全文获取类型
收费全文 | 10605篇 |
免费 | 997篇 |
专业分类
11602篇 |
出版年
2023年 | 59篇 |
2022年 | 139篇 |
2021年 | 290篇 |
2020年 | 138篇 |
2019年 | 191篇 |
2018年 | 237篇 |
2017年 | 197篇 |
2016年 | 315篇 |
2015年 | 551篇 |
2014年 | 609篇 |
2013年 | 660篇 |
2012年 | 1017篇 |
2011年 | 1019篇 |
2010年 | 589篇 |
2009年 | 514篇 |
2008年 | 781篇 |
2007年 | 752篇 |
2006年 | 680篇 |
2005年 | 614篇 |
2004年 | 555篇 |
2003年 | 507篇 |
2002年 | 447篇 |
2001年 | 107篇 |
2000年 | 54篇 |
1999年 | 69篇 |
1998年 | 72篇 |
1997年 | 55篇 |
1996年 | 25篇 |
1995年 | 22篇 |
1994年 | 19篇 |
1993年 | 17篇 |
1992年 | 30篇 |
1991年 | 18篇 |
1990年 | 20篇 |
1989年 | 19篇 |
1988年 | 7篇 |
1987年 | 12篇 |
1986年 | 18篇 |
1985年 | 13篇 |
1984年 | 12篇 |
1983年 | 15篇 |
1982年 | 11篇 |
1981年 | 14篇 |
1980年 | 12篇 |
1979年 | 7篇 |
1978年 | 11篇 |
1972年 | 6篇 |
1971年 | 6篇 |
1968年 | 6篇 |
1965年 | 5篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Lovastatin and other statins inhibit HMG-CoA reductase, which carries out an early step in the sterol biosynthesis pathway. Statins lower cholesterol and are widely prescribed to prevent heart disease, but like many drugs, they can interact with nutritionally acquired metabolites. To probe these interactions, we explored the effect of a diverse library of metabolites on statin effectiveness using a Saccharomyces cerevisiae model. In yeast, treatment with lovastatin results in reduced growth. We combined lovastatin with the library of metabolites, and found that copper and zinc ions impaired the ability of the statin to inhibit yeast growth. Using an integrated genomic and metabolomic approach, we found that lovastatin plus metal synergistically upregulated some sterol biosynthesis genes. This altered pattern of gene expression resulted in greater flux through the sterol biosynthesis pathway and an increase in ergosterol levels. Each sterol intermediate level was correlated with expression of the upstream gene. Thus, the ergosterol biosynthetic response induced by statin is enhanced by copper and zinc. In cultured mammalian cells, these metals also rescued statin growth inhibition. Because copper and zinc impair the ability of statin to reduce sterol biosynthesis, dietary intake of these metals could have clinical relevance for statin treatment in humans. 相似文献
992.
Jason Li Maria A. Doyle Isaam Saeed Stephen Q. Wong Victoria Mar David L. Goode Franco Caramia Ken Doig Georgina L. Ryland Ella R. Thompson Sally M. Hunter Saman K. Halgamuge Jason Ellul Alexander Dobrovic Ian G. Campbell Anthony T. Papenfuss Grant A. McArthur Richard W. Tothill 《PloS one》2014,9(4)
Targeted resequencing by massively parallel sequencing has become an effective and affordable way to survey small to large portions of the genome for genetic variation. Despite the rapid development in open source software for analysis of such data, the practical implementation of these tools through construction of sequencing analysis pipelines still remains a challenging and laborious activity, and a major hurdle for many small research and clinical laboratories. We developed TREVA (Targeted REsequencing Virtual Appliance), making pre-built pipelines immediately available as a virtual appliance. Based on virtual machine technologies, TREVA is a solution for rapid and efficient deployment of complex bioinformatics pipelines to laboratories of all sizes, enabling reproducible results. The analyses that are supported in TREVA include: somatic and germline single-nucleotide and insertion/deletion variant calling, copy number analysis, and cohort-based analyses such as pathway and significantly mutated genes analyses. TREVA is flexible and easy to use, and can be customised by Linux-based extensions if required. TREVA can also be deployed on the cloud (cloud computing), enabling instant access without investment overheads for additional hardware. TREVA is available at http://bioinformatics.petermac.org/treva/. 相似文献
993.
Viatcheslav Gurev Ted Lee Jason Constantino Hermenegild Arevalo Natalia A. Trayanova 《Biomechanics and modeling in mechanobiology》2011,10(3):295-306
Current multi-scale computational models of ventricular electromechanics describe the full process of cardiac contraction
on both the micro- and macro- scales including: the depolarization of cardiac cells, the release of calcium from intracellular
stores, tension generation by cardiac myofilaments, and mechanical contraction of the whole heart. Such models are used to
reveal basic mechanisms of cardiac contraction as well as the mechanisms of cardiac dysfunction in disease conditions. In
this paper, we present a methodology to construct finite element electromechanical models of ventricular contraction with
anatomically accurate ventricular geometry based on magnetic resonance and diffusion tensor magnetic resonance imaging of
the heart. The electromechanical model couples detailed representations of the cardiac cell membrane, cardiac myofilament
dynamics, electrical impulse propagation, ventricular contraction, and circulation to simulate the electrical and mechanical
activity of the ventricles. The utility of the model is demonstrated in an example simulation of contraction during sinus
rhythm using a model of the normal canine ventricles. 相似文献
994.
