全文获取类型
收费全文 | 1575篇 |
免费 | 261篇 |
专业分类
1836篇 |
出版年
2022年 | 10篇 |
2021年 | 23篇 |
2020年 | 14篇 |
2019年 | 14篇 |
2018年 | 27篇 |
2017年 | 25篇 |
2016年 | 41篇 |
2015年 | 80篇 |
2014年 | 58篇 |
2013年 | 107篇 |
2012年 | 62篇 |
2011年 | 62篇 |
2010年 | 51篇 |
2009年 | 65篇 |
2008年 | 70篇 |
2007年 | 70篇 |
2006年 | 58篇 |
2005年 | 51篇 |
2004年 | 40篇 |
2003年 | 46篇 |
2002年 | 48篇 |
2001年 | 39篇 |
2000年 | 57篇 |
1999年 | 48篇 |
1998年 | 43篇 |
1997年 | 36篇 |
1996年 | 33篇 |
1995年 | 23篇 |
1994年 | 19篇 |
1993年 | 20篇 |
1992年 | 38篇 |
1991年 | 35篇 |
1990年 | 42篇 |
1989年 | 25篇 |
1988年 | 33篇 |
1987年 | 25篇 |
1986年 | 27篇 |
1985年 | 32篇 |
1984年 | 13篇 |
1983年 | 19篇 |
1982年 | 22篇 |
1981年 | 8篇 |
1980年 | 8篇 |
1979年 | 18篇 |
1978年 | 14篇 |
1977年 | 18篇 |
1976年 | 15篇 |
1975年 | 16篇 |
1968年 | 8篇 |
1967年 | 8篇 |
排序方式: 共有1836条查询结果,搜索用时 15 毫秒
31.
The “Hill” equation for co-operative binding-systems has been extended to describe the effect of substrate-analogue on the binding of substrate to an oligomeric protein. It is demonstrated that the more negatively co-operative the binding-system, the more sensitive is the binding of substrate to inhibition by increases in the relative concentration of substrate-analogue. It is proposed that the physiological significance of negative co-operativity for enzymes may be complementary to the physiological significance of positive co-operativity. The effect of negative co-operativity is to make substrate binding more sensitive to inhibition by relative increases in the concentration of substrate-analogue (e.g. for many enzymes product of the reaction) at the expense of decreased sensitivity of substrate binding to relative changes in substrate concentration compared to a system with equivalent, independent substrate binding sites. In contrast, the effect of positive co-operativity is to make the enzyme more sensitive to relative changes in substrate concentration at the expense of decreased sensitivity to inhibition by relative increases in product concentration, compared to an enzyme without co-operative binding. 相似文献
32.
Hasan Demirci Leyi Wang Frank V. Murphy IV Eileen L. Murphy Jennifer F. Carr Scott C. Blanchard Gerwald Jogl Albert E. Dahlberg Steven T. Gregory 《RNA (New York, N.Y.)》2013,19(12):1791-1801
The ribosome decodes mRNA by monitoring the geometry of codon–anticodon base-pairing using a set of universally conserved 16S rRNA nucleotides within the conformationally dynamic decoding site. By applying single-molecule FRET and X-ray crystallography, we have determined that conditional-lethal, streptomycin-dependence mutations in ribosomal protein S12 interfere with tRNA selection by allowing conformational distortions of the decoding site that impair GTPase activation of EF-Tu during the tRNA selection process. Distortions in the decoding site are reversed by streptomycin or by a second-site suppressor mutation in 16S rRNA. These observations encourage a refinement of the current model for decoding, wherein ribosomal protein S12 and the decoding site collaborate to optimize codon recognition and substrate discrimination during the early stages of the tRNA selection process. 相似文献
33.
Ants are powerful model systems for the study of cooperation and sociality. In this review, we discuss how recent advances in ant genomics have contributed to our understanding of the evolution and organization of insect societies at the molecular level. 相似文献
34.
35.
Ahmed F. Salem Mazhar Salim Al-Zoubi Diana Whitaker-Menezes Ubaldo E. Martinez-Outschoorn Rebecca Lamb James Hulit Anthony Howell Ricardo Gandara Marina Sartini Ferruccio Galbiati Generoso Bevilacqua Federica Sotgia Michael P. Lisanti 《Cell cycle (Georgetown, Tex.)》2013,12(5):818-825
Cigarette smoke has been directly implicated in the disease pathogenesis of a plethora of different human cancer subtypes, including breast cancers. The prevailing view is that cigarette smoke acts as a mutagen and DNA damaging agent in normal epithelial cells, driving tumor initiation. However, its potential negative metabolic effects on the normal stromal microenvironment have been largely ignored. Here, we propose a new mechanism by which carcinogen-rich cigarette smoke may promote cancer growth, by metabolically “fertilizing” the host microenvironment. More specifically, we show that cigarette smoke exposure is indeed sufficient to drive the onset of the cancer-associated fibroblast phenotype via the induction of DNA damage, autophagy and mitophagy in the tumor stroma. In turn, cigarette smoke exposure induces premature aging and mitochondrial dysfunction in stromal fibroblasts, leading to the secretion of high-energy mitochondrial fuels, such as L-lactate and ketone bodies. Hence, cigarette smoke induces catabolism in the local microenvironment, directly fueling oxidative mitochondrial metabolism (OXPHOS) in neighboring epithelial cancer cells, actively promoting anabolic tumor growth. Remarkably, these autophagic-senescent fibroblasts increased breast cancer tumor growth in vivo by up to 4-fold. Importantly, we show that cigarette smoke-induced metabolic reprogramming of the fibroblastic stroma occurs independently of tumor neo-angiogenesis. We discuss the possible implications of our current findings for the prevention of aging-associated human diseases and, especially, common epithelial cancers, as we show that cigarette smoke can systemically accelerate aging in the host microenvironment. Finally, our current findings are consistent with the idea that cigarette smoke induces the “reverse Warburg effect,” thereby fueling “two-compartment tumor metabolism” and oxidative mitochondrial metabolism in epithelial cancer cells. 相似文献
36.
