全文获取类型
收费全文 | 2735篇 |
免费 | 290篇 |
国内免费 | 2篇 |
出版年
2023年 | 13篇 |
2022年 | 39篇 |
2021年 | 65篇 |
2020年 | 43篇 |
2019年 | 50篇 |
2018年 | 49篇 |
2017年 | 52篇 |
2016年 | 88篇 |
2015年 | 157篇 |
2014年 | 200篇 |
2013年 | 175篇 |
2012年 | 284篇 |
2011年 | 284篇 |
2010年 | 168篇 |
2009年 | 136篇 |
2008年 | 202篇 |
2007年 | 169篇 |
2006年 | 164篇 |
2005年 | 162篇 |
2004年 | 138篇 |
2003年 | 105篇 |
2002年 | 103篇 |
2001年 | 15篇 |
2000年 | 5篇 |
1999年 | 13篇 |
1998年 | 27篇 |
1997年 | 9篇 |
1996年 | 9篇 |
1995年 | 16篇 |
1994年 | 11篇 |
1993年 | 6篇 |
1992年 | 4篇 |
1991年 | 8篇 |
1990年 | 4篇 |
1989年 | 5篇 |
1988年 | 5篇 |
1987年 | 6篇 |
1986年 | 6篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 4篇 |
1978年 | 2篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有3027条查询结果,搜索用时 296 毫秒
141.
142.
Kristin L. Rosche Alanoud T. Aljasham James N. Kipfer Bryan T. Piatkowski Vjollca Konjufca 《PloS one》2015,10(6)
Infection of mice with Salmonella enterica serovar Typhimurium (Salmonella) causes systemic inflammatory disease and enlargement of the spleen (splenomegaly). Splenomegaly has been attributed to a general increase in the numbers of phagocytes, lymphocytes, as well as to the expansion of immature CD71+Ter119+ reticulocytes. The spleen is important for recycling senescent red blood cells (RBCs) and for the capture and eradication of blood-borne pathogens. Conservation of splenic tissue architecture, comprised of the white pulp (WP), marginal zone (MZ), and red pulp (RP) is essential for initiation of adaptive immune responses to captured pathogens. Using flow cytometry and four color immunofluorescence microscopy (IFM), we show that Salmonella-induced splenomegaly is characterized by drastic alterations of the splenic tissue architecture and cell population proportions, as well as in situ cell distributions. A major cause of splenomegaly appears to be the significant increase in immature RBC precursors and F4/80+ macrophages that are important for recycling of heme-associated iron. In contrast, the proportions of B220+, CD4+ and CD8+ lymphocytes, as well as MZ MOMA+ macrophages decrease significantly as infection progresses. Spleen tissue sections show visible tears and significantly altered tissue architecture with F4/80+ macrophages and RBCs expanding beyond the RP and taking over most of the spleen tissue. Additionally, F4/80+ macrophages actively phagocytose not only RBCs, but also lymphocytes, indicating that they may contribute to declining lymphocyte proportions during Salmonella infection. Understanding how these alterations of spleen microarchitecture impact the generation of adaptive immune responses to Salmonella has implications for understanding Salmonella pathogenesis and for the design of more effective Salmonella-based vaccines. 相似文献
143.
Karl C. Desch Colin Kretz Andrew Yee Robert Gildersleeve Kristin Metzger Nidhi Agrawal Jane Cheng David Ginsburg 《PloS one》2015,10(4)
Von Willebrand factor (VWF) is a large, multimeric protein that regulates hemostasis by tethering platelets to the subendothelial matrix at sites of vascular damage. The procoagulant activity of plasma VWF correlates with the length of VWF multimers, which is proteolytically controlled by the metalloprotease ADAMTS13. To probe ADAMTS13 substrate specificity, we created phage display libraries containing randomly mutated residues of a minimal ADAMTS13 substrate fragment of VWF, termed VWF73. The libraries were screened for phage particles displaying VWF73 mutant peptides that were resistant to proteolysis by ADAMTS13. These peptides exhibited the greatest mutation frequency near the ADAMTS13 scissile residues. Kinetic assays using mutant and wild-type substrates demonstrated excellent agreement between rates of cleavage for mutant phage particles and the corresponding mutant peptides. Cleavage resistance of selected mutations was tested in vivo using hydrodynamic injection of corresponding full-length expression plasmids into VWF-deficient mice. These studies confirmed the resistance to cleavage resulting from select amino acid substitutions and uncovered evidence of alternate cleavage sites and recognition by other proteases in the circulation of ADAMTS13 deficient mice. Taken together, these studies demonstrate the key role of specific amino acids residues including P3-P2’ and P11’, for substrate specificity and emphasize the importance in flowing blood of other ADAMTS13–VWF exosite interactions outside of VWF73. 相似文献
144.