Production of a particulate hepatitis C vaccine candidate by an engineered Lactococcus lactis strain
Parlane NA Grage K Lee JW Buddle BM Denis M Rehm BH 《Applied and environmental microbiology》2011,77(24):8516-8522
Vaccine delivery systems based on display of antigens on bioengineered bacterial polyester inclusions can stimulate cellular immune responses. The food-grade Gram-positive bacterium Lactococcus lactis was engineered to produce spherical polyhydroxybutyrate (PHB) inclusions which abundantly displayed the hepatitis C virus core (HCc) antigen. In mice, the immune response induced by this antigen delivery system was compared to that induced by vaccination with HCc antigen displayed on PHB beads produced in Escherichia coli, to PHB beads without antigen produced in L. lactis or E. coli, or directly to the recombinant HCc protein. Vaccination site lesions were minimal in all mice vaccinated with HCc PHB beads or recombinant protein, all mixed in the oil-in-water adjuvant Emulsigen, while vaccination with the recombinant protein in complete Freund's adjuvant produced a marked inflammatory reaction at the vaccination site. Vaccination with the PHB beads produced in L. lactis and displaying HCc antigen produced antigen-specific cellular immune responses with significant release of gamma interferon (IFN-γ) and interleukin-17A (IL-17A) from splenocyte cultures and no significant antigen-specific serum antibody, while the PHB beads displaying HCc but produced in E. coli released IFN-γ and IL-17A as well as the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-6 and low levels of IgG2c antibody. In contrast, recombinant HCc antigen in Emulsigen produced a diverse cytokine response and a strong IgG1 antibody response. Overall it was shown that L. lactis can be used to produce immunogenic PHB beads displaying viral antigens, making the beads suitable for vaccination against viral infections. 相似文献
995.
Marjorie C. Sorensen Tanmay Dixit Kevin J. Kardynal Jason Newton Keith A. Hobson Staffan Bensch Susanne Jenni‐Eiermann Claire N. Spottiswoode 《Ecology and evolution》2019,9(14):8294-8304
Migration can influence host–parasite dynamics in animals by increasing exposure to parasites, by reducing the energy available for immune defense, or by culling of infected individuals. These mechanisms have been demonstrated in several comparative analyses; however, few studies have investigated whether conspecific variation in migration distance may also be related to infection risk. Here, we ask whether autumn migration distance, inferred from stable hydrogen isotope analysis of summer‐grown feathers (δ2Hf) in Europe, correlates with blood parasite prevalence and intensity of infection for willow warblers (Phylloscopus trochilus) wintering in Zambia. We also investigated whether infection was correlated with individual condition (assessed via corticosterone, scaled mass index, and feather quality). We found that 43% of birds were infected with Haemoproteus palloris (lineage WW1). Using generalized linear models, we found no relationship between migration distance and either Haemoproteus infection prevalence or intensity. There was spatial variation in breeding ground origins of infected versus noninfected birds, with infected birds originating from more northern sites than noninfected birds, but this difference translated into only slightly longer estimated migration distances (~214 km) for infected birds. We found no relationship between body condition indices and Haemoproteus infection prevalence or intensity. Our results do not support any of the proposed mechanisms for migration effects on host–parasite dynamics and cautiously suggest that other factors may be more important for determining individual susceptibility to disease in migratory bird species. 相似文献
996.
Psychiatric hospitalizations, completed suicides, and suicide attempts are rare after predictive testing for Huntington's disease (HD). Case studies have shown that major depression can be a consequence of being tested, although no studies have shown how common this is. The present study evaluated the prevalence of major depression during the first year after disclosure. We conducted retrospective data and chart reviews of 153 persons (50 testing positive, 103 testing negative) evaluated every 3 months for depression. There was no significant baseline difference in the percentage of "positives" and "negatives" who had pre-testing major depressive episodes (14% vs. 12%, respectively). A senior psychiatrist reviewed data from the Schedule for Affective Disorders and Schizophrenia-Change Version, from the Beck Depression Inventory, and from clinical notes for every follow-up contact completed. The 1-year prevalence of major depression among positives was 6.0%, compared to 3.0% among negatives (p = 0.30), and an estimated 3% population prevalence. One-year prevalence of clinically significant depressive symptoms, whether or not major depression was diagnosed, was 20.0% in positives and 12.6% in negatives (p = 0.17). Although not statistically significant, depressive symptoms and major depression occurred more frequently among those who tested positive. Despite some evidence to the contrary, including our own studies, a positive predictive test for HD is not psychologically benign. Clinical testing programs should assess patients for depressive symptoms after testing, and patients with clinically significant complaints should be referred to a mental health professional. 相似文献
997.