Brett D. Welch Ping Yuan Sayantan Bose Christopher A. Kors Robert A. Lamb Theodore S. Jardetzky 《PLoS pathogens》2013,9(8)
Paramyxoviruses cause a wide variety of human and animal diseases. They infect host cells using the coordinated action of two surface glycoproteins, the receptor binding protein (HN, H, or G) and the fusion protein (F). HN binds sialic acid on host cells (hemagglutinin activity) and hydrolyzes these receptors during viral egress (neuraminidase activity, NA). Additionally, receptor binding is thought to induce a conformational change in HN that subsequently triggers major refolding in homotypic F, resulting in fusion of virus and target cell membranes. HN is an oligomeric type II transmembrane protein with a short cytoplasmic domain and a large ectodomain comprising a long helical stalk and large globular head domain containing the enzymatic functions (NA domain). Extensive biochemical characterization has revealed that HN-stalk residues determine F specificity and activation. However, the F/HN interaction and the mechanisms whereby receptor binding regulates F activation are poorly defined. Recently, a structure of Newcastle disease virus (NDV) HN ectodomain revealed the heads (NA domains) in a “4-heads-down” conformation whereby two of the heads form a symmetrical interaction with two sides of the stalk. The interface includes stalk residues implicated in triggering F, and the heads sterically shield these residues from interaction with F (at least on two sides). Here we report the x-ray crystal structure of parainfluenza virus 5 (PIV5) HN ectodomain in a “2-heads-up/2-heads-down” conformation where two heads (covalent dimers) are in the “down position,” forming a similar interface as observed in the NDV HN ectodomain structure, and two heads are in an “up position.” The structure supports a model in which the heads of HN transition from down to up upon receptor binding thereby releasing steric constraints and facilitating the interaction between critical HN-stalk residues and F. 相似文献
37.
38.
Christopher J. McNamara Thomas D. Perry IV Ryan Leard Ktisten Bearce James Dante 《Biofouling》2013,29(5-6):257-265
Abstract Microorganisms frequently contaminate jet fuel and cause corrosion of fuel tank metals. In the past, jet fuel contaminants included a diverse group of bacteria and fungi. The most common contaminant was the fungus Hormoconis resinae. However, the jet fuel community has been altered by changes in the composition of the fuel and is now dominated by bacterial contaminants. The purpose of this research was to determine the composition of the microbial community found in fuel tanks containing jet propellant-8 (JP-8) and to determine the potential of this community to cause corrosion of aluminum alloy 2024 (AA2024). Isolates cultured from fuel tanks containing JP-8 were closely related to the genus Bacillus and the fungi Aureobasidium and Penicillium. Biocidal activity of the fuel system icing inhibitor diethylene glycol monomethyl ether is the most likely cause of the prevalence of endospore forming bacteria. Electrochemical impedance spectroscopy and metallographic analysis of AA2024 exposed to the fuel tank environment indicated that the isolates caused corrosion of AA2024. Despite the limited taxonomic diversity of microorganisms recovered from jet fuel, the community has the potential to corrode fuel tanks. 相似文献
39.
Janelle R. Walton Heather A. Frey Dale D. Vandre Jesse J. Kwiek Tomoko Ishikawa Toshihiro Takizawa John M. Robinson William E. Ackerman IV 《Histochemistry and cell biology》2013,139(3):487-500
A proteomics survey of human placental syncytiotrophoblast (ST) apical plasma membranes revealed peptides corresponding to flotillin-1 (FLOT1) and flotillin-2 (FLOT2). The flotillins belong to a class of lipid microdomain-associated integral membrane proteins that have been implicated in clathrin- and caveolar-independent endocytosis. In the present study, we characterized the expression of the flotillin proteins within the human placenta. FLOT1 and FLOT2 were coexpressed in placental lysates and BeWo human trophoblast cells. Immunofluorescence microscopy of first-trimester and term placentas revealed that both proteins were more prominent in villous endothelial cells and cytotrophoblasts (CTs) than the ST. Correspondingly, forskolin-induced fusion in BeWo cells resulted in a decrease in FLOT1 and FLOT2, suggesting that flotillin protein expression is reduced following trophoblast syncytialization. The flotillin proteins co-localized with a marker of fluid-phase pinocytosis, and knockdown of FLOT1 and/or FLOT2 expression resulted in decreased endocytosis of cholera toxin B subunit. We conclude that FLOT1 and FLOT2 are abundantly coexpressed in term villous placental CTs and endothelial cells, and in comparison, expression of these proteins in the ST is reduced. These findings suggest that flotillin-dependent endocytosis is unlikely to be a major pathway in the ST, but may be important in the CT and endothelium. 相似文献
40.
Facilitated long chain fatty acid uptake by adipocytes remains upregulated relative to BMI for more than a year after major bariatric surgical weight loss 下载免费PDF全文
Fengxia Ge José L. Walewski Mehyar Hefazi Torghabeh Harrison Lobdell IV Chunguang Hu Shengli Zhou Gregory Dakin Alfons Pomp Marc Bessler Beth Schrope Aku Ude‐Welcome William B. Inabnet Tianshu Feng Elektra Carras‐Terzian Dieunine Anglade Faith E. Ebel Paul D. Berk 《Obesity (Silver Spring, Md.)》2016,24(1):113-122