL) identified multigenic obesity (MOB) loci on mouse Chromosome (Chr) 2 that influence the interrelated phenotypes of obesity, insulin resistance, and dyslipidemia. To better localize and characterize the MOB locus, three congenic mouse strains were created. Overlapping genomic intervals from the lean CAST/Ei (CAST) strain were introgressed onto an obesity-susceptible C57BL/6 (BL6) background to create proximal (15 Mb–73 Mb), middle (63 Mb–165 Mb), and distal (83 Mb–182 Mb) congenic strains. The congenic strains showed differences in obesity, insulin, and lipid traits consistent with the original QTL analysis for the locus. Importantly, characterization of the MOB congenics localized the effects of genes that underlie obesity-related traits to an introgressed interval (73–83 Mb) unique to the middle MOB congenic. Conversely, significant differences between the lipid and insulin profiles of the middle and distal MOB congenics implicated the presence of at least two genes that underlie these traits. When fed an atherogenic diet, several traits associated with metabolic syndrome were observed in the distal MOB congenic, while alterations in plasma lipoproteins were observed in the middle MOB congenic strain. 相似文献
93.
Rogers GC Chui KK Lee EW Wedaman KP Sharp DJ Holland G Morris RL Scholey JM 《The Journal of cell biology》2000,150(3):499-512
We have investigated the intracellular roles of an Xklp2-related kinesin motor, KRP(180), in positioning spindle poles during early sea urchin embryonic cell division using quantitative, real-time analysis. Immunolocalization reveals that KRP(180) concentrates on microtubules in the central spindle, but is absent from centrosomes. Microinjection of inhibitory antibodies and dominant negative constructs suggest that KRP(180) is not required for the initial separation of spindle poles, but instead functions to transiently position spindle poles specifically during prometaphase. 相似文献
94.
Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors 总被引:20,自引:0,他引:20
To test whether kinesin-II is important for transport in the mammalian photoreceptor cilium, and to identify its potential cargoes, we used Cre-loxP mutagenesis to remove the kinesin-II subunit, KIF3A, specifically from photoreceptors. Complete loss of KIF3A caused large accumulations of opsin, arrestin, and membranes within the photoreceptor inner segment, while the localization of alpha-transducin was unaffected. Other membrane, organelle, and transport markers, as well as opsin processing appeared normal. Loss of KIF3A ultimately caused apoptotic photoreceptor cell death similar to a known opsin transport mutant. The data suggest that kinesin-II is required to transport opsin and arrestin from the inner to the outer segment and that blocks in this transport pathway lead to photoreceptor cell death as found in retinitis pigmentosa. 相似文献
95.
Effects of nucleotide substitution and modification on the stability and structure of helix 69 from 28S rRNA 总被引:4,自引:1,他引:3
The helix 69 (H69) region of the large subunit (28S) rRNA of Homo sapiens contains five pseudouridine (Psi) residues out of 19 total nucleotides (26%), three of which are universally or highly conserved. In this study, the effects of this abundant modified nucleotide on the structure and stability of H69 were compared with those of uridine. The role of a loop nucleotide substitution from A in bacteria (position 1918 in Escherichia coli 23S rRNA) to G in eukaryotes (position in 3734 in H. sapiens) was also examined. The thermodynamic parameters were obtained through UV melting studies, and differences in the modified and unmodified RNA structures were examined by 1H NMR and circular dichroism spectroscopy. In addition, a [1,3-15N]Psi phosphoramidite was used to generate H69 analogs with site-specific 15N labels. By using this approach, different Psi residues can be clearly distinguished from one another in 1H NMR experiments. The effects of pseudouridine on H. sapiens H69 are consistent with previous studies on tRNA, rRNA, and snRNA models in which the nucleotide offers stabilization of duplex regions through PsiN1H-mediated hydrogen bonds. The overall secondary structure and base-pairing patterns of human H69 are similar to the bacterial RNA, consistent with the idea that ribosome structure and function are highly conserved. Nonetheless, pseudouridine-containing RNAs have subtle differences in their structures and stabilities compared to the corresponding uridine-containing analogs, suggesting possible roles for Psi such as maintaining translation fidelity. 相似文献
96.
Ho CC Siu WY Chow JP Lau A Arooz T Tong HY Ng IO Poon RY 《Experimental cell research》2005,304(1):1-15
Topoisomerase II poisons like Adriamycin (ADR, doxorubicin) are clinically important chemotherapeutic agents. Adriamycin-induced DNA damage checkpoint activates ATM and ATR, which could in turn inhibit the cell cycle engine through either CHK1 or CHK2. In this study, we characterized whether CHK1 or CHK2 is required for Adriamycin-induced checkpoint. We found that both CHK1 and CHK2 were phosphorylated after Adriamycin treatment. Several lines of evidence from dominant-negative mutants, short hairpin RNA (shRNA), and knockout cells indicated that CHK1, but not CHK2, is critical for Adriamycin-induced cell cycle arrest. Disruption of CHK1 function bypassed the checkpoint, as manifested by the increase in CDC25A, activation of CDC2, increase in histone H3 phosphorylation, and reduction in cell survival after Adriamycin treatment. In contrast, CHK2 is dispensable for Adriamycin-induced responses. Finally, we found that CHK1 was upregulated in primary hepatocellular carcinoma (HCC), albeit as an inactive form. The presence of a stockpile of dormant CHK1 in cancer cells may have important implications for treatments like topoisomerase II poisons. Collectively, the available data underscore the pivotal role of CHK1 in checkpoint responses to a variety of stresses. 相似文献
97.
