全文获取类型
收费全文 | 14172篇 |
免费 | 1958篇 |
国内免费 | 7篇 |
专业分类
16137篇 |
出版年
2021年 | 156篇 |
2019年 | 136篇 |
2018年 | 150篇 |
2017年 | 143篇 |
2016年 | 251篇 |
2015年 | 304篇 |
2014年 | 412篇 |
2013年 | 542篇 |
2012年 | 646篇 |
2011年 | 590篇 |
2010年 | 436篇 |
2009年 | 365篇 |
2008年 | 561篇 |
2007年 | 567篇 |
2006年 | 482篇 |
2005年 | 545篇 |
2004年 | 487篇 |
2003年 | 486篇 |
2002年 | 446篇 |
2001年 | 458篇 |
2000年 | 448篇 |
1999年 | 401篇 |
1998年 | 181篇 |
1997年 | 176篇 |
1996年 | 178篇 |
1995年 | 152篇 |
1994年 | 184篇 |
1993年 | 150篇 |
1992年 | 317篇 |
1991年 | 303篇 |
1990年 | 298篇 |
1989年 | 287篇 |
1988年 | 308篇 |
1987年 | 281篇 |
1986年 | 247篇 |
1985年 | 259篇 |
1984年 | 235篇 |
1983年 | 194篇 |
1982年 | 149篇 |
1981年 | 148篇 |
1980年 | 148篇 |
1979年 | 198篇 |
1978年 | 200篇 |
1977年 | 148篇 |
1976年 | 164篇 |
1975年 | 175篇 |
1974年 | 210篇 |
1973年 | 193篇 |
1972年 | 153篇 |
1970年 | 146篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
961.
Zhanhuai Wang Lindsay M. Hopson Stephanie S. Singleton Xiaochun Yang Wilma Jogunoori Raja Mazumder Vincent Obias Paul Lin Bao-Ngoc Nguyen Michael Yao Larry Miller Jon White Shuyun Rao Lopa Mishra 《生物化学与生物物理学报:疾病的分子基础》2021,1867(10):166179
Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-β signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-β-signaling-deficient mice (Smad4+/? and Smad4+/?Sptbn1+/?), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-β signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-β signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-β pathway in the treatment of CRC or other cancers. 相似文献
962.
963.
Kathie Y Sun Daniel Oreper Sarah A Schoenrock Rachel McMullan Paola Giusti-Rodríguez Vasyl Zhabotynsky Darla R Miller Lisa M Tarantino Fernando Pardo-Manuel de Villena William Valdar 《Genetics》2021,218(1)
Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176-kb candidate interval. A series of functional Xce alleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function structure basis and location of the Xce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross (CC) strains. Using published sequence data and applying a Bayesian “Pólya urn” model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20–30 cells contributing to brain. Second, CC founder strain NOD/ShiLtJ has a novel and unique functional allele, Xceg, that is the weakest in the Xce allelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xceb), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles. 相似文献
964.
Joshua Havumaki Ted Cohen Chengwei Zhai Joel C. Miller Seth D. Guikema Marisa C. Eisenberg Jon Zelner 《PLoS computational biology》2021,17(2)
There is an emerging consensus that achieving global tuberculosis control targets will require more proactive case finding approaches than are currently used in high-incidence settings. Household contact tracing (HHCT), for which households of newly diagnosed cases are actively screened for additional infected individuals is a potentially efficient approach to finding new cases of tuberculosis, however randomized trials assessing the population-level effects of such interventions in settings with sustained community transmission have shown mixed results. One potential explanation for this is that household transmission is responsible for a variable proportion of population-level tuberculosis burden between settings. For example, transmission is more likely to occur in households in settings with a lower tuberculosis burden and where individuals mix preferentially in local areas, compared with settings with higher disease burden and more dispersed mixing. To better understand the relationship between endemic incidence levels, social mixing, and the impact of HHCT, we developed a spatially explicit model of coupled household and community transmission. We found that the impact of HHCT was robust across settings of varied incidence and community contact patterns. In contrast, we found that the effects of community contact tracing interventions were sensitive to community contact patterns. Our results suggest that the protective benefits of HHCT are robust and the benefits of this intervention are likely to be maintained across epidemiological settings. 相似文献
965.
Mark E. Corkins Vanja Krneta‐Stankic Malgorzata Kloc Rachel K. Miller 《Genesis (New York, N.Y. : 2000)》2021,59(1-2):e23410
Cilia are microtubule‐based structures that either transmit information into the cell or move fluid outside of the cell. There are many human diseases that arise from malfunctioning cilia. Although mammalian models provide vital insights into the underlying pathology of these diseases, aquatic organisms such as Xenopus and zebrafish provide valuable tools to help screen and dissect out the underlying causes of these diseases. In this review we focus on recent studies that identify or describe different types of human ciliopathies and outline how aquatic organisms have aided our understanding of these diseases. 相似文献
966.