Jason E. Mills James A. Reinartz Gretchen A. Meyer Erica B. Young 《Biological invasions》2009,11(8):1803-1820
In this long-term study, we examined the invasion by the exotic shrub glossy buckthorn (Rhamnus frangula L.) and the response of co-occurring plants in a large, undisturbed wetland. We first sampled the vegetation in 1991 and
repeated the sample 15 years later using the same, permanently located sample units (n = 165). Despite dramatic increases in the abundance of buckthorn, the invasion elicited little apparent response by the resident
plant community. Species richness and cover in the herbaceous plant stratum had no apparent relationship with change in buckthorn
cover. The number of shrub species other than buckthorn showed no relationship with change in buckthorn cover, but the cover
of other shrubs decreased as buckthorn cover increased. Species composition changed independently of changes in buckthorn
cover. These results show that dramatic increases in the abundance of an invasive species do not necessarily cause large changes
in the native plant community and suggest disturbance history influences community response to invasion. 相似文献
998.
Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells. 总被引:4,自引:0,他引:4
Paul Sharp Sarah Tandy Sachie Yamaji Jason Tennant Mark Williams Surjit Kaila Singh Srai 《FEBS letters》2002,510(1-2):71-76
A divalent metal transporter, DMT1, located on the apical membrane of intestinal enterocytes is the major pathway for the absorption of dietary non-haem iron. Using human intestinal Caco-2 TC7 cells, we have shown that iron uptake and DMT1 protein in the plasma membrane were significantly decreased by exposure to high iron for 24 h, in a concentration-dependent manner, whereas whole cell DMT1 protein abundance was unaltered. This suggests that part of the response to high iron involved redistribution of DMT1 between the cytosol and cell membrane. These events preceded changes in DMT1 mRNA, which was only decreased following 72 h exposure to high iron. 相似文献
999.
Timothy N. Schaeffer G. Jason Smith Michael S. Foster Anthony DeTomaso 《Journal of phycology》2002,38(6):1090-1098
Unattached, nongeniculate, coralline algae or rhodoliths exhibit a range of morphological variability seemingly dependent on environmental factors. Rhodoliths have an extensive fossil record, and environmentally dependent characteristics make them potentially reliable paleoindicators. Species of the rhodolith‐forming genus Lithophyllum Philippi in Baja California Sur, Mexico were recently consolidated into one species. Under the new classification, L. margaritae (Hariot) Heydrich consists of several growth forms presumably reflecting local environmental conditions. We examined the genetic structure of four populations of this species using amplified fragment length polymorphisms (AFLP) to characterize the extent of genetic variation associated with foliose and fruticose growth forms. AFLP band sharing analysis revealed that foliose growth forms exhibited consistently higher intrapopulation similarities (0.75–0.85) than fruticose growth forms (similarity range, 0.55–0.67). This trend was also evident in comparisons of geographically isolated populations. These data indicate that the two morphologies are genetically distinct and that genetic exchange between foliose and fruticose growth forms of L. margaritae may be limited. Consequently, rhodolith growth forms appear to be the result of an interplay between both genetic makeup and environmental conditions. 相似文献
1000.
Fibroblasts derived from focal adhesion kinase (FAK)-null mouse embryos have a reduced migration rate and an increase in the number and size of peripherally localized adhesions (Ilic, D., Furuta, Y., Kanazawa, S., Takeda, N., Sobue, K., Nakatsuji, N., Nomura, S., Fujimoto, J., Okada, M., and Yamamoto, T. (1995) Nature 377, 539-544). In this study, we have found that Y27632, a specific inhibitor for Rho-associated kinase (Rho-kinase), dramatically reversed the round cell morphology of FAK(-/-) cells to a spread fibroblast-like shape in 30 min and significantly enhanced their motility. The effects of Y27632 on the FAK(-/-) cell morphology and motility were concomitant with reorganization of the actin cytoskeleton and redistribution of focal adhesions. Conversely, the expression of the constitutively active Rho-kinase in FAK(+/+) cells led to round cell shape and inhibition of cell motility. Furthermore, coincident with the formation of cortical actin filaments, myosin light chain (MLC), Ser-19-phosphorylated MLC, and MLC kinase mainly accumulated at the FAK(-/-) cell periphery. We found that the disruption of actin filaments by cytochalasin D prevented the peripheral accumulation of MLC kinase and that inhibition of myosin-mediated contractility by 2,3-butanedione monoxime induced FAK(-/-) cells to spread. Taken together, our results suggest that Rho-kinase may mediate the formation of cortical actomyosin filaments at the FAK(-/-) cell periphery, which further recruits MLC kinase to the cell periphery and generates a non-polar contractile force surrounding the cell, leading to cell rounding and decreased motility. 相似文献