Deshpande?Shayu CS?Chennakesava Rama?Soundarajan A?Jagannadha?RaoEmail author 《Reproductive biology and endocrinology : RB&E》2005,3(1):10
Background
The importance of estrogen in regulation of fluid absorption and sperm maturation in the rodent epididymis has been established from studies on estrogen receptor-alpha knockout mice. However, functional studies on the role of estrogen in primate epididymis have been few. The main objective of this study was therefore to extend these observations and systematically analyze the presence and function of estrogen receptors in modulating the function of the primate epididymis, using the bonnet monkey (Macaca radiata) as a model system. 相似文献98.
Lorey F Cunningham G Vichinsky EP Lubin BH Witkowska HE Matsunaga A Azimi M Sherwin J Eastman J Farina F Waye JS Chui DH 《Genetic testing》2001,5(2):93-100
Newborn screening is an accepted public health measure to ensure that appropriate health care is provided in a timely manner to infants with hereditary/metabolic disorders. Alpha-thalassemia is a common hemoglobin (Hb) disorder, and causes Hb H (beta4) disease, and usually fatal homozygous alpha(0)-thalassemia, also known as Hb Bart's (gamma4) hydrops fetalis syndrome. In 1996, the State of California began to investigate the feasibility of universal newborn screening for Hb H disease. Initial screening was done on blood samples obtained by heel pricks from newborns, and stored as dried blood spots on filter paper. Hb Bart's levels were measured as fast-moving Hb by automated high-performance liquid chromatography (HPLC) identical to that currently used in newborn screening for sickle cell disease. Subsequent confirmation of Hb H disease was done by DNA-based diagnostics for alpha-globin genotyping. A criterion of 25% or more Hb Bart's as determined by HPLC detects most, if not all cases of Hb H disease, and few cases of alpha-thalassemia trait. From January, 1998, through June, 2000, 89 newborns were found to have Hb H disease. The overall prevalence for Hb H disease among all newborns in California is approximately 1 per 15,000. Implementation of this program to existing newborn hemoglobinopathy screening in populations with significant proportions of southeast Asians is recommended. The correct diagnosis would allow affected infants to be properly cared for, and would also raise awareness for the prevention of homozygous alpha(0)-thalassemia or Hb Bart's hydrops fetalis syndrome. 相似文献
99.
Alpha-thalassemia is a common hereditary anemia due to decreased or absent synthesis of alpha-globin chains. The most common causes of alpha-thalassemia are deletions that remove one or both functional alpha-globin genes, with a small proportion of cases involving nondeletional mutations of the alpha2- or alpha1-globin genes. Herein, we describe a single-tube multiplex amplification refractory mutation system (ARMS) assay for rapid detection of six of the most common and severe nondeletional alpha-thalassemia mutations. These alleles are found predominantly among southeast Asian populations, and are associated with the most severe forms of hemoglobin (Hb) H disease or Hb H hydrops fetalis. 相似文献
100.
SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation 下载免费PDF全文
Wu G Lyapina S Das I Li J Gurney M Pauley A Chui I Deshaies RJ Kitajewski J 《Molecular and cellular biology》2001,21(21):7403-7415
Notch receptors and their ligands play important roles in both normal animal development and pathogenesis. We show here that the F-box/WD40 repeat protein SEL-10 negatively regulates Notch receptor activity by targeting the intracellular domain of Notch receptors for ubiquitin-mediated protein degradation. Blocking of endogenous SEL-10 activity was done by expression of a dominant-negative form containing only the WD40 repeats. In the case of Notch1, this block leads to an increase in Notch signaling stimulated by either an activated form of the Notch1 receptor or Jagged1-induced signaling through Notch1. Expression of dominant-negative SEL-10 leads to stabilization of the intracellular domain of Notch1. The Notch4 intracellular domain bound to SEL-10, but its activity was not increased as a result of dominant-negative SEL-10 expression. SEL-10 bound Notch4 via the WD40 repeats and bound preferentially to a phosphorylated form of Notch4 in cells. We mapped the region of Notch4 essential for SEL-10 binding to the C-terminal region downstream of the ankyrin repeats. When this C-terminal fragment of Notch4 was expressed in cells, it was highly labile but could be stabilized by the expression of dominant-negative SEL-10. Ubiquitination of Notch1 and Notch4 intracellular domains in vitro was dependent on SEL-10. Although SEL-10 interacts with the intracellular domains of both Notch1 and Notch4, these proteins respond differently to interference with SEL-10 function. Thus, SEL-10 functions to promote the ubiquitination of Notch proteins; however, the fates of these proteins may differ. 相似文献