J. Benjamin Miller Amitesh Pratap Akira Miyahara Liang Zhou Stephen Bornemann Richard J. Morris Giles E.D. Oldroyd 《The Plant cell》2013,25(12):5053-5066
The establishment of symbiotic associations in plants requires calcium oscillations that must be decoded to invoke downstream developmental programs. In animal systems, comparable calcium oscillations are decoded by calmodulin (CaM)–dependent protein kinases, but symbiotic signaling involves a calcium/CaM–dependent protein kinase (CCaMK) that is unique to plants. CCaMK differs from the animal CaM kinases by its dual ability to bind free calcium, via calcium binding EF-hand domains on the protein, or to bind calcium complexed with CaM, via a CaM binding domain. In this study, we dissect this dual regulation of CCaMK by calcium. We find that calcium binding to the EF-hand domains promotes autophosphorylation, which negatively regulates CCaMK by stabilizing the inactive state of the protein. By contrast, calcium-dependent CaM binding overrides the effects of autophosphorylation and activates the protein. The differential calcium binding affinities of the EF-hand domains compared with those of CaM suggest that CCaMK is maintained in the inactive state at basal calcium concentrations and is activated via CaM binding during calcium oscillations. This work provides a model for decoding calcium oscillations that uses differential calcium binding affinities to create a robust molecular switch that is responsive to calcium concentrations associated with both the basal state and with oscillations. 相似文献
967.
Kristyn Echterling-Savage Florence D. DiGennaro Reed L. Keith Miller Sean Savage 《Journal of applied animal welfare science : JAAWS》2013,16(2):181-197
Problem behavior of companion animals poses a threat to caregivers, other targets of problem behavior (e.g., strangers, other nonhuman animals), and those animals engaging in problem behavior. This study examined the effects of an aggression reduction procedure (ARP) on dog problem behavior. After a baseline condition showing caregivers were unsuccessful in reducing dog aggression and the behaviors preceding aggression, caregivers were trained to implement a procedure to address dog problem behavior in relatively simple contexts. Generalization programming then was used to target caregiver plan implementation and dog problem behavior in more complex contexts. The ARP effectively reduced dog aggression for all dogs. A slight reduction and increased variability in dog precursor behavior was observed when the ARP was implemented. In addition, caregivers and experts rated the goals, procedures, and effects as acceptable. Implications of these findings are discussed. 相似文献
968.
969.
Human aorta has been shown to possess multiple forms of N-Acetyl-6-D-hexosaminidase (β-2-acetamido-2-deoxy-D-glucoside-acetamido-deoxyglucohydro-lase, EC 3.2, 1.30). The enzyme was separable, by gel electrophoresis, into 2 enzymatically active bands representing A and B forms. By gel electro-focussing, A and B forms were further subdivided into at least 5 and 8 bands, respectively. The B form consisted of 4 bands (B1) and 4 bands (B2), which were not inactivated at 50° for 3 hr. (at pH 4.4) in the presence of serum; whereas, the 5 bands found in A form were completely inactivated. All forms of the enzyme were active towards naphthol-AS-BI-N-acetyl-β-D-glucosaminide and the corresponding galactosaminide (about one-eighth of the hydrolysis rate of the former), suggesting each single enzyme acts on both substrates. The N-acetyl-hexosaminidases of bull epididymis, by comparison, were also found to be active towards both substrates and to possess 13 bands having pis more alkaline than those of the B form of the human enzyme, By heat inactivation we found that the aortic enzyme consisted of 51% of A and 49% of B (B1 + B2 .). Neuraminidase had no effect on either form of the aortic preparation. Both forms were partially purified and separated by conventional methods. They required BSA for their maximal activity; the A form being more dependent BSA than the B form, With PNP-N-acetyl-β-D-glucosaminide and the corresponding galactosaminide, Km of 1.04 mH and 0.54 mM, respectively, for A form and of 1.74 and 1.48 mM, respectively, for B form were obtained. While the purified B form was stable and did not transform into other species, the purified A form gradually transformed into B form as well as into other new forms during storage at -20°. 相似文献
970.
Jeffrey B Driban Grace H Lo Lori Lyn Price Jincheng Pang Eric Miller Robert J Ward David J Hunter Charles B Eaton John A Lynch Timothy E McAlindon 《Arthritis research & therapy》2013,15(5):R153