Ameeta S. Kalokhe Ratnaprabha R. Potdar Rob Stephenson Kristin L. Dunkle Anuradha Paranjape Carlos del Rio Seema Sahay 《PloS one》2015,10(3)
Domestic violence (DV) is reported by 40% of married women in India and associated with substantial morbidity. An operational research definition is therefore needed to enhance understanding of DV epidemiology in India and inform DV interventions and measures. To arrive at a culturally-tailored definition, we aimed to better understand how definitions provided by the World Health Organization and the 2005 India Protection of Women from Domestic Violence Act match the perceptions of behaviors constituting DV among the Indian community. Between September 2012 and January 2013, 16 key informant interviews with experts in DV and family counseling and 2 gender-concordant focus groups of lay community members were conducted in Pune, India to understand community perceptions of the definition of DV, perpetrators of DV, and examples of DV encountered by married women in Pune, India. Several key themes emerged regarding behaviors and acts constituting DV including 1) the exertion of control over a woman’s reproductive decision-making, mobility, socializing with family and friends, finances, and access to food and nutrition, 2) the widespread acceptance of sexual abuse and the influences of affluence on sexual DV manifestations, 3) the shaping of physical abuse experiences by readily-available tools and the presence of witnesses, 4) psychological abuse for infertility, dowry, and girl-children, and 5) the perpetration of DV by the husband and other members of his family. Findings support the need for a culturally-tailored operational definition that expands on the WHO surveillance definition to inform the development of more effective DV intervention strategies and measures. 相似文献
145.
Intraskeletal isotopic compositions (δ13C, δ15N) of bone collagen: Nonpathological and pathological variation
下载免费PDF全文
![点击此处可从《American journal of physical anthropology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Karyn C. Olsen Christine D. White Fred J. Longstaffe Kristin von Heyking George McGlynn Gisela Grupe Frank J. Rühli 《American journal of physical anthropology》2014,153(4):598-604
Paleodiet research traditionally interprets differences in collagen isotopic compositions (δ13C, δ15N) as indicators of dietary distinction even though physiological processes likely play some role in creating variation. This research investigates the degree to which bone collagen δ13C and δ15N values normally vary within the skeleton and examines the influence of several diseases common to ancient populations on these isotopic compositions. The samples derive from two medieval German cemeteries and one Swiss reference collection and include examples of metabolic disease (rickets/osteomalacia), degenerative joint disease (osteoarthritis), trauma (fracture), infection (osteomyelitis), and inflammation (periostitis). A separate subset of visibly nonpathological skeletal elements from the German collections established normal intraindividual variation. For each disease type, tests compared bone lesion samples to those near and distant to the lesions sites. Results show that normal (nonpathological) skeletons exhibit limited intraskeletal variation in carbon‐ and nitrogen‐isotope ratios, suggesting that sampling of distinct elements is appropriate for paleodiet studies. In contrast, individuals with osteomyelitis, healed fractures, and osteoarthritis exhibit significant intraskeletal differences in isotope values, depending on whether one is comparing lesions to near or to distant sites. Skeletons with periostitis result in significant intraskeletal differences in nitrogen isotope values only, while those with rickets/osteomalacia do not exhibit significant intraskeletal differences. Based on these results, we suggest that paleodiet researchers avoid sampling collagen at or close to lesion sites because the isotope values may be reflecting both altered metabolic processes and differences in diet relative to others in the population. Am J Phys Anthropol 153:598–604, 2014. © 2013 Wiley Periodicals, Inc. 相似文献
146.
147.
Robert J. Yamulla Eric G. Kane Alexandra E. Moody Kristin A. Politi Nicole E. Lock Andrew V. A. Foley David M. Roberts 《Genetics》2014,197(4):1285-1302
The Wnt pathway is a conserved signal transduction pathway that contributes to normal development and adult homeostasis, but is also misregulated in human diseases such as cancer. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling inactivated in >80% of colorectal cancers. APC participates in a multiprotein “destruction complex” that targets the proto-oncogene β-catenin for ubiquitin-mediated proteolysis; however, the mechanistic role of APC in the destruction complex remains unknown. Several models of APC function have recently been proposed, many of which have emphasized the importance of phosphorylation of high-affinity β-catenin-binding sites [20-amino-acid repeats (20Rs)] on APC. Here we test these models by generating a Drosophila APC2 mutant lacking all β-catenin-binding 20Rs and performing functional studies in human colon cancer cell lines and Drosophila embryos. Our results are inconsistent with current models, as we find that β-catenin binding to the 20Rs of APC is not required for destruction complex activity. In addition, we generate an APC2 mutant lacking all β-catenin-binding sites (including the 15Rs) and find that a direct β-catenin/APC interaction is also not essential for β-catenin destruction, although it increases destruction complex efficiency in certain developmental contexts. Overall, our findings support a model whereby β-catenin-binding sites on APC do not provide a critical mechanistic function per se, but rather dock β-catenin in the destruction complex to increase the efficiency of β-catenin destruction. Furthermore, in Drosophila embryos expressing some APC2 mutant transgenes we observe a separation of β-catenin destruction and Wg/Wnt signaling outputs and suggest that cytoplasmic retention of β-catenin likely accounts for this difference. 相似文献
148.
Timo Kanzleiter Michaela Rath Sven W. Görgens Jørgen Jensen Daniel S. Tangen Anders J. Kolnes Kristoffer J. Kolnes Sindre Lee Jürgen Eckel Annette Schürmann Kristin Eckardt 《Biochemical and biophysical research communications》2014
The health-promoting effects of regular exercise are well known, and myokines may mediate some of these effects. The small leucine-rich proteoglycan decorin has been described as a myokine for some time. However, its regulation and impact on skeletal muscle has not been investigated in detail. In this study, we report decorin to be differentially expressed and released in response to muscle contraction using different approaches. Decorin is released from contracting human myotubes, and circulating decorin levels are increased in response to acute resistance exercise in humans. Moreover, decorin expression in skeletal muscle is increased in humans and mice after chronic training. Because decorin directly binds myostatin, a potent inhibitor of muscle growth, we investigated a potential function of decorin in the regulation of skeletal muscle growth. In vivo overexpression of decorin in murine skeletal muscle promoted expression of the pro-myogenic factor Mighty, which is negatively regulated by myostatin. We also found Myod1 and follistatin to be increased in response to decorin overexpression. Moreover, muscle-specific ubiquitin ligases atrogin1 and MuRF1, which are involved in atrophic pathways, were reduced by decorin overexpression. In summary, our findings suggest that decorin secreted from myotubes in response to exercise is involved in the regulation of muscle hypertrophy and hence could play a role in exercise-related restructuring processes of skeletal muscle. 相似文献
149.
Girijavallabhan VM Chen L Dai C Feltz RJ Firmansjah L Li D Kim SH Kozlowski JA Lavey BJ Kosinski A Piwinski JJ Popovici-Muller J Rizvi R Rosner KE Shankar BB Shih NY Siddiqui MA Tong L Wong MK Yang DY Yang L Yu W Zhou G Guo Z Orth P Madison V Bian H Lundell D Niu X Shah H Sun J Umland S 《Bioorganic & medicinal chemistry letters》2010,20(24):7283-7287
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles. 相似文献
150.
Gentner R Gorges S Weise D aufm Kampe K Buttmann M Classen J 《Current biology : CB》2010,20(20):1869-1874
How motor skills are stored in the nervous system represents a fundamental question in neuroscience. Although musical motor skills are associated with a variety of adaptations [1-3], it remains unclear how these changes are linked to the known superior motor performance of expert musicians. Here we establish a direct and specific relationship between the functional organization of the corticomuscular system and skilled musical performance. Principal component analysis was used to identify joint correlation patterns in finger movements evoked by transcranial magnetic stimulation over the primary motor cortex while subjects were at rest. Linear combinations of a selected subset of these patterns were used to reconstruct active instrumental playing or grasping movements. Reconstruction quality of instrumental playing was superior in skilled musicians compared to musically untrained subjects, displayed taxonomic specificity for the trained movement repertoire, and correlated with the cumulated long-term training exposure, but not with the recent past training history. In violinists, the reconstruction quality of grasping movements correlated negatively with the long-term training history of violin playing. Our results indicate that experience-dependent motor skills are specifically encoded in the functional organization of the primary motor cortex and its efferent system and are consistent with a model of skill coding by a modular neuronal architecture [4]. 相似文献